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Ness Motley Documents

Exemption Application

Date: 27 Jan 1964
Length: 103 pages
60043407-60043509
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ness 00038224

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Produced by: CTR

Affected Defendants: CTR, ATC, B&W, LOI, PMI, RJR, UST, H&K, ALL

Type
Application`
Characteristic
Author not identified
Named Person
Hahn, Paul M.
Wootten, Harry M.
Digest, Readers
Hahn, Paul M.
Cullman, Joseph
Darr, E. A.
Few, B. F.
Halley, William J.
Hartnett, T.
Hutson, J. B.
McComas, O. P.
Peterson, J. W.
Peterson, J. W.
Hoyt, W. T.
Lynch, K. M.
Bing, R J.
Cattell, M.
Jacobson, L.
Kotin, P.
Little, C. C.
Reimann, S. P.
Rienhoff, W.
Wilson, E. B.
Hockett, R. C.
Brady, J. M.
Bonner, J. T.
Fawcett, D. W.
Gurney, C. W.
Mirsky, A. E.
Runnstrom, J.
Steward, F. C.
Berardino, M.
Freed, J. J.
King, T. J.
Lima-De-Faine, A.
Nemer, M. J.
Perry, R. P.
Rudkin, G.
Schultz, J.
Talbot, T. R.
Armitage, A. K.
Domino, E. F.
Hansson, E.
Hoff, E.
Hockman, C.
Larson, P. S.
Pelikan, E. W.
Sabelli, H. C.
Seltzer, C. C.
Wenzel, D.
Cooper, P.
Goldring, I.
Klein, M.
Reed, M.
Gey, G.
Agress, C.
Albanese, A.
Angelakos, E.
Angevine, D.
Ayres, S.
Barnes, F.
Becker, R.
Bellet, S.
Bickerman, H.
Bing, R.
Bock, F.
Bonner, J.
Bowery, T.
Brozek, J.
Butt, E.
Byerrum, Richard
Carnes, W.
Cerecedo, L.
Clark, W.
Clarke, H.
Coffman, J.
Comroe, J.
Conners, D.
Cooper, P.
Damon, A.
Dawson, R.
Dibner, A.
Domino, E.
Dorfman, R.
Eckstein, J.
Falk, H.
Farnsworth, D.
Ferguson, F.
Fisher, R.
French, F.
Freund, J.
Furst, A.
Gocke, T.
Gore, I.
Gottschall, G.
Griffin, A.
Grossman, M.
Gruhzit, C.
Haag, H.
Hafkenschiel, J.
Havel, R.
Hawthorne, H.
Heath, C.
Heizer, P.
Hest, L.
Hoff, E.
Holman, R.
Homburger, F.
Hull, R.
Jacobson, G.
Jacobson, J.
Jacobson, J.
Jarvik, M.
Kandutsch, A.
Kaplan, A.
Katz, E.
Keys, A.
Kirsner, J.
Knudtson, K.
Kosak, A.
Kuhn, R.
Kuschner, M.
Belle, C. La
Laipply, T.
Larson, P.
Laurenzi, G.
Leuchtenberger, C.
Lindseth, E.
Linnell, R.
Lombard, H.
Long, J.
Lynch, K.
Mann, D.
Martin, C. M.
McArthur, C.
McCants, C.
McGill, H.
McKee, K.
McKennis, H.
McKusick, V.
Miller, J.
Montgomery, H.
Montgomery, P.
Moore, G.
Motley, H.
Pace, D.
Pelikan, E.
Pollak, O.
Pollard, M.
Pomerat, C.
Pratt-Thomas, H.
Protzel, M.
Redisch, W.
Reimann, H.
Richards, V.
Rigdon, R.
Rittenberg, S.
Roe, B.
Rubin, B.
Russek, H.
Russell, W.
Salisbury, P.
Saltman, P.
Schmidt, A.
Schour, I.
Segal, M.
Sherwood, C.
Simon, D.
Soloff, L.
Sondeheimer, E.
Sonneborn, T.
Sorof, S.
Stare, F.
Steffee, C.
Strong, J.
Sulzberger, M.
Tagiuri, R.
Thomas, C.
Toman, J.
Travell, J.
Warner, E.
Warren, S.
Wechsler, R.
Weller, R.
Wender, S.
Wenzel, D.
Whiskin, F.
Williams, R.
Wood, S.
Wyatt, J.
Day, T. D.
Heston, W.
Homburger, F.
Hull, R.
Kensler, C.
Poel, W.
Shear, M.
Stephano, C.
Stewart, H.
Todd, G. F.
Beadenkopf, W.
Dawber, T.
Gore, I.
Gallo, G.
Lyons, M.
McGill, H.
Richards, M.
Mann, G.
Rinzler, S.
Thomas, W.
Wakerlin, G.
Hoff, E. F. Dom E.
Larson, P. S.
Pelikan, E. W.
Seltzer, C. C.
Wenzel, D.
Cooper, P.
Agress, C.
Albanese, A.
Angevine, D.
Ayres, S.
Barnes, F.
Becker, R.
Bellet, S.
Cahill, M.
Freedlander, B.
Gey, G.
McIver, F.
Recipient (Organization)
IRS
Original File
TobDocs1
Named Organization
Hill & Knowlton
American Tobacco Company
Inc.
Benson & Hedges
Bright Belt Warehouse Association
Brown & Williamson Tobacco Corporation
Burley Auction Warehouse Association
Burley Tobacco Growers Cooperative Association
Larus & Brother Company
Inc.
P. Lorillard & Co.
Maryland Tobacco Growers Association
Philip Morris & Co.
Ltd.
Inc.
R. J. Reynolds Tobacco Company
Stephano Brothers
Inc.
Tobacco Associates
Inc.
United States Tobacco Company
Burley Stabilization Corporation
JAMA
Drs. E. L. Wynder & E. A. Graham
Kansas City Medical Journal
AMT
Benson & Hedges
Bright Belt Warehouse Association
Brown & Williamson Tobacco Corporation
Burley Auction Warehouse Association
Burley Tobacco Growers Cooperative Association
Larus & Brother Company
Inc.
P. Lorillard & Co.
Maryland Tobacco Growers Association
Philip Morris & Co.
R.J. Reynolds Tobacco Company
Stephano Brothers
Inc.
Tobacco Associates
Inc.
United States Tobacco Company
Hill & Knowlton
Scientific Advisory Board
Author (Organization)
TIRC
Site
www.house.gov./commerce/TobaccoDocs/documents.html - Bliley/Commerce Committee site - set of 39,000

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Page 1: 00038224
To be ~ed in duplia~e • -Ith ~he ~or for your District X 60043407
Page 2: 00038224
I~ H~VE ~'OU ~£O COP~ g~ ~P~TE OF THE ~WI~G WHICH YOU ~RE REQUIR~ TO for ~ ~a~. ~n appllcaUo~ ~iLl n<: be considered ~or exemption ff ~zadon has had le~,. ~n 1~ mon~ o~ ~ve opera,on (not me~e existence ~t- ~c~ivi~F prepa~ ~o major ~ahe~ ~s appL -~or... completed and all i~o~atJon and ~ ~red ar~ at~ch~d, file in dup~ca~ wi~ your ~r~ ~i~r of Inter~! ~evence. As ~n as practicable ~er ~e snzo~on ~d dz~ are ~lv~, ~e o~a~on ~11 ~ added of ~e ~iss~ner~ d~on L~d of ~e ~! ~:~s which will. ~ ~qui~d ~ ~ file~. ~eTy at~chment t~o~ld s~ow the .sine and ~.~e~ of ~e o~Lni~t[on, the da~, In idenC~ab]e h~dinG end that it In addison to the d~umen~ and s~men~s )is~ed which ~= ~ ~led, any sdditio~Ll info~ation citin£ cou~ deci- si~s, ~lin~, opinions. ~t=, may ~e filed ~o; pu~os~ o~ C. ~os%~ oF ~ the or~Ln~- n expec=~ ~ ~ repTesen~d in person or acr~, 1£ s~r. ~'i~ e~r DITL~ f~ ~e ~u~ O~ e~eh J I . , ~I~I _ I e~en~ whl~ ~e In d~it ~ ~stv~ o~ ~our ac~v~ ~ o~.,t w~ch e~l~s ~ty &~y sl~¢~ scUvlLicS ~&t ~ s~temnl ~kith d~ri~ ~e ~r~w~ O~ee ~n i~ DF~ (r~. ~ g~ e~ or mi~r~} or ~ wk~h ~u J Ow~ sn Jn~st u~dcr s~k k~ ~e~cr ~;~ (o~ er ~11 IKSTRU~O~S. by co~es~ndence br an z~#~t or an attorney-, a power a~rneT spec[fi~II~ ~u~zi:.: the a~en~ or a~o~e)" ~ rep- r~en~ the or~on mos~ be ~led. . C~;~t ~ A ~ere claim or contention by an organi~tioc tha: exempt fTom income ~x under s~Lion 501 (a) o~ the Inter- hal ~v~ue ~e will ~ relieve the or~aniza~on from ~ling~come ~x ~tu~s ~ payin¢ the ~ny ~to~tio~ which is submitted in the appli~t~on or in suppo~ o~ it and which is detrained by ~e ~i.ioner ~ relate ~ any trzde secre~ patent, precis, style of work, or appamtus, ~y upon ~uest bz withheld ~rom public in- sp~on if ~e ~i~[oner dete~ines that the di~losure of such Info~ztion would adver~ly aff~ ~e or~tion. Such ~qu~ m~t (I) ~early idenUfy ~e material ~thheld (~e d~eu~ p~, ~rLgrLph, Lud lin~}, (2) elude~e ~ for. ~e orcani~tion'z position that ~e fo~aUon is of ~e ty~ which ~y be withheld gram publ~ f~tion, and (~) ~ ~led ~<~ the d~um~ in whi~ ~e- ~te~al ~ ~ ~held is confined. DECLARATIO.~ I declare und,. ~nal:: .., of perjury ~.h~t I hs~e ~-~ami~ed this application (i~lu~in~ accomp~n~ng ~-¢emenM) and to the best of my k.,~owle~.. " and i,.'--~cf it is true, correct, and complex.. 60043408
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" • i-:c= Cc~___i~tee h~.s no £o.---~.-..~i che_-~.er. A eo=cern~u'.g i~= orl,,-~-_ a=8. l:'~',-~ose Is =t-~.che~ E~,~ibi~ A to the By-La'~.~ . 60043409
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To~xcco ~[.~DUSTR~ RES~.~.RC~r The Tobacco o_-.~%!ze~ ¢o aid =~ ass~% h~l~ ~.~ ~o ~n~e~e scien~Iflc rese~ch the public. (See a:~zci-~nt to 60043410
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BY -LAWS of the TOBACCO IRDUSTR¥ RESFARCH COMMITTEE The undersigned hereby organize themselvesas the Tobacco Industry Research Committee (herein called ~he " "Comn~ttee") for the purposes ar~l objectives and with the powers hereinaf.ter stated: Purpose~ and Objectives The purposes and objectives of. the Co--hi,tee are to aid and assist research into tobacco use and health~ and particularly into the alleged relationship betveen the use of. tobacco and lung cancer and %0 make available to the public factu~l ir~or~ation on this subject. The statement dated January 25, 195~ signed in the r~une of the Co~ittee : by Paul M. Hahn, Chairman, and attached hereto as Exhibit A, is hereby ratified and adopted by the Co--hi,tee. II. Or~ani zation Each corporate member Of' the Co~ittee shall f.rom time to time appoint an Indlvldu~l to ser~e as the personal member of the Co~mlttee representln~ such corporate me=bet and any such personal member may designate an indi- vidual to serve as l~Is alternate who shall~ while so servlr~, 60043411 ........ CTR-STF:ITE--OF FLOI IDR
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have ~he sure stat~s ~s a personal member. All such appointments-~.~d designations s~l be in ~ti~ flled vt~h ~he C~tee a~ each cor~ra~e ~mber s~ll~ subject ~ the prov~sions o~ these By-~vs~ be bou~ by the ~etion~ as a ~rso~l ~ber o~ the C~¢~ee~ o~ its represen~t~ve so ap~nted or desi~ted ~tll due ~itten notice o~ the re~ocat~on thereo~ a~ the a~otn~en~ or des~s~tion successor to such represen~tive or a~ter~te ~s been fileA vith the Co, tree. A ~orlty of the members of the~Co~ittee ~y f~ its rules of proced~e~ fix the time a~ p~ce of its meetin~, dete~ne its ~ction witch the li~te of the p~ses ~d ob~eetives herein s~ted, enter into such contracts as ~hey deem advisable, e~loy such officers~ a~ents a~ e~loyees they ~y deem necess~y~ incl~in~ a C~ir~n to serve for a term of one year and ~til his successor is elected @~lifled~ a~ fix the re~neration of such o~ficers~ agents a~ e~loyees~ i~ a~ It bei~ u~ersto~ ~eas~-er-o~ ~he C~l~ee s~l at a~l ti~s ~e me~er of the Co~t~ee. ~1 ~rso~l ~m~ers of ~he Co, tree s~ll sere vlt~ut re~neration. Limitations on Liability and Creation of .Obli~atlons Pe_r_s.o.nal~members of the Committee s.h~.ll not have any liability whatsoever for the liabilities of the Committee ~ • 60043412
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Each of the cigarette ~an~acturlng corporate ~e~ers hss ~1~ge~ ~ ~he Co~t~ee for ~n~ ~efo~e one th~s~8 o~ ~-~i~ ci~ettes ~r~uee~ ~y such co~ in 19~3 as est~t~ b~ ~ ~. ~ootten pu~lish~ ~er the ~te of Oa~y 15~ 1~ ple~ to the C~%tee for ~nt d~ ~1~ ple~. Such co.rate ~ers be ~d re~in .liable for any obl~tion cr~t~ or e~e i~e~ by resolution o~ ~e ~r~o~ c~ttee ~opte~ by ~ority vote of the ~r~o~ c~%tee for any a~ditio~l ~ts assessed a~inst such co.rate ~er by resolutio~ of the ~erso~ co.tree ~opted ~ority vote~ such liability of such cor~r~te to be in pro~rtion to the res~ctive ~r~uetion ~id cig~ettes of such co.rate ~ers~ by ~ry H. ~tten, f~ the ye~ ~iatelM prece~ t~t ~in ~hich such resolution is ~op~; pro~e~, h~ever, t~t a~ such co~r~te ~er vhos~ represen~tive on the ~rso~l c~ttee ~d ~t vote in favor of such resolution ~y ~thin ten ~ after the ~Optlon o~ such resolution file in ~i~i~ ~th the Secre~ its dissen~ from such resolution a~ its resig~tion ~ the co.orate c~t~e~, in which c~e such co.rate ~ber s~ not
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be liabZe for the o~.ll~tion created .by such resolution and s~ll only he ~l~.~.a~ie pro~ortiona~ely as ~. ~- ~ .~, ~or such ~rtion~"such assess~nt ~ for s~ch ~o~rtlon o~ any ~sessments ~er~r levl~ as s~ represent its pro~io~te ~t o~ other obli~tio~ ~ ~es o~ the C~ttee authorlz~ or the resolution which ca~ ~he filt~ o~ such ~88ent ~d resi~tion. ~e other co~a~ ~ers s~ ~ve no liability to the Co~Ittee~ or for any of it~ o~tlo~ except to the ~ent of ~eir res~ctlve volun~ contrlbutio~. ~e C~ittee ~y not create o~li~tio~ beyo~ the l~Its so fixed. Resi~n~tions . . Any corporate ~e~ber of the Connnittee ~ay resign at a~ ti~e by filin~ ~it~n notice ~ ~t effect ~ the Co, tree ~ess~ ~ the ~rso~ ~ber ~en ~cti~ ~s C~ir~n, ~y such re~i~tion ~ ~e effect u~n receipt of such notice Or a~ ~y ~ter ti~ ~cifi~ therein~ ~ided t~t (except where acc~~ by a dissen~ as ~ovlded in ~ticle llI her~f ~ then o~y to the e~ent prodded in said ~icXe IlI) such resl~t~on ~i ~ ~elease. ~y ci~ette ~ct~l~ corporate 60043414
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me~er ~'ro~ ~ts propor~:tor~te l~rt of any ob1~a~on ~e~o~ly &u~ho~ze~ by ~or~y ~e o~ ~he Co.tree nor fro~ 8o mch of &~ aseees~nt thereafter le~ed to ~y o~l~gat~o~ a~ e~e o~ .t~ Co.tree authorized ~y ~Jor~ty ~te o~ ~e ~reo~ c~ttee ~rt~ to ~uch rest~t~on.~ ~e resl~tton o~ co.rate ~e~er s~ll c~y vlth ~t the res~tton the ~r8o~1 ~m~er re~esent~n~ ~uch co--ate Ve , Contracts The Co~n~tttee my enter Into contracts d~rectly or it my e~loy Hill e~l Kuowlton, Inc., or such other or~n£zat~on as the Co~n~ttee n~y deter~ne~ to enter lnto contracts on its behe~. A~ contracts entered Snto by the Con~tttee d~rectly shal~ be executed ~n ~he r~ne o~ the Conn~tttee by its Cha~r~n a~l its Secret~ry or its Treasurer. Ad~ltlonaZ corporate ~e~ers ~y be ~ed to the C~ttee fro: t~ ~'t~ ~th the .a~l Of at least t~ee*fo~ths (~/~) in n~er-of t~ then co.rate ~erz. ~h such ~t~o~ c~ette ~act~ co~ra~ ~ s~ be su~ect to aseess=ent ~n the ~er ~o~ded ~n ~lcle IH her~. 60043415
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Amendment to By-Lays of the Tobacco Industry Research Co'tree Distribution of Assets Upon Terui~tion of Activities ~o part of the assets or net earnings of the Co~Aitte~ sh~ll inure ~irectly or indirectly to the benefit of any private person, fir~ or corporation. In case of t@rmination of its activities for any reason, all of the proper~y or assets of the Cor~ttee then rem~inin~ sb~ll be distributed to such or~nization or organizations exen~o.t under Section 501 (c) (3) of ~he lntern~l Revenue Code of i~4 as the Committee by a majority vote of the corporate members thereof shall determ4ne. Subscri~e~ an~adopted~y the undersigned corporate. member aS Of ~ i~. (Ado~te~ ~oven~er ~, 60043416 .CTR-ST.RTE OF PLORID
Page 11: 00038224
o Vll. A~endments All by-~vs of the Com~ttee ahall be subject to alteration and repeal by the e~firm~ttve vote o~ majority of the corporate me=bersj provided that .the pro~isions of Article I "Purposes and Objectives" not be altered except vlth the un~nimous consent o~ all the corporate =e=bers. ~nis document my be executed in several counterparts and ea=h counterpart vhen so executed shall constitute ~n oriEtnal instrument; all such counterparts • shall ~ogether constitute but one and the sene document, Subscribe~ and e~opted by the undersigned corporate members as of ~anu~ry 1~ CTR-STI:::ITE 13F F'I 60043417
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General 60043418 C..TR-STRTE OF FL ORIDR
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STATEH~T CORC~I~G TEE ORIGIN AND PURPOSE OF THE TOBACCO INDUSTRY RESEARCH COM~/TTEE AND ITS PROPOSED FUNCTIONS EXHI3IT A The responslble chief officers o~ nine o~ the cigarette and tobacco ~r. oducts manu/acturln~ co=panles in Amerlca~ and ~IYe or~nlzations oT ~rovers of lee/ tobacco and tob&cco warehouse assocSatlons have formed the Tobacco Industry. Research Comities In the Interest.o~ %he public as well as or the industry widely publlcize~ re~orts in the .press~ purporting to llnk tobacco s~oklr~ vith the cause o~ lun~ cancer. To avoid possible con~uelon and mlsunfers~andlng concerning the orlgi_n~ purpose an~ ~nctlon the Cc~,-~-.Ittee makes the ~ollovln~ Events Just~n~ Formation o~ Co~ttee The for~atton o~ the Colti~tee was prompted by the appearance of certain ~l~eat~o~ c~ an es~B~shed re~t~o~pbe~een ci~et~ s~ki~ a~ I~ ~ic~l of ~ese re~rt~ Is ~ article app~i~ in ~he Jewel o~ the ~er~c~ M~cal Associat~on (1~3 J~A ~9, ~Y ~% 1~0) vherein ~s. E. L. ~er ~ E. A. Gra~ re,fred t~t appllcatio~ o~ ciB~ette ~s to the backs of ~ce ~d pr~uc~ skin c~cers. -.-CTR-ST.I::ITIZ .... CIF" F'-I-l-lie Thl::I 60043419
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In an address before the Annual Fall Clln~cal Conference of the Kansas City Southwest" .Clinical S.oclety, held ~n ~sas Ci%y~ ~sso~i on Sep~e~er 28, 1953, Alton Ochsner ~a~d: "~is ~ec~ent~ ~ncrease ~n ~he ~ncidence of hronc~enic c~cer~ we ~e con~nced~ is due to the c~ci~genlc e~fect of ci~et~ s~ki~" (~as C~ty ~Aical Jo~, Vol. ~ No. 6~ ~ov~er-Dec~ber, 1953 A% a recen~ ~e%~n~ o~ ~he Grea~er ~ew York Den~l ~ocla~ion~ %hese s:e d~%ors re~e~a%~ ~ased on ~Is%ical ~ 0~her a~lyses# ~% ci~e~es con~n a c~cer ~uc~ Tac%or. ~ese asser~ions~ and o%hers %o ~he s~e e~[ec~ ~ve been given ex%e~ive pu~lici%y In m~zin~ clrcula:~on, such as T~e (Nove~er 30, i~3), (Dece~er 21, 1953), a~ Re~ers' DiEe&~ (December 1953)~ ~ions~ h~ever~ reveals ~z ~y ~ac%ors# su:h as v~ious ~s o[ air ~u$1on, as ~ell as-~hacco s~ke ~ve been sus~ct~ ~ causes of i~ c~cer. ~ho~h ~ch ~s been ~i%~en concerni~ ~he incidence o~ I~ cancer~ there s~ill a ae~h o~ authori~%Ive ~i~in~s on the. I% is ms~e %o say ~ no ~rsuaslve a~ de~In~ve conclusion ~es~c%i~ %he cause o~ ~hls d~s~e~ or %h~ re~on o[ s~k~ng ~here~o, ~s been ..... CTR-STI::ITE OF FLORIDI:::I 6oo434~b
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the a~sence of au%hor~a~Ive ~r~1$n~.) ~ere b~li~y on ~he ~ of.~e ~~n~ of ~he ~n~act~er~ ~d other~ e~g~ ~n ~he ~o~cco ~ustry to aid ~n the ~1 deter~t~on o~ t~.~ controversy. It ~s the e~nest vtsh o~ the ~ustry to e~o~e co~te~. scientific authority to ~ ~t~te f~cts vh~ch d~s~l the present co~ston ~ to c~cate ~uthort~: ~lan of ~e Co.tree anno~ce~ ~n a ~1 ~vert~s~n~ a~e~ ~n ~ nevs~ers e~rc~ted throu~out the United States on "~y~ 3~y ~t it v~d =ee~ the c~llense o~ these re~rts. eigni~ ~ers o~ the ~cco I~ustry Rese~ch Co.tree a~e~ contr~ted ~y ~d~ eo~es~ rese~ch ~er the c~ge ~d d~ection o~ a scientist un~eacha~le ~nte~ity and ~tio~l re~e. ~v~se in ~s ~teld, scientists dls~nterest~ in the ci~ette t~ustry a~ o~ r~os~ze~ a~litty ~ro~essto~ s~d~ in ~tctne~ education as~oc~at~ ~c~ence~ vt~1 ~e tn~e~ to act as ~ ~V~sory 60043421
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Benson & Hedges By Joseph F. Cullman, Jr.p President Bright Belt Warehouse Association By F. S. Royster, President Brown & V£11iamson Tobacco Corporation By Timothy V. Rartnett, President Burley Auction Varehouse Association By Albert Clayp President Burley Tobacco Growers Cooperative Association By John W. Jones~ PresSdent Larus & Brother Company, Inc. By ~. T. Reed~ Jr., President P. Lorlllard & Co. By Herbert A. Kent~ C~lrman Maryland T~bacco Growers Association By Samuel C. Llnton, General Manager Philip Morris & Co.~ L~xl., Inc. BMOo Parker McCo~as~ President J. Reynolds Tobacco Company ByE. A. Darr, P~esident Stephano Broth=rs~ I~. By C. S. Stephano, Sc.D.~ Director of Research To%acco Associat~s~ In=.~ an or~nt.zatign of flue-cured tobacco ~rov. ers By J. B. Hutson~ President .- United States Tobacco Compauy- By J. ~. Peterson, President 60043422 CTI -STATE F'I
Page 17: 00038224
Formation o~ the Co~.ttee ~. Paul H. Hahn~ President o~ ~e ~er~can ~bacco Co~ on ~c~er i0 ~d ii, i~3 t~k the ~%lal steps ~n the ~o~t~on %ele~ sent %o the ~oll~i~ ~ople: ~. Joseph Y. ~, Jr.~ ~es~dent, ~on & H~es ~. E. A. ~r~ ~es~dent ~. B. F. F~ ~es~dent L~ett & ~ers Tobacco C~ny ~. ~r~d Corny -" ~. T~othy V. H~tnett~ ~es~dent~ ~. ~. ~. Hutson~ ~es~den~ Tobacco A~a~ates~ Inc. ~. O. ~rker ~Co~s~ ~es~dent~ ~h~ ~s ~ Co.~ L~.~ Inc. Un~t~ S~tes ~cco C~ny le~ tobacco units ~et res~e ~o these published ~er~a~ter~ those ~n~t~ v~th one except~on~ York C~ty. ~ Liggett & Myers Tobacco Compan7 ----C-TR-STATEE--- OF" PLORID 60043423
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At these ~eetiu~s the conclusion vas reache~ - that the tobacco industry must ~e public action-to ~et these v~dely publicized c~. ~e a~ the ~ o~ H~ll ~ ~lton, Inc. or ~O F~h Avenue~ ~ York~ Nev ~ork~ ~s e~aged to ass;st the e~ect~ ~ts ~8e. ~e o~cers o~ the C~ttee seZec~d vere ~oseph F. ~n~ Jr.~ ~eas~er~ ~ Vllson Hill & ~l~n~ Inc., Secret, It was the ~ressed intention oT ~'e Co.tree ~o ~e ~he c~i~hlp Co.tree ro~ted every t~ee ~n~s. It ~s e~es Tot the Co.tree's acti~t~es~ ~nclu~ e~endtt~es for rese~ch, the ~vertisl~ ~he e~lo~ent o~ Hill ~ Knovl%on ~ other s~l~ e~es~ vould de~rayed by do~fo~ [rom the m~b~ [~ b~ on the~ ~1~ of business and by contr~butio~ ~ b~ ~e~ u~n by other ~mbers. ~a~e~nts v~e th~ ~rfecte~ for ~ertton o~ the ~ve~lsement re£e~ea ~ in the news~pers ~oughout the ~e .Bright Belt ~eh~se Ass~latlon~ the ~ley Auction ~areho~e ~s~lat~on~ the ~ley Gr~ers C~r~tive Ass~iat~on, ~us ~ ~6ther Inc., the ~~ ~cco Gr~ers Ass~iatiou, Step~o ~others, Xnc. were invited to ~oin v~ the origi~l ~p a~ bec~e ~bers of the Co,tree. 60043424 CTR-STRTE OF FLORIDR
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L~mtt of Povers 1~e l:~.~';:~ses and ob~ectlves o~ ~he Co~t~ee ~e ~ aid ~ assist research ~nto ~o~cco ~e S~ "health, a~ ~ticu~ly into %he ~leEe~ re~tionship betveen use o~ tobacco a~ 1~ c~cer~ ~ ~ ~e s~le the ~blic f~ct~l i~o~tion on this subject. Zt 18 the co~llere~ ~ent of the C~ttee t~t i~ ~ctlvltles s~l ~e co~in~ to the ~ses set forth a~ove, It is Inn~Ise ~ ~e co~id~e~ or to operate as a tr~e ass~lation or to ~rtici~te in ~y acti~ty, or give co~ideration to ~y ~tters~ affecting the ~usiness conduct or acti~tles of its m~bers~ a~ t~t its acti~ties in ev~y respect s~ co~o~ to law a~ decrees or Jud~nts ~of co~s ~fecti~ or re~ti~ the to~cco i~us~y. To this e~ the Co.tree pr~e~i~ ~er the ~ce of le~l c~sel selected from ~ the co~sel or n~nees of its ~ers. TOBACCO INDUSTRY RESFARCH C01.RI'ITEE Dated: Nev York, Ne~ York Chairman 60043425
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T~e Co~J.¢¢ee derives all of iCs f~.~ds .'~z'o= its nam~ars ~ud engages in ~o ftu~d raising actlv~.tles or business enterprises. • 60043426 CTR-STRTE OF i='l n~Tnm
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~r.e T~cco Zn~us%~ ~ese~ch'Co~tee %o~acco ~ %obzcco w~%o~e =e~e~ch ~n~ e~uc~%ion. This ~o~ scc.~ of %he Co~%%ee's rese~ch ~:o~ ~ e~l~tes sclen~If~c finales %'~h %he zss~s~nce of %he sc~e=%ific s~ of ~he Copies Co~ the ye~s l~l ~ i~2 ~e z~:hed %:~ ~-~cE%e %he Co~ee's ~ne CoW, tee acts vith t~&acco use ~d he~. I~ is the Int~tlon of the ~bacco I~ust~ Rese~ch Co~tee to continue to ~uCtion in ~t~e s~ost~i~y ~ outl~.ed above. 60043427
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NO c~c in zctivi£ies .em~ase~ in or ~owev=.-~ ~th the increase in the ~t of about It fr~ a ~o~inz n~er of sc~ces~ ~he Cc~:ee's ir2o~:io~! ~c~ivi~les ~ve be~. reduced ~. recen~ ye~s. 60043428
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Ca;it rl but.Ion-'- re.calved Hesearch grants -"nd /'ellowahlps General, administrative and other ope,'atln~; expense~: Salary° Cool,tee C~lc~n Servl~ea'. ExeCutive Dleec~oe secretarial Salaries, Scientific Director and PeP dlem allowancea and expenaea rela~l.8 ~o ac~lvltlea o~ Scientific Advlsory P~vl~lon ~oP de,erred co~pe~;ua~ln. I~en~ and ~ac~lltlea Telephone a~ ~elesraph ~ut~se a~ expresa 3~atloner~ and office Depreciation Photo~tnt~ ~ltlll~hln~. etc. Prlntln~ ~oo~let~ re~rlnta~ aubacrlp~lon~, mlacel~aneou~ publ lcat ton~, Fopelgn Co~t o£ pubLIc ~nnouncc~n~ o~ ~or~1on pur~¢o o~ Che 3peclal reports, surveys, e~lbl~, etc. ,,. ?n~velln$ ex~n~e~ '.*~3. ~Advances ~o~ expenses and alPllne depo31~ ~ ~ ~?nanalatlon a~ tem~ry help , ~oellaneou~ Total expenoes Chanaes In Fund balance du.rlnK year Fund balance. January 1 AdJueCmen~a to ~flect chanl~e In accounCln~ method From cash to acc~al baals: Provl~lo~ ~or 8rant~ a;~d Fellowohlpo payable, Decembe~ ]1~ 1558 Accoun~ payable, ~cembur ~t, 1958 Provision ~o~ duFurred ¢umpun~u~lon, December ~1, 1968 ~r~vel advance and depoal~ ~;~ balance~ ~cembur ~1 '£O~ACCO H~DUS'rlW I{~S~AltCll COMNITT£g 1~.~0 Ba~t 4L'rld Street, New York, N. Y. 1001]' SCII~DULE A~TACIIb'.D to FOi~M 1024 1. 5UPPOH~ of. ITKM It(d) COMPARAT1V~ STA'i'.<HENT o|' CIIANGES In FUND BALANCe Y,:ul':; Endud De.cembev ~t {Cash l~31s) 124~111 481.391 702.290 555.372 I~,000 30,000 30,000 30,000 ¢,376 8,~Y7 5,338 8,3~9 37.4e9 ~0,~81 39.707 41,787 ~,727" 2,689 3,59~ },~66 14,326 4b,999 48,~oo 4u,~oo 17,iRl 34,427 29,~6 ' 31,558 ~7,~ 60;000 6o,ooo 6o,~0 132,012 159,130 I~0,666 I~0,992 3.729 9,841 I~,846 ' 14,532 3.410 4,084 4,000 6,~4 t,875 720 599 956- ],710 1.502 832 1,995 1.392 1.603 1,568 ' 3,999 330 673 695 7O9 4.947 4.163 ~,Y39 ~ 6,139 37,764 30.092 5,9o4 b0,~46 5,627 5,4~9 7,oP5 7,~ti 2~3,962 4.276 7,320 8,791 5,685 8,051 3,~0 425 2,263 14,395 .4,40£ ~ 4.~JO T45, 5~4 949. B~6 L. 09o. 300 i .06~. ~08 495,1*8 346.29~ 284,617 $884.599 418,217 30,000 6,]55 • 40,66'/ 36,766 40,000 81,967 5,619 1,381 882 7s~ 3,580 33,39o 1,160 I ~, 294 6,99fi ' 2,~38 2,~82 375.914 794.~ 90.468 301,778 C C
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TOBACCO 1N.UUL;THY I(ESF-ANCII CO/~IITTEE 150 Eaut 42rid $~.reet, I&:~ Yo=-~ N. ¥. [O01T SCIIEDULE ;d'TACHFJ) to FORM ~024 1. SUPPORT of ITEM ] l(d) COHPAR~tTIVE STATEM~J4T or CHANGES In FUND BALANCE 124, I)1 481.391 '[0~. 290 _.~~ lg exp~nses: lb,000 30~000 30,000 30,000 • ~,376 8,577 5,33~ ~,329 37,42~ 40,58~ 39,707 41,787 1,727 2,689 3,594 3,466 ;an&s~ '14,326 45,999 48,400 48,400 ~K ~o 57,500 60,0~ 60,000 60,000 ~a 132,812 159,130 120,666 150,992 3,729 9,841 ~2,8~6 ~,532 ~,~0 4,084 ~,000 6,09~ ~,875 720 599 996 1,710 1,502 832 1,995 1,392 1,603 1,568 3,999 330 6?3 695 4,947 4,163 ~,739 6,139 37,764 30,09~ 5,904 58,446 a~ ~53,96~ t Co~i~ ~,~76 ~4,8~6 7,3~0 8,79~ 5,68~ 8,05~ ~ 3,000 2,263 14,395 4,401 4,290 . 9.547 ~ 4.925 ... 621.44~ _~ 3~8.OIO 505.9~ 499, I18 3~6.292 2fl4,6~7 ~ ~¢hod $884.599 30,000 6,155 51,357 2,581 40,667 36,766 40,000 81,967 14,532 5,619 I, 381 882 724 3,580 33,390 1,160 12,294 6,995 2.438 ___L.BS~ 3oi, 1"18 Year.~ l~Me,I Oeccmber 31 (AccrUal Basls} 30,000 7,28~ 53,994 2,622 3,000 30,000 5%063 14,532 4,176 29~ 1,213 786 3,632 13,869 8,450 600 308,603 ~95,52~ (~56.197) 392,246 18,000 18,000 7,194 5,732 59;848 58,81~ 6,752 6,682, 62,467 72,719 43,92~ 37,406 16;467 ~ 0,000 30,000 2,207 62,978 15,484 15,960 4,660 3,922 2~3 160 1,295 1,282 1,225 "1,440 843 850 3,789 ' '3,416 23,506 17,132 ~0,859 18,000 7,3~? 62,801' 4,743 76,300 ~5,351 17,200 680'00 ,953 15o960 213 I,IL~' 1,623 4,2~I 17.553 35,200 2,614 1,256 1.5oo .... 3.o~ 36~.987 378,878 99~,~0~ 1.ooo.507 _6~) _ 92.288 I09,160 1,710 3,017 420,7~9 1,073.917 63.70~ 124,702 27,204) (,2,o00)
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~494,3~0 |~4~;167 $~81,29| |299,0~6 $~89,822 |309,0~ |230,0~6 |314,182~ ~40~,4~0 6,~9~ 6,~ 'T,053 7,128 7°35O 0,369 0,499 8,499 8,992
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60043432 CTR-STI:::ITE OF F'L Ole 'r~l::::l
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Tobacco ][.~.-DUST~ I:~ESE~tCH (~Oag~'fTZE 150East ~2n~ Street New Yo~>:, Eev York IC017 J==u~.~" 27, 19S~ Occupies s;~-~e as no=th-to-~o~th tenant ~3 h~s no ~Titt~n lease. ~Tl~_C, TClTi=--~i= i:'1 r~TrMSD 60043433 .....
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See By-laws. CTR-STATE OF FLORIDA 60043434
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TOBACCO Z~,'DU~Z~T I~F.SF.4~C~ CO~ 3.~0 .~,~t ~2nd Street .New York, I~ew See ~y-~-~'~'s. 60043435
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60043436
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SCIENTIFIC ADVISORY BOARD to the TOBACCO INDUSTRY RF, SEAi~CH COMM ['['I'EE KENNETH MERRILL LYNCH, M.D., $c.D.. LL.D.. Cl~'rn,an Ci~ancellor Medical Collcic of ,South C=roliaa Charles|on, South Carolina RICHARD J. BINO, M.D. Pro/cant aad Cl,;.irman. Dcpnrlmcnl Of blcdi¢inc Wayne $|aic Univcniiy Collc$¢ O[ DctroiG.Micb~gan McK~N CA~ELL. P,.D., M.D. Pro/euor ~erilm a~ Pharma¢olo~ Corncll U~vc.ity Mcd~l ~llcl~ New York, N. Y. LEON O. JACO~ON. M.O. ~ro]o~or oJ Med~ine, U~ve~ity o( Chi~io Director, Ar~nne Cancer Rese~cb Jiospi~l Cb~a~. lU~ob ' PAUL KO~N. M.D. Paul relrc¢ Pro/cant o/Pat~olo~ Unlvc~ity ~s Aalel~. ~lifom~ C~RENCE COOK. LI~E, So.D., LL.D., L~. D. • c~nti~ Direclor, Tobacco lad~tcy R~ Director Em~ti~. Ro~ B. Jac~a Mc~tl D~ llar~t. Maine SfANLEY P. REIMA~. M.D.. ~.D. . Ph~l~ddph~a, WILLIAM F. RIENHOFF, Ja.. M.D. Ptole~,r ol Johns llopkim Univcr~ty ~h~l of Mcdic~c Btltim~c, M~La~ EDWIN B. WI~ON. P,.D.. LL.D. ProJeuor Emeritus o/ Vital $lal~lio Ila~a~d Unive~silF Camblid$¢. Ma~chu~t~ ROBERT C. II~K~. Pu.D. J. MORRISON BRADY. M.D. TOBACCO ]/qDUSTRY RE.SRARCII COMM]TTI~ Statement of Poliey Containing Conditions and Terms • Under Which Project Grants Are Made 0 0
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I. General Policy Th~ Tobacco |nciusuy Research Committe© is dedicated to the support o! the inve~tigatiun of fundamental matters relating to a connection be- tween tobacco u~¢ and human health, la so doing the Tobacco Industry Re~earch Committee r¢cog- nize~ the impo~ce ol independent rcseaxch by competent iave~tigatox~. Research p~licy and pro- f/amming axe t~© re~po~ibillt~ of the Scientific Advbory Board. Grant~ a~e made ¢ndy alter cameo fel coaddera~n by the Sc.i~ti~ Adv',tWry d th~ merits d propo~.~l~ and of the qualifications ol the individual and his institutiun uadertaki-g th~ work. TI~ Committ~ d~ix¢~ to havG ~ica~t~ work with the greatest freedom and without domination d any kind. It will make no attempt to dixext the administration of the project once started, to in- llu~nce its cou~: or to conlxol its results od:er than to be a.~urcd that the |unds arc properly czlw.nded for the puxposm ol the gr-,mt and that all finding~ arc reported in accordance with bc~t ~cieatific practice. H. Payments and Budget: Unlcts otherwise requested at the dine of tot- flaring a specific grant, paymcatt will be made quarterly in advance to the institution at which ~.~atch i~ being coa~ucw.d. Grant~ may not be ua~.ffct~ed from one institu- lloa to another due to a change in alrdiation by the principal' investigator wilhom express permission. The contract for a grant may be terminated pdox to normal expiration date by the grantee .upon notification to the .Executive Secretary o! the Tobacco Industry Research Committee with a statement of the reasons for termination. Budgets arc presumed [o be accurate at the time of L~uance of a grant. However il, for un- foreseen reasons, additional funds or reapportion of funds are required such request will be con- sidered upon receipt of a complete statement of reasons for such change. At the time o! expiration of a grant or in the ©vent of its termination, uncxpended fund5 5hidl be returned to the Tobacco Indust~ Re, catch Committee. 1~, at such expiration or term. ination, additional projects are anticipated and aze ap- ,proved such funds may, upon ~cquest, be applied against the new Want at the time of its issuance. IlL Reports Grantees are to furnish a report o! activlti~ semi-annually. These need not ~ extc~ivc but should be su~cntly ~o~ativc to ~t ~e ~icn~c Advhow Bo~d of the Toba~o ~d~ Research Commitlec to know what ~ being ac- comp~hcd. At ~e conclusion of a proj~t a de- ~1~ r¢~ h cx~tcd which sh~ ~ ~vcn ~ wd~g to ~c ~ieatific Adv~o~ Bo~d. ~ cx~nditur¢ rc~ should be made by thc ~¢ :oral-annually. IV. Exchange o/ln]o~mation W~ the cogent of ~dv~sor~ Bo~d ma~ t~o~d-~.~x~g~ interim ~fo~afioa ~tWccn ~vcsfigato~ work- ~g on different proj~t~ ~dica~ a rc!afio~hip ~twcca proj~U. would only ~ done wi~ ~d ~it~g woxk ~ V. Publication and Public ln]orm~ion The Tobacco Iod~Uy R~eaxch Committee approv¢~ the inidal pre,watafioa by ~e ~v~fi- ~tor d r~a~ r~d~ ody ~ ~p~ m~ ~d ~en~c jou~ or ~fore a~p~ or science s~ic~, h h~ no ~jccton to d~ semination to the pub~ of any or ~ sio~ from proj~ ~ ~e ways. ~o~a~on Irom ~cmi-a~ual or will ~ rclc~ pubficly only wi~ ~c of ~¢ ~v~figator. ration ~ any fin~n~ &ore a p~oj~t ~c ~n~c • Advho~ Bo~d will exit a s~t of ~uact fwm dm ~tcc ~vcdng ~¢ date ~d genc~ subject matter of h~ p~en~tion. Whi~ no 5~cial funds are provid~ to pubScation of rcsul~ cow~g c~ of iHus~at~g, ty~sct~g or o~cr cxienditurcs, the Tobacco Ind~ R~c~ch Committee will co~der a ~u~t for such f~ u~n pr~ntafion of man~ript to ~ publ~h~d. 0 0 LI.J
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~eooo oooooooo. oe,O,O ~oe, o ooo o=, O0~OOO000000~ too= oo ooo. (.) c.) ~0.BACCO ItQ~JS~Y RESEk.RCH C0.'..Q..~ ZpO Ez=~ E~n~ S~eet, " ]]ev Yo£E~ ]~ev YccE 10017 60043439
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---
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---
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---
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$CI~{TIFIC ADVISORY BOARD to th© Tobacco |ndustr~ Rc~carch Committcc KENNETH MERRILL LYNCH, M.D., SO.D., LL.D., Ch~rman Chancellor and Pro/asset ol Patholo&y Medical College of South Carolina ' Charleston, South Caro|h~a RICHARD J. BING. M.D. Prole~or and Chairman. Department of Medicine Wayne Stale Unlvusity College of Medicine Dctrolt, Michigan . MeKEEN CATTEIA..~ PILD., M.D. Prolezsor F.meritu3 o[ Pharmacology Comcll University Medical College , New Yo.~k, N. Y. j co os, M.D. • ", P/olesso¢ mul CKairman. Dcpaxtment of Medicine Unitcrsity,. of Chicago Director, Argonne Can¢.¢~ Reseaxch Hospital Chicago, Illinois PAUL KOTIH, M.D. Chiel. Carcinogencsis Studies Branch National C.ancer.lnsdlut~ Bethcsda. Maryland CLARENCE COOK LII"I'LE, Sc.D., LL.D.. IJx1.D. $cien#ili¢ Dir¢¢tOro Tobacco Industry Research Committee Director Emeritus, Roscoe B. Jack,on Memorial Labotalo~y B~" Harbor, Maine STANLBY P. REIMAHN, M.D., Sc.D. Director Emerim.¢, The [nstitule for Cancer Research Philadelphia, Pennsylvania WILLIAM F. RIENIIOFF. Jit.. M.D. Proleasor Emeritus o] Surgery Johns Hopkins Univ©nity School o! Medicine Baltimore, Maffland EDWIN B. WILSON, Pu.D., LL.D. Pro]¢$:or Emeritus o] Vitnl $lati~i¢~ tlarvafd University Cambridge, Massachusetts ROBERT C. ilO4~KETT, PII.D. !. MORRISON BRADY, M.D. A~al¢ Scienti~¢ Director AJxociaIe ~cienti~¢ Director Introduction . 'During tile past year the Tobacco Ina~ustty R~,~.arch ~omatitt~ has continued and cxtcncled iL~ support of research. The major ~er.~ co~- tiauc~ to be into some.o! the many clinical~ and expc~hnental factors, that still need to be identified, investigatcd and,It ©valuated in coasldc~atloa of the origin o! lung cancer, caxdiovascular diseases, and other coml~ks constitutional ailments. ~ While these'research studies have increased our factual knowledge, they have at the same tinge continued to make clear and to cmphasLv.~ the great and critical gaps in that imowlcdge. They have confirmed the sound- ncss o! the position heAd.and expressed by the T.I.R.C, Tlds p~sitlon is that there does not cxist the essential ~pc~imcat~l and cllnkal Imowled~e with which science can even dcfi.na or identify the multiple factors o¢ ia~ueaccs that may conUibute to the origin and prog~e.ss o! these disca.w& This statement holds good as a generalization. It also applies with even greater slgnificancc to judgments .'concerning the causes o! then: diseases in any individual human being. Them have been and will continue to be speculations and opinions on the causes, but it fl a matter o[ ~ciemlfsc /act thai, in our pre~¢nt Stale of knowled&~, no oat know~ tat answtr~. Rel~tilim Studies I.cor~lu.i~ Reporlcd Cpidemiological findings, gesulting from similar *u~cys ~t u~ qucstionna~es and intc~icws, indicale ~rtaia "a~ia~ms" ~twccn the ~idcn~ of the~ d~a~s and ~ ~ more environ~nlal heron, incl~ing tobacco u~, cs~ia~y when ~at particul~ facto~ is sin~ed ~t [~ study. ~c mclh~oi~y of ~ch su~eys and aim the intc~t¢lat~a ~ ~ ~ findin~ ~ve ~cn czamincd and cfitlci~ by comment ua~ ~ a~ epidcmlolo~sa.
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It is no( surprising tha| every time another survey o! this ty~ is con- dueled under conditions thai a~¢ broadly similar, th~ .~ general ~e ~tain~d. ilowcvcr, th~ r~p~i~ion of an ~i~ecl or u~atislaclo~ ~ien- ~c pr~edur¢ d~s not add to the friability ol the. data coHcc~cd by previous cflo.s of ~hc ~amc Rcv~ and rc~r~ cominuc ~o ephor, based mostly on or~n;cd surveys. ~ .nq~stib~ng, un~c~cd c.~rsemcn~, as conclu~ve. ol .oh such rc~xifiv~ rc~, wh~ curtains no new or original d~la but ~h pla~ an obs~ck ~ ~ pa~ o~ accu~at~ reco&nifion and analys~ o~ ~ s~tcd. ~t ~ps ~t in knowledge of t~ causes of can~ and of c~ov~l~ d~a~ ~ ~ult in a larsc dc~cc from the lack of a~uatc and con~o~cd mcth~s of bioassay of sus~tcd pr~s subs~, and from thc ab~n~ of controlled clinical studies fufly'utilizinS avaHab~ hi.heroical ~cs~ ~ ~ta~l~ and ho~onai cha~gcs and dcvclop- mcu~ under di~crcnt physiol, physiological, an~ mental cnv~o~cnts. ' [mpro~men~ oj Re~rc~ ~: T.I.R.C. ~ cont~uing its ac~ivlt~s in sUp~ning ~ientific ~d ~ ~nducling ~f~cs of ~i~ni~ in order In ~lincal~ meth~ ~prov~g rc~ ~ ~ di~t~. As ~ and op~uniti, for ~e establ~hmcnt of new ~ki~ a~ ~fiucd, studies will ~ ~it~tcd and c~tinucd ~or what- cvcr ~ h ~ to solvc thc many compkx problems that vc~y mc ~ ~ ly~g a~sd. It ~ ho~d t~t it may ~a ~ ~iblc for varies ~tc:cstcd o:Kani- ~, ~w conducting ~ sup~nin~ rc~rch ~dc~n~nlly o~ one ~c~, to c~gc in orKan~ng pwzrams of mo~c ~p~stica~d and ~Ccu~lly more sibilant studies aim~ at ~ling the ~aps in ~r knowl- ~ should lead to pm~css more intclligcmly than d~s cxploitin~ c~ivcly ~y onc ov~-simpl~cd hy~thcsis of s~cifc cnvkonmcntal causation, ~ ot ~livc cmpha~s on any'uric factor statistically ass~iatcd with c~ain cau~ of ~c n~ for s br~r, mo~c ma~.~c and more divc~si~cd of ~s~h wu c~dcnt ~ ~sulU of some ~vcstigat~ns rc~n~ during 1962. DurinG thai year, scicntil~c work continued to support the view that the quest fur a single, si,.plc "maKic. bullet" to explain thc causes or pro- vklc the curc for cancer and of hcan diseases is unrealistic and i~'obably futilc. The interaction of many conslJtutional ~d cnvJronmema| fact.s and inllucnces, some o! which still may bc undetected, is becoming increas. inKl.y cvidcnt. For this season alone--the fact that research indicates a posslblc volvcmcot for these man), factors and inllucnccs.~it is at present scientifiCo all), unwlsc and indeed ma), bc ha~ml'ul to at~butc a ~mplc~ dc~m|tlvc, causative role to any one of them, or to'attempt to assign them ~clativ© degrccs of |mpo~ancc. ~_ ' • The smoking of tobacco continues to bc o~ of the subjects t~qukinS stud)~ in the lung canccr problem, as do man), o~hcr agents and ,influe.nccs i,n modern living. Science does not yct know cnou~h about any suspected fa.ctors to judKc whether thc¥ may opcr~ alone, wh©thcr the), may operate in conjunction wit/, others, o~ whcthcr the)' ma~ affect o¢ bc xffcctcd by factoes of whose' cxistcncc set©nee is no~ yct I~wzrc. Indeed. it is not known .whctl~..r these factors actually ~rc U
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Research Findings and Studies During 1962 tile Scientific Advisory Board to T.I.R.C. made granls [or a number of new projects and awarded granl renewals for continuing work in th© broad areas of laboralory expcrimenl.ation, clinical invcstiga, fio~. and epidcmiology. Pwgrcs~ of the co.arch is partly reflected in pa~rs ~blishcd by ¢¢cipicnls o[ Manls. $i~c I1¢ 1961 Rc~rl, 60 addi. lio~l r¢~s have ~cn published, bringing Ihe Iolai Io date to 282. " Abst~cts o[ ~hc new pa~ ap~ar cl~whcre in this'Re.ft, and may ~ns~l~ Ior dctai~s on pro~F~ o[ rc~arch. ~ancc the Ooagd's objective ~l ~fimulat~g ~cscarch that will pr~ucc help- ful k~dge a~ut what ~ involved in the problcm~ oI lung cancer, cor0~a~ di~a~ and olbcr ailments. F~r~e~ ~ Cancer World-wide ~ientific interest in the vital theory oI carcinogenesis is obvious ~d ~owing. Con~dcrabl~ attention was given to this subject at ~ Vllith lnlcrnational Cancer ConFc. held the summer o[ 1962. ~e ~0 pa~ related to t~ ~ssibili~y o~ a viral etiology o[ caner wcxc ~ntcd, compared wi~ only ~our pa~n on that topic at Ihc Cancer ~n~ held only tout ycan prcvio~ly. ~is incrca~d interest in and attention to vi~s~anccr rematch is i~icatlvc of the rapid changes that can ~ke place in re.arch ¢o~cpls concerning ca~cr. Vi~s ~vc bc~ shown to induce a variety of cancers in ~vcral an~al s~cics. In 1962 there wcrc ream that human adcnoviru~s known to ~u~ rcspirat~ ailmen~ such as colds, when inimical into mental animals, ~d r~uJtcd in Ihc development of cancers in the animals. ~s with other agcnci., the T.I.R.C.'s research grants in this Acid have ~n increasing in re.hi ~ars. One T.I.R.C.-sup~ncd study ~ seeking to dctcrminc whether ~j~t~ v~al agents, citer alone ot in combination with various cordon- mental factors, will result Jn measurable effects on the trachcobwnchial t~e and puimona~ tis~cs of laborato~ animals. Th~ work al~ will cxtcn~d to include ti~ues in organ culture. Another study in ptogrc~ involves the question of any interrelated role that influcn~ vi~ infects, cx~surc In cigarctlc smoke and othc~ factors may have in the deve~pmcnt ~ pulmonary and bronchial lesions in mice. ~is particular study ~ an extension of work that has ~cn sup~rted for ~vcral years into the cor~latcd histolo~, cylolo~, and cyt~hcmist~ Ihc Irachcobronchial tree ~d lungs of c]~rimcntal animals. Also ul~Jcr way is a project i.volving Ihe use of chemical e~ots in virus-free animals.to ~c whether il is ~ihlc Io clucida~c I~ ~l~ti~shJp, i[ any, ~lwccn viral a~ cbcqfical carcinogc~s~. Cell ~:udie~ OI vital.im~rtan~ Io virtually all cxwd~nlal sc~nt~c e~avor is work involving the cell. For )'¢~s ehc T.I.R;C. hu ke. b~ic ~il r~arch, aiming primarily at ~ I~ain~g o[ m~¢ workers ~d at the" ~vclopmc~t ~ mo~ ~liab~ and ~c~ lec~ucs. Whil~ ~rcvious interest tended to co~cntratc ~n Ihc motoholo~ oI c¢i~, a~ mo~hologicai changes, the cmphas~ ~s~w ~n sh~ to I~ meta~bm a~ ~bav~r ol c¢i~ i~ res~ In v~io~,ireal~nu. ~i and abnomlal, or ~, ~1~ in viuo~ ~c~[~. oI "" may ~ aff~ by the challenge of ~mc cxt~m~ agent. Of ~u~, ~ s ~ a no:ma] cell in a c.lt.re medium is not exacdy "nom~" it ~ ~cn rcmvcd from the medium ~ its ~natural ~L In ~c h~ramry ~icnzb~ found that c~nuo~ ulttav~t ~d~. lion ol the nuckus of • living ~11 W~uc~ ~mg~ io thc nuckus. S~il~ damage was ~Mto ~ wi~ t~ ~ of ~etsin chcm~fl a&cnu. One lm~ant lmpl~ti~ ot this pardcul~ work is '~c ~b~ of ~vclop~s and ~I~ting a mot~ rapid and ~cumtc b~y ~. A ~s of agcnu, atonal ~m ~lyclcl~. hId~~ ~c tcs~d in ~ ho~ of ~vc~ping a ~mi~uand~tivc bio~y ca~ino~cnic ~tcnt~l or ~ivity oI a multitu~ ~ sub~sn~ ~ Ap~ 21, 1962. t~ ~cnti~ Adv~ ~a~d s~ l~ on c~ diKc[cntiation at the l~fitmc f~ ~r. Rc~. ~l~s. A~g t~ t~ics di~d ~ the in,oral ~n were toa within ~lb lcading to ~nd guiding di~c~nt~ti~, and ~c on ~ of var~ cnvitonmcntal factors. ~cm~l rccon~tu~n diflctcntiatcd to digcrcntiatcd cclls rcccivcd at~nti~. D~d wcrc ccUu- lar a~ tissu~ ~tcnt~b, influence ol chromosomes and series, v~ious Io~s of ~mulation," orgsn~tion o[ ti~ucs, and ot~r topics.. In a~il~n to sta~ mcm~ and mcm~ o[ ~c SAB, the/oilow~s wctc p~cnt: DR. JOi~ T. BONNER. P~in~t~ Uaivcalty, Prin~t~. DR. ~H W. PAWCE~, lls~ard Univ~ily, Cambridse, DR. ~LIFFORD W. GURHEY. ~nivcaity of Ch~azo. Chk~go, IlL DR. ALFRED ~ MIRSKY. R~kctcllcr ~sd~mc. Ncw Ymk. DR. JOIIH RUN~ROM, Wcnncr~cn Imllmlc. Sl~k~lm. DR. F. ~ ~WARD, ~ncil Unive~ly, Ilha~. N. Y.
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From th~ lmtitut~ for Cancer Research: MARIE Di BERARDINO. Ph.D. " JEROME J. FREED, Ph.D. THOMAS L KING. Ph.D. A. LIMA-D~FAINE. F~I. D~r., Re~e,~ch Fdlow MARTIN L NEMER. Ph.D. ROBERT P. P~RY, Ph.D. GEORGE RUDKIN. Ph.D. ~ACK ~HUL~, Ph.D. TIMO~IY" R. TALBOT, ~R., M.D. • Cardiovascular ~tudiea Support of cardiovascular research continues to be an imporlanl part ~ ~c Advi~ B~rd's rcscarch pro~am. This is a complicated and com- plex field and encompass, of ncccsslty, a variety of s~cific (opics. Work ~inu~ on a T.I.R.C.-sup~¢d project which is ~cking to determine i~ ~vbonmcnlal factors have any effect on the development of athcro~lcr~is ~ revealed by autopsy studies of acci~nl victims. Trained ~(¢~iewcn ~e ~eking ~o learn all they can a~ul ~ v~fim's life--his ~c(. hb smoking ~nd other habit--to compare or connect th~ i,fo~a- fios ~ ~s~b~ ~ih ~¢ suto~y data. In t~ ~¢ &choral field, s T.LR.C. g~anlec has ~c~¢d ~ndin& ~at du[ing s~ing Ih~ was a r~ m ~mm ~r¢c fatty acids (FFA) in I? px~n~ wi~ ~cd my~ardial infarction, aged 3~4. A lesser rise was lound du~ng smo~bi in 16 n~orona~ paficnls, and Ihc rc~chcr su~cslcd that ~e ~ealer FFA rcs~n~ in the cowna~ paticnis rcs~i~cd f~ a grcatcr rclca~ o( cancel•mine oiler nicolinc stimulation. This di~- [crc~c in ~n~, i[ construed, may reflect a constitutional dilic~ence ~- Iwccn ~ who use wcdis~d co comna~ disease and tl~c who it is, of c~r~, not known whal the cffccls may ~ o( rc~lilivc rises in ~hc b~ levels o(~A, which actually a~e a vital ~y fuel. Pos~-morlcm companions o( the ~cc u~ ulhcro~lcrosis in the cocona~ arteries of smokcn and nonsmokers have shown no significant dilicrcnccs. Animal cx~r~mcms ca~ricd out un~r t~ T.I.~.C. program have also shown no clear differences in the ~grcc of a(hcro~lcros~ in choicstcml-fcd animals o[ ~vc~al s~cics as a con~qucncc o~ chron~ nicotine ini~ation. 5mo&~ ~ BI~ FIo~ OI ~na~e In lh¢ catdiovascu~r field is a rcxarch proj~t that ~u~t to ~wsfiga~¢ th~ effect o( ~bacco smoking on skclelai mu~lz 10 blood flow. Th©ro hu bc©n coo~licling evide~:a on this subject in tim few stucfics cxlsting in d~c a,:cdical litclaturc. Wodc~ng under a T.I.R.C. ~ant, two ~ invcsti&ato~s us~l disappe~ancc rate of • radioactive is~opc from skeletal muscle as • measure of its nutritive blood flow. O~ 17 ~d subj~ Si~d, 14 • e ndio~olo~ disap~arancc ~a~ durst ci~¢tlc ~ok~g d~pi~ ~ngcs in ~tal ~11 bl~ flow and ~ usu~ d~l ~ sk~ tem~ tmc. T~ mcchan~m of luch an ~ sidl ~a~ unsown. According to4he ~ientists, this work reveals ~tancy ~ ~ i~t~ a~ ~at ~ha~ti~ ~ not a factor. ~e investigators ~c~¢d Ihat ¢vidcntl~ an ~1 ~ous ~pply • c fimb h u~a~ sin~ three o~ ~our ~ympa~tom~d fimbs aim ~w~ ~ i~r~d d~p~ ntc dung imokbi. A~bi sk~ bl~ ~ow d~s not ~c~ ~ sympat~ctom~d i~bs du~g smok- ing, they sai~ the ]nc~a~d~ap~a~an~ ~ ~ not rcpt~t a sbi~t o~ bi~ from ~ vas~onsgtictcd sun tO ~ mu~. whether ~inafion of mcla~lil~ of n~ ~ of c~n monoxi~ ~ ~c bl~ 5~cam will give mo~ accurate ~o~n oo ~ ex~nt which ciga~ u~n ~alc t~ smoke. Ni~lin¢ is ab~. In ~ ~ t~ bu~ cavity and to a ~cstcr dc~ ~oUowing ~¢p o~ ~okc. ~n monox~, on ~c o~ hand, ~ sepu(~ Io ~ only on deep Jn~lafinn. P~[¢cl~ of such ~ ~y ~it a~u~te ~t~minafion oI ~uc physlo~al ~oke ex~um from ei~, pi~s sod titan than q~siionnai~s. ~ s~k~g ~b~ a~ ~plh ot inhalai~n, and thus may ra~ cot:c~fiou stud~ to.a new ~o ~lh~s ~vclo~d in th~s study will ~ ~ by ~ to help intc~rct r~ults of another project ~ ~ rclatio~h;p ~twccn steroid lcvcb ~ ~y fluids and va~ous fo~ms of hc~t di~a~ ~d cc~ain ty~s of malf~ant tumon. ~is laths p;oj~t h to ~ sup~ by a fc&r~ agc~. An inv~tlgat~n has ~cn inaugu~tcd wi~ regard to ~a mon- oxide. ~c ~ounls ~ ~r~a monoxide t~l ~n ~ ab~d cvcn vc~ ~avy smokes ~vc ~cn shown to llc wcH ~low ~¢ tox~ ~vcl. the ~aces of ca~n monoxi~ p~csent in ciga,ct~ smoke ase sctativcly ~nstant, th~ study wiH ~ck to dctc~mi~ w~thcr b~ revels ~ cas~xy- hcmo~obin,, which can ~ dctc~mlncd vc~ accurately, will sefl~t !1 ~r c~ co, I
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d~t[crcnccs between the atnounl el" :~,,~ok¢ contact with Ihc nlveoli involved in xvcral dilfcrcnt fm~ o( smokh~8. Work also ~ ~,g sup~zlcd w~h the objective of learning ~mc- ~g a~ut ~c c~ccts ~ n~i~ on ~he cerebral circulation. ~ technique o~ ~gio~aphy has ~n ~vclo~d w~rcb~ it ~ ~ble ~o take whal amounls' to x-ray "movies" of Ihe bl~ flow in lhc cranial vcssab inctud- ~g Ib¢ ~allcd "c~c~ o[ Will~," ihe si~ucl~ral distribulion ~yslcm Ihal mo~ors regional ~rcb~l a~tcr~l flow. This lccb~iquc has already ~how, ils v~u= ~ diagnos~ of circu~loq obst~ction. ' Th~ and'~dmr ~udics arc suppicmcnta£y to pier]Dug indications tha~ nicol;ne'm~y have ~timulaling or. in some ways. lranquil~i,g ~cnual~ous. ~ystcm. ~ ~nfcrcn~ on the c~ts ~ n~tinc on the central nc~ous system w~ held by the ~ientir~ ~vi~ Doard in Hew York on ~pt. 28. 1962. work u~cr way in thb a:ca and s~ci~c topics in need of further research wcrc ~i~us~d by pantccs and oll~c, investigating this pa~icular 6cld. in ~ition to mcm~rs of t~ T.LK.C. sta~ ~d of the board, ~c following DR. ~. K. ~KMIT~G~ Kinj's Collcjc Ilospilal Mcdical ~1. don. DR. El)WARD F. ~MiNO ~c University of Michigan Medical ~h~l, Ann ~I~¢. OR. F.SKIL HAHN. Unlvc~,y o[ Call/Drain Mcdic~l Cen~er, Angcl~. DR. EDgE CURTIS I[OF~ ~N~ DR. CHARL~ H~KMAN, Medical CvlIc~c o[ V~ia. Rkhmo~ DR. PAUL S. ~RSON, Medical College o{ Virginia. R~hmond. DR. EDWARD W. PELIKAN. B~on University ~h~l o~ DR. H. C.,SABELO. Change M~cal ~h~[. Ch~a$o, IlL DR. CARL C. SEL~R, lizard U~vc~hy, Cambr~ge, M~. DR. DUANE G. WEN~L, Univ~r~ly of Ka~as. Lawrence. New stu~es now Ix:log supporlcd in the general circulatory a~ca are co~;crncd with va~-ular responds In tobacco smoking in patients with vascular disease, the release o/ calccholand,cs |rein the isolaled henri. the cfYcct of nicotine and r~lated substance on amine levels in ti:¢ nervous system, and the ~fllluenc© of drugs on a~tcrial acid mucopolysaccharides. 12 A study was und©rtaken toinvestigate the cofltrovcrsial qucslion whether Iiucrgcfs dL~case and general paipheral Vascular separate clinical cntilics. Rematch done undc~ authors to conclude that they are. ~e ~tudy invesfigat~ syndrome in patknts, most of whom wgg¢ ~avy smokers, in t~ O~nt, w~re it was found to ~cur with relatively high frequency Jn Japan and g~ca among ~rsons o~ low s~i~conomic class, and in the United State~ it was found that Iho~ alg~dy a~icted with wcr¢ gnsitiv¢ to tobacco, but there w~ no implication that a tim,at gnsi- tivity ~curs in ~gsons with general ~;ipher~l vagular d~ag..Multip~ factors td undetermined cdolo~ teem to ~ involved. Work M this particuhr fic~ is c~dnuing w;~ d~a~ among various Jewish ethic ~oups in Israel. ~me gknt~ts have rc~ned that, fog ~mc still unknown rca~n, m~ Jews more than tho~ of any ot~r O~ intcg¢~ in ¢otona~ g~earCh are previously ge~d on t~ gclation~ip di~as¢ and tt~¢~. O~ survgy ~vcred 10,~ phys~ians, dentistg ia~cgs su~ividcd ac~gding t0 ~c gelatlv~ '~,e,~u~, of ~ a~- fies. 1~ author, a cagdiov~ular s~c~,st. ~' ap~a~ to ~ an im~nt 8~c~ating f~ct~r d~t is relatively high in animal fat. Other rc~gs have g~tcd ~'ding an ~iat;on ~twccn coro~ d~easc and emotional sty. and s~in. ~ Jnvcsti~ Js about ~ undertake ~ sire;lag study wi~ ling magkct workers under a T.I.R.C. grant. Smoking and Protein Meh~boli~m it has long bc~,en known that young ~'0imals expend to t~a~ smoke or treated chr~ically with nicotine, gain wci~t at a lower rate ~an non-cx~d cunuo~. If Wotcin accc~ ~ adjust, su~iv~ .of ~ ~im~ ~ ~t impaired. Following sc~gts f~om England that rats so cx~ cx~ct~ m~ nitrogen ~an controls dur~g the duradon ~ t~ eyesore, ~ ~vestigation was ~n to ~tcrminc whether an analago~ c~cct con ~ ~ed ~ heathy, youn8'human ~.bjccts. Og continuing interest to d~ Scientific Advisory Do~rd and to othcn is the t~lativcly uncxpImcd problems of the va~jing and differing charactcro istics of [goplc--.gcncdc. psychological and physiological--and the hearing of such difl'crenccs on di~asc predisposition. 13
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I¢ is now rc.~ognized from a number of. studies here and abroad d~at II~¢re are mcasurablc or dclcclablc dit~crcnccs ~h among ~oplc who smoke in various ~ays a~d ~lwccn tho~ ~ho do and llm~ wire no~ smoke, su~cstlng that ~mo~ing practices may in part reflect consgilu- lional ~aclors ~hag may in~e diffcrcnl di~a~ prcdilcclions~ One sludy o[ ~alc palicn~s ~1 ches~ clinics re~rlcd that Ihc ~rson- elily Irails at lung ~nccr pa[~n[s d~c~cd si~candy ~wm cnn~r-t~c ~t~. A T.I.R.C.-sup~cd s~udy ~ a biologically and cuhurally homo- ~cn~us ~oup o~ Ilalian-A~rican ~aclo~ workers, a~osl all born in Ihb cobnlry, t~nd ~hat the ~ancr individuals smoke si~6candy more Ihan t~ s~ou~ or,int, bu{ no~ m~ular, ones. Conlra~ ~o o~her previous ~ smokers in ~hJs ~oup were no Icu marline in phys~ue, no more acgive, and consumed no ~re a~l ~han nonsmokers. Anolhc~ conlinu~g study is ~king to ~le~in¢ or dc6ne ~h¢ pro- cu~n ~ hy~ncns~ apd ~rona~ a~c~ d~a~ ~ a poup o~ mcdlcal ~! stu~n~s. Rc~rls already have indicated Iha~ a ~amilial (aclor is invert.. A prm~ctiv¢ pha~ o[ [his ~ng-lcrm projccl is Ihc ~nalysis ot ~um drawin~ oblain~ from Ih¢ s~u~nls; !~ is ~licvcd ~hal Ihcsc ~aw~ may provid¢s simple, c~cctive, psychological ~ecning dcv~¢ t~ Ihe ~r~nall~y a~pra~l ~ no~ sub~c~. AI~ condnu~ b s sgudy o~ ~he psycholo~cal, cultural and health cha~tcrisiics ~ a~g snwk~ and nonsmokers. Anolher invcsligadon just ~81nning will ~ck ~ examine ~he ¢xlcnl o[ and conslhudonal basis fm di~crcnccs in ~¢ ~nsi~ividcs, and II~ir ~ib~ co.clarion wi~h any con~i~ufi~i prcdis~ion ~o palhologic conditions, wilh di~crcnccs in smoking practices and wilh ~ dislikes. AI~ ~cgdng under way is a s~udy inlo psycho~gical ~accs u~n ~hc Iransla~n o~ modvcs into acdon wi~h smoking ~havior is an insane. Chemi~t~ a~ Bi~heml.~ The ~cnd6c Adv~ Board awar~d a oan~ Io ~cnfis~s a~ Norlh Carolina Sla~c College W ~asu~c lh¢ levels o( ar~oic absorption by Iobacco plants ~ relation to ~il ¢OnlCnt o( {~ elemenl and ~o eslima~e ~hc ~sidual ~vcls of ar~n~ in the ~ils u~d for Iobacco ~owlng various p~rts of ~ state. ' ~c x~dy ~ound Ibl~ a~nic in ~ils ranged ~om I ~o S parts million (ppm). ~ ~ ave~e ~or all areas o[ ~hc s~agc o~ 2.8 ppm. value i~ cl~ to ~e 4 ppm ~ed by J. E. Grooves in 1913 ~or a virgin ~il ~ Ihus ~u~ ~ ~c h~s ~cn no mcasurab)c increase hum ~ prcv~ u~ o~ ~rscn~l ~clici~s in ~hc ar~nic conl~nls i~ which Iob~cco is ~o~. 14 The invcstigato~ reported a~cnic in the culed leaf of Iobacco grown in these soils was h~m 0.5 to 3.55 pwn, w~th an average ~or all.lca~ samples og ].5 ppm. AI~ un&r T.I,R,C. zup~ i~ a study ~i~ncd to ~ whc~er va~o~ amounls of trace reclaim, ~cludin8 a~nic and n~kcl, when ad~d to toba~o, will have any effect on Ihc ~cid~nce of pulmona~ S~rain A mice that inhale t~ smoke from ~uch Iobac~. ~onlrol studi~ will adminisler the s~me m~tals by olhcr ~olhcr supported project will allcmpt Io idcndIy ~divlduai ~l~ phenolic com~un~ in cigarc./te smoke and ~ ~limale ~ir ~n~.. ~cgc feasible, thc~ com~unds will bc prc~rcd, for future or ~ncurg~t studi~ on ~cir mcla~lism and ~ssible effect ~on human ~in~. Epldemiolof~ Area " ~ . A study h now u~ way ~to ~ influence ~ ~ ~v~cn~l facton ~ the genesis of neopl~lic'di~ ~l~c~ ~te work is ~ing ~ by f~r Califorpia ~nt~ w~ r~ived a ~nt hum T.I.R.C. Io au~nl ~ cuncnt • ~b that m~cal ug~ of ~diati0n are a~i~d ~ of kukem~ ~ oth~ mali~anci~. ~ T.I.R.C.-~up~ed project will ~ek ~tudy ~ intimate of lung ca~r ~ o~cr cancer ~ lu~rculosis patients with.a would ~ceaain ~e re~l~n~ip, if any, ~twccn ~d ~rce f~tm~lu~fcu~b, smoking habili~ ~d AI~ un~r way in Mas~chu~lls Is an ep~miolo~cal lung ~n~ ~tudy ~n~ to c~ck a previous ~vcsd~atio~ T~ ~v~tiga~:~ f~ad in earlkr work Ihat Ihcre ap~ar~ ~ ~ a stat~lJcal co~clal~n ~lwecn. lung caner ~ figu¢i~ ~moking, ~csp~to~ iaaess, ~avy c~mptio~ of alcohol, and outd~r ~cupation. ~cy ~id Ihat while t~ ~alhtical couelation ~lw~n long cancer and ci~rclte smoking was slr~lesl, dala tu~cstcd that a threshold in ~umpti0a had to linear rc~lion~ip ~currcd. ~c dala fu~lher ~owcd. they reined, that I~ same level of cigarette u~ wilh addition.of pi~ or cigar smoking dimin- ishcd the disca~ ass~ialion, a ~csull di~cult Io intcgprcl.. ~ pha~s of lh~ a~ual mechanical work ~ ~ human lung ~ma~ a my~lc~ Io ~ience. O~ such pha~ cxacUy how d~s ~hc lung remove inhaled par~clcs. A sludy now under way in ~is subjccl deals wilh the phag~yict found ~ ~e pulmona~ 15
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"i~c work began with the concept of m©asufing th© overall lung clcar- anne capacily of heahhy, inlacl rabbits. Radioactive silver iodide. 1-131. (which L~ also used by mcloomlogists to sc©d clouds for production of rain) W~ introduced into the lungs ol~ the rabbits by a non-inhalation procedure. The movement o! IJ~ radioactive element wa~ then traced with ~¢nsitivc measuring cqulpmcnt. It was /ound tha~' eventually all of the ]-131 was engulfed by, the alveolar phagocyles and carried to the alimcn- ~ canal whence it was excreted.. , ". ..'~e "currcn| phas~ o! th© study encompasses lira inhalalion o~ whole c~garc~.l~ S..mokc following inl~oductioo at the 1-131 in order to determine the 6vd:rall cllcot bn clearance rates and. the r~latlvc rates by alternative routes. Other ]inimatt ate 1o be used in the projcc¢ in addition to the rabbit, and drugs that allect the flow of mucous also are to be investigated, as well as the efIects o/other inhaled gases and aerosols. Alv¢oli 8~udled in PulmOnary £mphyaema Recent discovery tha! a powcdui surfactant substance lines th~ alvcoli has gone far toward eaplaining the hitherto mysterious physical character- istic~ of these structures and their behavior during expansion and contrac- finn. Moreover, the ¢fl'ect~ of this agent and the consequences o| deficiency sugges! Ihat & biochemical approach to the investigation of the ctiology of emphysema may now bc within reach. A pro~©cl has been sponsored in which lung lissues obtained at ~urgc~ and at autopsy ar¢ heing studied. It will altcmpt to measure the relative activity of this su~actant recovered from lungs all|icted with carcinoma, emphysema, and bronchicctasis. Effort will he made In dctcrminc whether iobacco smoke inhalation aft'otis the activity of this su~actant, and study of it~ chemistry will b¢ undertaken. A report by a T.I.R.C. grantee in 1962 said Ihal bronchial disturb- antes may produce an obslructive airway mechanism leading to air trap- ping as well as indirccdy influence sudacc tension phenomena in the lung or impair clearance of entrapped pollutants. In Ibis way, the rcporl said. cro~ion of ~hc alveolar membrane Ls initiated. Among the other projects, which arc under way in institutio~ throughou! the country, are: A study of the nasal and pharyngeal bacterial flora of smokers, non- smoker~ and former smokers. The classification, prognosis and possible etiologic factors in primary lung lumor~ as dclormined from postmotlcm observations. 16 A compatativc study of the clients of 3~mcthylcholanfl~cn¢ and .cig. arctic smoke condens.ate applied to the oral lissucs o1' Swiss mice in which liver damage has bccn p~cviously induced. The purification and structure detcrmin'ation of the chlorate01. "c ackl Mechanisms o~ Ihe psychotroplc clients o~ nicotine. Fellowship Program• in 1962, as in cvcq~ previous year sinc~ 1955, th~ T.I.R.C., upon recommendation of the gAB, provided funds for the granting of fellow- ships 4o the nation'.~ accredited medical and o~copathio schools. Nearly 600 young men and women have so far ~.eivcd fcllov,~hlps. Deans of the ~choqis choo~ the I'cliows, a~d the studeaL~, working with thclr facuit; advisor's, deterrainc thc ~ul:jccls they wish to study dur-" ing summer or other off-term time. The fellowship program ~e¢l~ to stimu. I'~tc interest in basic research among medical ~hool stud~L~ and any subject of study may b¢ sclcctcd by fellows, ~sthout regard to ks relevance to tobacco u~ or el/cots'- . { 5qmma~ . " • . . ' L ' 'Ibis narrative section seeks only to indicate btlcfly ~om© ~ the more seccnt findings and uead.~ Marc complc~ del~il~ will be found in previous Ahnual Reports an~.in the abstracts they co,lain. Wod~ i~i many of thc~¢ ficids is continuing to ~eeslvc support. In closing. II seems appropriatc to rcitcrzlc the bask: bclkf underlying the Advisory Board's position, which was fdly ¢spresscd in the Board's rcporl two yca~s ago. That report concluded with this paragraph: "As Ihe tobacco industry continues its sopport o/the search for I~ulh and Imowlcdgc, it must recognize, as is always the case in tru¢ ~cie.,Rifi¢ research, there can b¢ no promise Of a quick answer. The important thing is to keep on adding to knowledge until the accumulative facts provide the basis for a sound conclusion." 17 O i- C F I F
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Abstracts o[ Reports • Each 'rccipicnt of a Tobacco Industry Rcscarch Commlttcc ~aot-ln- aid is responsible for the initial prc~ntation or publication of thc results of his research in scientific macting~ or in approprtate ~cicnlilic journals. Fellowing arc abstracts, approved by the authors, of sescarch reports acknowledging support item the T.I.R.C. that have appeared in seicntific journals since the I961 Report t~l' the Scientific Director. Th¢~c abstracts have I~cn grouped under the following headings: I. Slud~s at the Cellular Level; II. Pulmonary Physiology and Anatomy; III. Casdlova~ular Studies; IV. Psycho-Physiological Studies; V. Tobacco ChemistLy and Biochemistry; VI. Pha:macology; VII. Other Studies; VIII. Review. !. Sludies at the Cellular Level "INDUCTION OF CHANGES IN SURFACE ACTIVI'I'~ OF S~TRAIN L CELLS AT GAS-MEMBRANE INTERFACES," By Philip Cooper, Irene Goldrlng and Ivlorris Klein, Departmcnls of Surgery, Alherl Einstein College of Mcdlcinc and Bronx Veterans Administration Ilospital, New York. N. Y. Scienc¢. March 2, 1962, pages 725-726. (T.I.R.C. gtautcc: Cooper) During an i~vestigalion of the elfecls of various gaseous agenls on Ihe growth of attain L a~nd ilcUa cclL~ in cell cullure, the immediate direct cfl'cct of the passage of particulate and non-panicu "late ga~s over tit© sudacc of Ihcse c©iis, in a Ro~c pcrfusion chamher, was observed. The gaseous agents included smoke from the combustion of cigarettes, of cigarette tobacco only, of cigarette paper, and of onionskin paper, and non-~mokc.gases such as carbon monoxide, hydrogen sulfide, illuminating gas. oJtyRcn, and helium. Immcdial¢ly alter the injcclion of all gases tested there is a very rapid increase of the surface area of the cell as well as increased granularity,. Most cvidcnl, however, is "blcbbing" of the surface of the cclls, which ts most ma~kcd near the center of the bubbles of gas amJ is, nol sccn o. the stufaccs of neil~hboring celia. Tim "blcbbing" persisl~ as long as bob'bits of gas remain in the per- fusion chemist. If the contaminated medium is replaced by fresh medium within i0 to J $ minutes after contamination, the cclls arc promptly restored expend to air or medium alone, under various degrees of increased pressure. II ap~:ars thai the "bkbbing" results from ,a disturbance of the sol-gel rclationsh,p of the cell surfaces and apparently can o~cor at a gas-membrane interlace. "ALTERATIONS IN GROWTH OF STRAIN L CELLS EXPOSED TO SMOKE GASES." By Philip Cooper, Morris Klein and Irene P. Goldring. AIl~n Einstein Collcge of Medicine and Bronx Veterans Administration Hospital, Ncw York,N. Y. Proceedinfs o! the $ot-iefy [or Experimental Biolofy and Medicine. Volume II0, pages 11-13, May 1962. 18 Tim present sctic~ of studies was undertaken to elucidate further the direct action of sn,okc on living ~lh maintalncd ia a collate medium. The test subslanccs included smoke from II~c ~ntbu~ioa of ciga~ll~ clga~tte tobacco, ci~arcltc pa~f, oni~sk~ pa~r, and to~wwrap~ Smoke was collected under sterile condkio~. ~e culture flasks w~ in- vexed and I~ prc~ri~d v~um¢ o[ smoke was inlr~u~d inlo each ~k. " ]he flasks were re-invoked, the fluid medium w~ al~wcd ~o wa~ cells," and tl~ flasks wcrc g~ntly agitated until all smoke w~ abs~ by the ~dium. Control cultures were treated in exactly t~ same manner, egypt that they re~ivcd similar do~s ~ stcri~ air. T~e e~cct ~ non-smoke ga~s, cludin~ illumi~ting gas a~ carbon monoxide, W~ stu~cd u~r ~m~ar condioom. ' ' . Undcr [hc condil[~s of [h~ s[udy J[ ap~a~ [ha[ [here Js a,"~ox~~ c~cc[ "o~ smoke R~s on slrain L cells in cul~urc. ~ respln.~b ~ ~T- phologieal changes in [hc cells and in akcra[~ in ~owl~ ~ ca[cd by lhc rcducfion of cc[l ~pu[afions. ~c smoke ~om [~ com~[u~ ~ cil~r cigere~c ~r or ~ionskin pa~r ap~ared [o ~ m~¢ [hart lhal from ~he combusfi~ o[ w~Ic cigare[~ ~ ci~[[¢ [o~ ~o~ ~mkc from pa~r'contai~ m~e paniculate meter t~n m~ ft~ cig- arcllc I~o of the whole ci~rcttc, su~g ~ ~e part~u~r p~ in smoke ga~s may ~ ~ sign~e'. "CULTIVATION OF NORMAL AND MALIGNANT HUM~ LUnG Ti~UE. !. THE ~DLISBM~T OF TilRE~ ADEH~ARCIHOMA CE~ ~lHS. By Ma~ V. R~, Ph.D., a~ Genre O. Gcy, ~.~.. Finned-Howell ~acer Re.arch ~t~, ~p~eat of ~ge~, ilopkt~ tiospital. Baltimose, Md. ~b~a:~ ln~s~igatio~, Vol. 1 i, pages 638-652, Aunt 1962. (T.I.R.C. grant~: Gcy) ~ The ultimate goal of t~ Jtudics is ~ est~bi~cnt of autologo~ stra~s of normal and maligns lung cpi~um for ~u~t studies with each othe~ and with e~onk lung ~ih ~ gc~d m ~to~ and hi.heroical c~racteristics and res~s to v~. S~clmcns from 41 human c~s provisionally diamond ~ l~g c~om~ and f~om i i human cmbyronk lun~ wce~ ~ltu~ ~ rol~ on ~Ua~en, in plasma clot, and on ~e ~ seduce with diaercnt con~w unties of un~ppkmcnted human ~rum ~d of ~m fofl~ wi~ ~edc media: No~mal bmnchi~ epithelium gave cady tc~s wi~ cUia ~iv~g 2 to 3 months. Iluman ca~inoma ~!~ ff~ the lung ~ mc~lk over t~ n~mal p~oto~s as dctc~incd by ~tr preferential austral and gro~h in continuous culture, Stromal dom~an~ may midgate agai~t s~h ~n~s ~d often a~uats for faUu~s to ~ ~r no~ or mali~ant ~11 ~owth in continuous coitus. ~e ~cc human tumorous cpit~ ~11 s~ns d~ pa~r am ~ the ~cond, fouflh and fifth y~ ~tivcly. Two were tablished from ~dy di~efenda~ a~n~uc~omas of ~ lun[, ~d wa~ a metastatic c~cinoma of t~ b~a~t to ~ lung. ~ch J~m ti.ctly diacrcnt cytologic and growth charactc~sfi~. 19 O ~- ~r o o
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I t~r~4"ro~ra~ora~ American Cancer Society and National Cancer Institutc. "EFFF_J~J'S OF SEL~C'I"|V E ULTRAVIOLE'r.IRRADIATIOH OF TIlE NUCLEI OF LIVIHG CELLS." By P. O'B. Montgon~cry. F. Van Ordcn. L. L. Huudlcy, C. L. Chapman ~ J. E. Cook, Dcparlmcnl of Palholow, . Universily of Texas Southwcslcru Medical School, Dallas. Proceedings o! • ~h¢ Sot/cry Io.r F.xperimenud Biology and Mrdic'ine, Volume 108, pages ~72-3.?$, Novcmher 1961. (T.i.R.C. gramce: Montgomery) ",(~.o~i,nuous ultraviolet irradiation of the nucleus of a living cell pro- duc¢~ nut, lear damage. Although this damage sesemblcs nuclear damage , which occurs when the entire cell is irradialed, it is less severe due to the pro.~oction of the ezIoplasm from the effects of irradiation. Conlinuous ultra- viol¢! irradiation of'the nucleus of a living cell produces cytoplasmic damage resembling that which occurs when the entire cell is irradialed, but is less pronounced. "EFFECI'$ OF" ACETONE AND PHFA~IOL ON I~TAI3LISHED CELL LINF~ CULTIVATFD IN VITRO." ~y Doiiald M. Pucc and Alice Elliutt, in.irate'for Cellular Rc~carch, Department o[ Physlulogy, University of Nebraska, Lincoln. Cm~cer R~z¢~rch, Voi. 22. p-',ges 107- I 12, January | 962. (T.I.R.C. grantee: Pace) Acetone and phenol, which are common constituents ol cigarette smoke, have been studicdin various concentrations with reference to their short- term cffe¢ts on mous~ fibroblast and human skin ceils cultivated in vhro. Concentrations of acetcmc, 10.0 mg/ml and above, a~e toxic to both typcs of celL~. Th~ skin cells a~c more ~cnsilive to acetone effects than arc the fibroblasl cells. Ahhou~h $.0 mg/ml acetone is not toxic to fibroblasts within n lO-day Period, it I~ noticeably so ¢o the skin cells. Phenol in concentrations of 0.2 mg/ml and above is very toxic and kills th~ ccUs within an hour or two. in concentrations of 0.1 and 0,16 mg/ml some o! the fibrobiast ceils were still living after 10 days, but a definite inhlb.itory elicit was indicatcd: only 13% of the cells survived !or that p~. J~od. The skin cells appeased to I~ less sensitive: $7% of the cells sur- wved 10 days after exposure to 0.16 mg/ml of phenol conccnt~-',te. O~her grJm8or~ The Cooper Foundation, through the University of Nebraska Foundation. "Tile EFFECTS OF SULPHUR DIOXIDE UPON ~ADLISIIED CFA..L LIN .E3 CULTIVATED IN VITRO." By James R. Thompson and Donald M. Pace, Institute for Cellular Rc~carch, U.ivcrsity of Nebraska. L~oI~. Canadian lournal ol Biochemistry and Physiology, Volume 40, pagca 207-215, February 1962. Gaseous ~lphur dioxide has been cited as one of the major contami- nants of the air. yet very litll¢ i~ known about its mode of action upon living ~c other than as a "respiratory britant." The !¢asibilily ol utilizing tissue culture methods for Iong-Ierm studies of the ¢llccts ol low concentralio~s ot sir ix~utants upon cells was demonstraled by the exposure to SOs and its salts t~r culluses o~ Strain L mouse cells (fibroblasts), mouse liver ;nd HcLa cells derived from an ¢pitheliaJ carcinoma of the human cervix. 2O The licLa cclls wcrc mmc scnsltivc ¢o SO~ exposure than ~ mouse ceils, which seems to support the general the.sis that humans arc more tiv¢ to sulphur dioxide than other mammals. , Cells cultivated in biological medium grow in concentrations of SOn up.to 2000 p.p.m., although somewhat inhibit©d. Cells subjected to n concentration of ~00 p.p.m, in this medium a~e not gready a!~ccled and their growth is comparable to those ccUs in control cultures. ~ addition various salts'of SOa in concentrations from 10 to 200 mg % produced responses ranging from compi~ inhibition of '~'owth (by 200mg HaNSOa) to apparent sdmulation of growth by some cogu~tradons of "INFLUENCE OF N ICOTINE ONCELLS OF RABBrI'S' AORTA AND MYOCARDIUM IN TISSUE CULTURES." By Tatsuo Kokubu and O, J. Poliak, Dover Medical. Research C'.~ntor, Dover, D~L E~l~rimemal and Molecular Pathology, Volume l, pages 293-.30:3, Jun~ 1962. (T,I,R.~, grantee: Pollak) . • The association of cigssett© smokiog with onrdiovasculnr dise.as~s in several statistical studies prompted study of th© effect of ¢i~¢tte smok~ condensate and tobacco comtitu©nts on cardiovascular ccUs ~n vltto, This paper c0nccrns the effect of nicotine added to nu~iont media be.-. fore inoculation or a/t~r growth of aorti~ and myocardial calls from and hypercholcst©remi¢ rabbits. The concentrations of nicotln¢ used wer~ arrived at by trial and error, Solutions w~ak~r~than 1:40,000 added te nuuicnt b~[ot~ inoculation were ineffective; solutions of greater ram~ntra- tiou than l: 1,000 proved too slrong; otlu:r l~Sls weJe at ¢once.ntratioas of I;2,500, I:$,000 and l:10,000. | Addition of nicotine to th© nhtricot b~[e[r© inoculation' inhibited growth, resulting in fewer positive cultures,, an~ theru was s~ve~u and often [j~tal damage to the structure o! various cells. ~nhibition o/ccU growth re- fleeted by ll~ number o[ positive cultures, d¢~resslon of cell proli/~ratioa and multiplication, damage to cell structure, a~l tl~ Sl~ed am/degree of recovery from damage all mirrored the concenlration of.nicotine applied, Character and extent of morphologic d~unage ai well as su¢,ovcry from depend.cd also on the cell type. Length o[ ~ expo~ur© to.nicotine was • strong laetor in recovery o/calls. ~I ' Otl, er l(tan~o¢ ~ National Hear~ Institute.. "MORPHOLOGICAl. AND CYTOLOGICAL STUDY OF HUMAN AMNION CEI.I.S IN TIIE COURSE OF RECOVERY FROM RADIA- TION INJURY." By Masahiro Mizutani, Yuh H. Nakanishl and C. M. Pon~erat,. University of Texas Medical Branch, Galveston.. T~uz~ Reporta on Biology .nnd Medicine, VoL 19, pages g[ I-$24, Winter 1961, (T.I.R.C, grantee: Pomerat) A well-~stablished human amnion strain which was culti~aled in chambers was irradiated with 1000r from a cobal~ source. The maledaLs thus Ireated were stained with Jacobson's method daily for live successive days |oliowing irradiation. The changes in cell populatio~ and mitotic ~x and the incidence o! giant and muhinucleate c~lls wer~ examined. A po0ula- tion of this strain which had a mc~dal chromosome number o~ "/5 ~we.d s~vere injury a!tor irradiation. The cell cultures grown from th~ r~ovcry 21 LtJ
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of radialcd cell cultufcz wcrc characterized by a mudal chlumusomc izumbcr o1 ?~. T~ nzccbanbm of zianl ccll Emmztioo and [he changes in Ihc m(~al ch~usomc hUmOrs have ~c. dizcu~d in ~c~crcncc Io rc~lcd cvi~ncc. Ol~er Jr~nlorz ~h~l of Aviadon Medicine, USAF, Kandolph Aic Farce il. Pulmonary Physiology and Analomy "PgOTECTIVE EFFr:CT OF PARASYMPATIIETICOMIMETIC AGPNT$ ON CILIAT~D M~CUS~ECRETING EPITiI~LI~M." Hans L.'~alk. Ph.D., Paul K~in, M.D. and ilcrla M. Ttcmcr, Ph.D., Dc- p~tmcnts of Pathology, Univ~sily of ~uthcrn California ~h~ of Mcdi- clne and ~s Angdcs County General Hospital. Journal ol the ~ational C~cer Ira:irate, V~iumc 27, paget 137¢-1392, Dcccm~r 1961. (T.I.R.C. grantee: Falk) Exposure of ciliatcd mucu~sccrcting cpithclium of the e~pphagus of Ihc frog Io par~ympalhcficom~clic agents prolccts against the cllccls irritant acro~ls so that ~hc ~owing of mucou~ slrcam induced by thc lallcr d~s hal ~cur..Thc agCnl~ slud~d i~ludc l) acctylch~ and cholinc-likc drugs, 2) chofincstcrasc inhib~ors, and 3) com~unds ~clalcd to acid. Prior application oi su~ parasympathctkomJmctic agents cxc~ls a prophylactic effect a~inst t~ subsequent aclJ~ I~ritanls prc~nt ~ I~ ~icula~ phax ~ cigarette smoke and urban ~lutcd air induce a ~owing in the rate of flow in the mucou~ ztfcam, proba- bly ~ a zcsult of altcrati~ of ciliary activity and m~i~ztioa of mucous ~crction. In yiv~ thiz has ~cn zhown to facifi~tc prolonged xc~ntion of panisultte.~lt~r ~alJn~ ~ ~ rcsplrat~ eplthchum of m~, rats. and rabbJts.W~n Ihe pa~cuhtez ~sizt of or contain known carcinogenic agents, Ihcir ~i~ fo~ in the palho~c~csis su~cs~d. ~z~zc Zhc ~mo~Zrzzion at ca~cino~cn[c a~cms in ~l]uzcd urban air zod ci[zrczzc smoEc, znzlyz~ o~ rpldcm[olozica] dazz reveals zhzZ by f~r z~ Zrczlcr majmizy ~ Iho~ cx~d ~o ~vclop pulmona~ cao~c To ~ an attractive ~ plausible explanation fur this cpidcmiolo~ical palZcrn b that I~] and s~z~m~ h~ fzczurs azc si~n~cznzly ~ncd O~her ~r~xo~x Hz~nz! Cancer lnszlzuzc a~d Amcrican Cancer ~iczy. "PANLODULAR EMPIIYSEMA: ANATOMY AND PATHODYNAM. I~." Dy Jolm P. Wyatt. ~.D.. Vc.m~ W. Fisher. and Iicr~rz C. Swccz. M.D., FCC~, ~pzrlmcn~ o~ ~azholosy a~ Mcd~inc, St. ~uis University ~1 of ~cdiclnc. 5~. ~ub. Mo. Oisr~ ol ~ C~sL Vol. 41. pa~cs 23~-259, March 1962. (T.I.R.C. ~rznzcc: Panlobular cmphy~ma b • morpholo~ic denominator common m such un~c conditi~s as p~imary humpbacE chest dc~mizics. I~ali~d hardcn- in~ ol the hilu~ o~ I~ lung. ~ br~c b~onchial airways ~e~mi~ics and con- ~cnizzl "lobar ' cmphy~mz. ]~ wcll-dcfincd is zhc airway obstruction in ch~Jc b~onchJlJz ~nd b~o~l~hiccla~J~ absolved Jig many cases o~ established particular emphysema. An additional cmph~scmazous ~roup without 22 rural brohchial dcformily was ah0 found, but Ihc~ were usualJy a.~ocia~d with Icssc~ degrees of cmphy~ma.. ' Broa~hia] dhluxbanc~ may p~ not oaly an ob~i~ mcchanhm lcad~g to air uap~ing, but ~dircctly ~flu~ sudacc phc~mcna within the lun~ or zmpair cl~r~cc of cnUap~d ~llul~u in this way initiate erosion of I~c air ~c ~mb~ncs. ' lly~lrophy of the right vcat~clc w~ a frequent com~oa of tzblbhcd ca~ of gcncral~d pan~bularcmphygma. ~e ~-tmbi~ c~n~iag ~urfacc ~ t~ ~lmona~ coatribution t~ ~mz~sh -- ~ ~c~vcly destroyed through aivco~r sac db~lulion with the loss of I~ ~rfusing lung ~d ~ing fcs~asible [~ ~ common mznifc~latio~ of car ~lmonzlc. . ' O~cr ~lcrminants iavolv~ in the development of car pulmn~ pathologic by-passes ham aacry to vein, bg~pulmona~ shuntiag ~- Ikulady in cmphy~ma with fibx~is and a ~ating ~1 pulmonary vein sysicm..Thc~ mo~phologkal find~S react the. p~im~ nn~rtancc of t~ pulu:~a~a~diac d;~a~ in tbc natmal hi~y of form of cmphy~ma. " . . " 111, ~rdiov~cu~r $xudies "~t~ VIDR~ARDi~RAPHIC ~ERCISE T~ FOR Weber, ~rdiova~u~ Rc~r~ ~alo~,~ U~vut~y of ~fomia, ~- • pa~lmcnt ~ Medic, ~ Angcks. Californ~.~ dmerk~ JOur~l O] C~di~ olofy. VoL 9, pages 541-546, Ap:il 1962. (T.! ~C. ~aai~: A~). ~e ~ia oblala~ from ~is sludy ~epres al a small ~oup of and, Ihcrdore, can only ~ co~ed as a I rcl~ re~. S~ palienl~ ~cted were. a ~cfully-stud~ ~ ~, h~ev~, ~caler ~u~ can ~ ex~cd Ihan from mass ~m col~l oa. T~ exe~ ~cst ~do~cd. is a ~uantilalive I~l dc~ endear on a nu~al su~cmenl only, and h free ~ qualilalivc ~rp~ clal~ ' -laitial deflectio~ ol Ihe vib~a~diosra~ we~ me~ed ~[~e ~d after a single Iw~stcp lest in 81 palicnl~ incl~ din~ ~lh normah and sons with my~a~dial i~mia. ~he no~:d ~es. ~ w~ a winning of the wave initials, exprcs~d as a ralio of iolai syst~ Ic, the incrca~ ran~ng from $ Io 2~%. In abnormal subjcc~ Ihc~c was a dec~e~ ganS~ from 5 63~. No~al and [uncllonaily n~mai paficats ,~onelatcd with thc~ clini~ diarists ia 87% of the fa~l by Ihf Iw~lfp Ifsl and 94~ by Ihf cardio~raphlc inte~al.lcst. In abnormal palic~tl the couclatio~ were 66~ and 88% * rcs~clivcly. An additional 85 ca~s including ~lh single and ~ble tw~stcp tes~ have ~cn addcd Io the study with no e~nlial c~ngc ia t~ a~ve conclusions. "EFFE~ OF NICOTINE ON Tile CORONARY BLeD F~W AND RE~D CIRCULATORY PARAMETEr. CORRELATIVE~UDY IH NORMAL ~S A~D ~S WIll CORONARY E~CY." and ~'EFFE~S OF PERSA~TIN (RA,), A ~EW COROHARY 23 L! U I I-
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VASODILATOR. ON CORONARY BLOOD FLOW AND CARDIAC DYNAMICS IN TIIE DOG." By Samuel llcllct, M.D., James W. Wesl, Ph.D., Ot|o F. Muller, M.D. and U~o C. Manzoli, M.D., Division of Cardi- qlpgy,...Philadclphia General Hospital and Department of Pham~acolosy and Rol?ihctte Foundation, Univ©rshy of Pennsylvania 'Medical Scl,~l, Philadelphia. Cifculalion Re;e&ch, Vol. i0, pages 27-34 and 35-44, Jan- uary 1962. (T.I.,R.C. ~an|ce: 13cllc[) . . Tic cl[cct of intravenously administcrcd n~colinc (20 micro- gsamslKg/min) on coronary blood l~ow and related hcmodynamlc paramc- [ors was studied in the normal inlaCt dog and in the dog with induced chronic coronary insu~cicncy. Nicodnc increased cardiac work m;~rkedly in both croups oi" do~s by an increase in I~¢ mcan ar~crial blood prcssurc and cardiac output. •Mcan control coronary blood flow was mod©ral¢ly decreased in dogs with coronary artcry ligsdon and markcdly decreased in doits with narrow- ing of lh© two main branches of [h© [c|t coronary arlery. Incrcase in coronary bloc~d flow produced by nicotine in ,ormal dogs was observed to ~ as high as 125% on an avcrag© ovcr ;h¢ control value. The averagc incr~a~ was 82.$% witls ligadon of on¢. coronary arlcry branch a,ld 83.3% witl| n.',rrow- ing of the ewo ,~ain branches. 'Tl,c response of the coronary flow was directly rcl:,tcd Io d|c degree o! coronary narrowing an~I/or occlusion; the gre-',¢er the impairment, the smallcr was the incremcm in coronary blood flow, which hequcndy druppcd below the control value in lh¢ pos[-inIusion period. Cogonary vascular r©- slstanc© and myocardixl oX~ygca u¢ili~ation d¢clincd during nicotine admin- istration. Pcrsandn. a new coronary vasodilator, produced an aw'ragc increase in coronary blond ~[ow o~ I~9% over conlroivalues in normal animals, of 165% in dogs wilh [igatlon o[ one -'oronary artery br'~nch, and of 51% in dogs whh coronary artery narrowing wilhout increasing card;-',c conl.-,clility or cardiac work. " O~her ,(ronrorar The Eli Lilly Company. the Lilt Insurance Medical R,:.- ~carch Fund, and the American Hear! Association. "EFFECT OF CIGARETTE SMOKING ON FREE FA'i-rY ACIDS IN PATIENTS WITH I IEALED MYOCARDIAL INFARCTION." ny Alhcd Kcrshbaum, M.D., SamucI Ocllct, M.D., FACC, Raymond F. Caplan, M.D., and Leonard ~. Fcin~rg, Ph.D., Philadelphia Gcoeral Hospital, Pennsyl- vania. ,4n~¢ric~n }~urnul ol C&diolo~7. Volume 10, pages 204-208, August. 1962. The ¢{[ec[ of smoking on serum freo fatty acids (FFA) was studied in i ? patients wilh healed myocardial in[arclion, aged 36-64. including one female. T'. :re was an average maximal rise o| 65.6% in FFA in all subjects in 10 Io 2~! minules alter smoking Iwo cigar¢l[es in a 10 minute period. Some elevation usually ix:rsisted for 40 minutes. In 16 non-coronary patients FFA city,dons alter ~moking svcraged 27.2%, and in I0 normal subj~:cLs the average maximal rlsc was 24.6%. In J3 non-smoking controls, there was an average maxi~nal rise of 1.'/% during the test period. !! is sur.gcslcd [hat ¢h¢ crealcr FFA response in myocardial infarction patients is the result ol a j~reater catccholamine release alter nicoline slimulation. OON'r I~rnnrc~r; Nalional Ilca;t ln~itut¢. "METAIIOLIC. IilSTOL~IC AND IIIST~HEMICAL ASPENS OF TIlE IlOM~RA~ED HEART." Uy.R. ~. Bin~ and (by ~vitation) C. Chiba. A. Chrysohou, S. G~hjarnason, and P. L. W~f, Wayne State Unive~sily College o[ Medicine. ~roi[. Mich. Tran~aClio~ ol Ihe ti~x ol Anwric~n Pkysici~s. Volunm 74. pages 318-332, 1961. (T.I.R.C. ~an~¢: Bing) Ko~ p¢cpa~a~bns hi~h r~pi~a[ory quo[icn¢~ exisling [oBelher wi~.~re~cd pyxuval¢, ~¢~1iv¢ my~ardial kclone ¢x[t~[inm, and ~mini~d pH coro~w vein bl~. The ~¢~nl~ge ~ucos¢ oxygen ¢x1¢~[i~ ca[los f~e- quendy ¢xc¢c~d I~. ~¢~ changes succeed ~iy~b, wi~ a down o[ pyguvu'e lh¢ou~h I~ [a~y acid ealhcr Ihan Ih¢ I¢i~x~l~ acid cycle. ~e r¢~pir~Kmy chain, huwever, ap~a~ed ~o ~ ~la¢l. ~ce di~- • . f¢~cn~s in oxidalion ~¢ducli~ ~[en¢ials ~lween co¢o~w ~¢~! and vein o1~ weee negative. Appa¢cmly, homoMa~[ ¢e~c[i~ resulled in cc~ ~m~¢ab~ily wilh ~ ~ ¢~ymcs and c~nzymes from [h¢.~ll. ~uf[cd ~ans w¢¢¢ g~anu~malous my~rdills s~ilar Io ~hc acute pmli[cra- ~iv¢ sta~¢ o~. ~hcumal~ lever but lack~g fibrinold necrosis a~ nccr~b a~lct I days of vbbilily. Thb p~llcrn b robs[ likely .duc mu~ I~su¢ ~s~ns¢. Hlsl~mlcal slud~ dc~slrll¢ active o( RNA p¢o1¢~ in the oa~i and m~kcd rcduc~on in malic dchyd~og~na~ in the donor hca~ ahcr Oallin~. ' "TRANSP~NTATION OF TItE llE~RT."PBy R~rd J. Bing. Chiyo ~iba. AIh;nasbs Ch~u. Paul L. Wolf an~ Sigmundu~ Gudhjarna~n. ~rlmenl ol Medicine. Wayne Slale Univers~y Col~&e of Med¢ine }l~r~r ilospital, ~lroil. Mich. ~itodal. in Ci~c,lati~. Volume 25, pages 273-276, Februar~ 1962. "l'ransplanl~h~ immunily, resul~g in Ih~tejcciion d ~ ~ ;~ result ol anligcns ~ the grail, which, on~cachin~ I~ ~egin~l lymph n~cs, slimulal¢ pr~ucdon )~ lymphoid cells ~ich in~ll;;l¢ Ihc Mail and dcslroy ih Transplan~tion immunky n~y ~ acl~ly a~uited, and ada~iv¢ ~munky Io ~he homo~ra[I also ~s ~¢n demonsUa~d. AIt~gh ol ~e ~li~c~ ~ nol known, il has ~cn showR Ihai ~lls can ~ I~ally d~sinccgratcd wi¢houl dcslroying lhe~ ~wcr ¢o civil transplants- lion immunily, and it has ~cn dcm~tratcd Ihai t~ anliOn~ subslances ~¢ es~cially c0nccnlr;led in the nuc~ar fradlion o( dls~nlcoalcd cc~s. in Ibis la~)¢alo~, two dissimibr patholog~p~¢s~s were in homo~rahcd canine ~a~ts; one Icsi~ consislcdo[a di~u~ (g~anulomalous ~hralion) thai was st~ikinBly similar Io. ~ proliferative siage o~ aculc rhcumali¢ fever. ~c second I~ of change ob~wed was acul¢ my~ardlal necr~is with inlcrslilial cdems and ~l~mo~honuc~& ~cutrophil~ in~hralion o[ Ih¢ frn~mcnled my~ardial li,u¢. I~ is ~ likely ~1 homoMahs o( Ihc ~ari will ~ o[ any clinical im~anc¢ in Ih¢ gu;urc. However, it b probab~ Ihat some fundamental knowledge 24 25
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gai~cd from a curcl.I .~pdy c~ ,lu: c~rrclafi~n I~tw©~n I~ pm~css~ '~HE ~EI~TIONS[~P ill, WEaN CORONARY I~[X)OD FLOW, MY~ARDIAL OXYGEN CONSUM~'IOH ANI) CAROIAC WORK ~ INFLUSNCEi) liY P~R~NTIN." By Vcrn~ ~ Wcndl,.M.i).. F. S,~dcrm~ycr, M.D.. Pancra~ U. ~'n Uakkcr, M.D. and Richard J. M.D.. FA('('. I~pa~ln~nl o~ Mcd~in¢. Wayne Sla~¢ tJnivcrsi~y (~11¢~c o~ Mcd~ and Ila;Fr Ilnspilal. I~lmi~, Mich. Ae~eri('gitl Journal ~1 u#y, Volume 9, pages 4;9-454, March 1962. The ¢ffccl o[ a pyrimid~-py;imidinc dcrivadvc, I)er~ndn. on coronaw bl~ ~ow, my~a;d~l oxygen co,utopian and cardi~ ~rk was sludicd in ni~ padcn~ whhou; c~diova~ular ~¢asc. Pcrsantin caused a in cor~ary v~ular rc~lanc¢. The dis~ialiDn ~lwccn ¢a;diac work and my~ardial oxygen consumption sup~csts Ihat Pcrsanlln acl~ upon c~liular mcla~lbm, causing an incrca~ in Ih¢ o:~gcn demands and n¢cczsilaling an inc¢ca~ in coronary b]~ ~ow. The administration o( Pcr~nlin r~sullcd in a decline in I~ raljo o~ le(I vcnl~Jcular work to my~ardlal oxygen con- ~umpl~n. II i~ concluded Ihat ~b¢ drug. like nitroglycerin, dinzinislcs cardiac work in ~omc palicnl~ and has a dixccl effect on cardiac mcta~l~m. "CATECIIOLAMIH~ IH HOMOLOGOUS IIEART GKA~S." ~y A. Wc~nn, C. Ch[ba, A. Chr~mhou a~ R.J. ~in~, Dcpazlmcnt of Mcdi- cin¢. Wayne Slate Univ¢~shy Co1~¢ of Medicine. Detroit. Mich. I'r~'rrd. inX~ ol dz¢ S~i¢~y Iof Exp~rim~n~ol Di~o~y o~zd Mcdit'inr. Volume. 109, pa~cz 54~-54~, March 1962. Complete 4¢~rvat~n of pu~py hear~, was accompl~hcd by hom~ Iogouz Iran~planladon. Cardiac ~lcnl and inl~cllular dzztribulion of catc- ¢holami~z remained unallecled the ~rsl 24 hou~ following Iran~planlalJon. • Wilhi~ Ihb lin~ ~ri~ ~¢icraled ~ejcclian did ,ol bzfluc,c¢ II¢ mine ¢~lcnl of tic hca~ g~ah. After 72 houx~ no ¢alccholami,¢~ could ~ detected in ~an~pbnted ~ad. "STUDIE~ ON THE TRANSPLANTED ilEART. ITS M~ABOLISM AND ili~OL~Y." fly C. Chi~, M.D., P. L. Wolf, M.D., S. Gudbja~na- ~n, Pk.D., A. Ch~hou, M.D., H. Ra~, M.D., U. Pca~on, M.D., and R. J. Biag, M.D., ~p~lmcnlz ~ Medicine and Palh(~lo~y, Wayne Stale University College of M~e, ~ Hater Hospital, I)clrod. Mich. ol Exp~rin~rn~o/ M~dicin~, V~ume 115, pages 85~-~bb. April ~ mcla~li¢ ¢hze~¢~ in I~ homo~aflcd canine ~i wcrc ~ludicd ~ o~ to de,no the b~hcm~l altc~a~ions accompanying homoAraft • jcctJ~ ~zc honm~raflCd heart ~¢lca~d pyruvalc and laclalc as well as m~dic ~hydmgcnasc and aldola~. ~lmclion of glucusc by' ihe grafl usually maincd In ~veral cx~rimcn~, homoKrafl rejection wa~ acc¢~ralcd by p~ior ~nd~lion of the host animal Du~mg the accclcralcd ~cjcclion, the ¢clea~ of pyruval¢ and ~cZal¢ w~ more pronouaccd, and even gluco~ ap~rcd in mc~ca~d concen~rati~ in ~onz~ vein bl~. In many cxwimenls t~ resp~a~o~ quotient of the Iranzplanled a~ well a~ ils gluco~x~cn cx~acllon ral~ wcrc elevated. It ~¢mz likely Ihal the elevated respiratory quotient~ were the result of the conversion of carbohydrates to fat. "i'he n~etabolic block or bilks prc~nt in the planted heart a~c likcl~ Io ~ the result of diminul~n ol mltacc~ular and ¢~nzymc~ rcsullmg from increased cellular ~rmcabilily. O~ker gr~tore: U.S. Public Health ~vice, Amer~n tleatt A~ia¢ion, Michigan Ilca~l Ass~iation, Life insdra~¢ Medical Re,arch Fund, I]urn,~Glls-W¢llcomc Fund, and John A. Harl~ocd Founds[ion. "MY~ARi)IAI. 'M~TABOi.ISM IN A PATi~ WITH " MOTO'S THYROI~ITIS AND HV~THYROIDISM.".Dy P. ~. Bakkcr. M.D., J. F. ~rmc~cr. M.D.,.V. ~ Wendl, M.D;, M. ~lhaney, M.D., S. Gu~jama~n, Ph.D., and R. J. B~ng, M.D. Am~ic~ ]ou~i Medicine. Volu~ 32, pages 822-826, Ma~ 1962. ' A c~c o~ llashimo[o'~ Ihyroidilb w~lh hy~thy~idbm b prccn[~. Cardi~ oulpul, corona~ bL~ ~owand my~rdial oxy&en con~umpt~ wc~e within ~he normal range. ~te and ~c~1¢ w¢~ cxlca¢~ by hca~ during Ihe ba~l ~lal¢ and relca~d by ~ ~arl on ¢x¢¢c~. A marked increase in my~ard~l gluco~:oxygcn ¢xlr~cdon ~llo w~ found ~d differences in ox~lion-rcduclion ~lendal ~¢wccn .a~ri~ and comnaW • ein bl~ were ~itiv¢ at ~est and cxcrc~. ~h¢ ~s~l~ ~u~l in the cardiac muscle of this individual in the preface o¢ ~mal oxygen usage. '~HE RE~X-~T~TIAL OF THE ~A~-PYRUVk~ TEM IN UL~D AS AN INDICATOR OF ~E FUH~IOHAL STATE OF CELLU~A OXIDATION." Uy 5iAmundur Gudbja:na~ and R~rd J. Bing. Bi~kimica rl Biopk~ica Acla, Volumo ~, ~gcs 158-162, Ju~ 1962. ~ ~dox-~lendals or bea~l muscle, anerlal and ~ron~v~ bl~ have ~cn calculalcd from I~ ralio of l~la~c/p~mval¢ in ~'pr¢~ and absence of my~aed~) anoxia, In ~b~nc¢ol my.~ardi~ ~x~. i~ po(enlial o~ bea;l mu~le is m~e ~siliva l~n~l~l o~ ancdal bl~; In my~ardial anox~ lha redox-~l¢nti.l o~ ~art mu~I¢ b ~¢ ncgaliv¢ lhan Ibal o[ a~e~ial bl~; ~ha~ o[ ~r~-sinu~ bl~ approaches ~ka~ the mo~. T~ ~¢sul~t of ~his study so~csl I~ altc~atio~ in ~Eb • c hca~ reflect parallel changes in the my~r~um. "FREE FA~Y ACID COHC~H~ATIOH ~HD COM~SITIOH ARTERIAL UL~D." By Matin E. Rothl~,~rJ~inc B. Rolhl~ and Vernon E. Wcndt, I~pa~mcn¢ ~ M~icinc~ Way~ State Univc~ity of M~Jci~, ~l~oi~, Mich. Anlt~icon ]o~[ oi Phy~ioloxy, Vol. 203, pages 30~310, Augusi 1962. (T.I.R.C. Oanlc¢: Bing) • • ~ effect of the adminisir~ti¢~ of n~¢p[~ph;i.¢, Kl~o~ and ~nlobarbilal, and Iiy~ncnsin on Ih¢ arlcrial ¢onccnlra~n and com~- lion ol plasma free ~al~y acids (FFA) ~s ~cn slud;¢d ~ man and Wilh a ri~ o[ ~e ~A conccnlral;on as p~u~d by nompi~p~i~. c~l~bu~n ol o~ic acid Io ~h¢ Iotal WA incrc~d, while ~at o~ s~ar~ and palmidc acids d¢~e~d. The [c~c~ changes ~ the WA were o~rv~ when Ihe~ sacral level fell under ~h¢ ~uc.~ ~ o~ ag¢nls siud~d. ~ WA com~sidon was dC~cBI O~ ~ WA 27 C F C F U F (.
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or ;inimal ai thc~thnc oi' analyi~s. At high FFA l~vcls, ti~ ~I'~ approa~tliai. , of ~t fah and Ii¢~minio ~a~s, M.D. J~nu~ ol ¢he American Afedicul ~imion. pages 871-873. ~ptcm~r 8, 1962. These ~tud[cs have indented that o~ygcn lack le'ads to rapid dephos- pho~taGon oi hlgtgg g~g~ phosphate ¢om~nds and to thg togmati~ el inorganic p~p~ua. Jn the ~agt comp~tely dgp~ivgd of o~y- ~n, glycogen al~ d~ap~ar~ rapidly. Aitcmtio~ in tkc carbohydrate inter- mcdiatc~ during m~ag~ai aaox~ agg ~ well d¢li~d. ~ manifold ~v¢~ dlsturbanccs.in intcr~dia~ mg~m pr~d by anemia well ~ad to ~prcssion og my~atd~al contracti)hy in sh~k. IIb ~lSO qmlc ~[bl: thai I~c ~lcl~ad~ of my~rd~! cxpu~iw ~wc# contr~bulcs to "OXIDATION REDESIGN IN IIEART MU~[.~. ~EORF~ICA[. AND CLINICAL CONSIDERATIONS." By S. ~udbjam~n. Ph.D.. ~. O. Ha~n, M.D., W. E. Wcndt, M.~., T. B. St~k, M.D. and R. ~pagtmgnt o[ Mgdi~ing, Wa~ Stat~ Uni~¢g~ity Col~g~ o[ Medicine, ~tgoit, Mich. Circulator, V~umg 26, page~ 93~-945. November 1962. ~ put~ of thi~ grOgS i~ to ~t out that changes in th~ o~gcn- ~g hgagt mu~c~ ~gflg~t altgtation~ within h~agt m~l~ cglb. A clinicat and g~ncntal 6~ by thc~ ~ulho~s an~ GlUts i~lu~t~atc~ limited value of calcu~.s of the ~latc of cellular o;iflali~ in .cart m~cl¢ from a comparison o[ I~ ¢c~x ~icnl~l in arlcgial and c~onary vein bl~. ~o~ slmuld ~ mad~ to ~mpG~h' ih~ goal by more s~cific and refilled b~mical ~a~. lncor~ral~ o[ ladled pg~ur~gs into ~tgatcs pres- ent In co.haft vein bI~ may pmvc a ~clul ~ub]cct log ~tudy. ."CATECHO~MINE CONTENT OF VARIOUS ORGANS IN EX- PEglME~AL tiYPERTENSION." By A. Wegmann.' K. Kako, and R. Bing, Wayne ~ats University College of M=d~in~, ~tgoit, Mich. Americ~ Journal o~ Physiology. VoL 203, pa~cs ~-~, Octo~ ~962. Ncphmgcn~ hy~gtc~n in dogs pg~uccd by a unilaterally placed Goldblatt chmp rg~ultgd in di~nishcd calccholamJnc content in t~ thoracic a~m, ~th kidneys, and in ~c ~plccn. ~ catccholaminc ~tcnt ~ hcaa. bcai~ a~ Ihe adrenal ~ands remained unaffected. Neugogenlc hy~tcnslon, induced by partial gcfion o[ buffer nc~, had no ~i~ificant ¢gcct on the ¢aicd~la~inc content o[ Ihc~ ~OTAL CALF AND MU~LE NUTRITIVE BLeD FLOW DURING TOBACCO SMOKING." By ~a7 D. Coffm~n, M.D. and S~nley lhe New E~¢laadC~d~vm¢~ $~ie~y, Volume 20, pa~¢~ 37-39, 1961-62. 28 flOW. In the 'u ~ 1 o[ a piclhysmoggapk alone it h appazcnt that incrca.~cs in nmtcle bl~ flow may ~ hidden or eaa~a~d by ~ng~ ~ the disap~aranc¢ rat~ of a radioactive ~oto~ from skdc~ m~lc M a measure o[ its nutritive bl~ flow. Of a poup of IT no, mat subjoin. 14 showed ~ ~e~ in ~el¢~' mu~i¢ nutfkiv¢ bl~ ~ow a~ me~uRd by ~ ndioimto~ tale during cigarcll¢ ~mokin~ ~pi~ ~1 change~ ~ t~ calf b~ flow and ~e usua/de~ea~ in ~k~, tem~¢atuC¢. ~ m~nism of ~h ~¢a~ h ~he unanswer~ que~lion. Th¢~ tludi~ ¢¢vcal. iB ¢o~la~y su~ thl ~halati~ b not a fact~. , 3 of ~s 4 ~ympa[h¢~omi~ limbs ~mw~d a~ iatr=~ d~p~a~ du~iug'sm~ing. ~um~g thai skin bi~ Bow ~s not ~ca~ ~ sym: pa~tom~d lin~s dug~g ~ga~ette ~ok~ it. h ~ a s~pk ~t ot b~ fgom ~ va~ktcd akin m I~ m~. "NORMAL RO~TGEN~PHJC ANATOMY OF THE HUMA~ CIRCEOF WILLIS." By Ro~ A. Kuhn, M.D.. ~pu~nl suggcw, New Y~k Me~I C~kge, New Vogk City. Amcdc~ R~ntge~iogy. RMium Therapy ~ Nucl¢~ Mid, inc, Vpi. 86. pag~ 104~i~9, ~m~r 196l~ In propagation f~ a study of the ¢8¢ca ol tob~ on ~ ~ggbnl cir- culation, it was tin,giant to ~bl~h ~e nodal v~u~ ~t~ of human cbck of WilliS. ~c ~ctu~i dhuibm~ syuem whkh gcgional c¢~¢bgal agtcgi~ flow. ~vg~nt ~ t t~u¢ of gUo~a~ ccr~gal an~aphy to dct¢gm~¢ ~¢ flow patterns was a~pU~ed. v~v~g the ug ofa 50~ hypaque ~t~n. ~e t~hn~u¢ avbi~ compktely ~cssu~ agd[~ and a~cnd~ju~. . C~a~ v~suali~fion ~ obt~d ot ¢om~ngn~ ~ ~ ~ ~ W~I~ by ~ m¢~. ~e ob~atio~ indite ~t ~ human c~c~ og gungtionaBy a ~gclc ~ name o~y. ~ ~nt antc~g seg~n~ po~ maj~ diffcgc~s in functi~ ln~i ~rOl~ ~w ~r- maUy suppli~ ~¢ ipsilatcral hall o[ t~ antcgi0~ g~cn~ but a~t o[ indiv~uals ~ss the capacity to maia~ ~ [uncd~al c~c~ latoff flow to ~th hcmbphcrcs o[~c brain by,way of o~ ~t¢~al ~g~id P~tcdor ~gmcnt circulation is chagactg~gd by bilateral of a ~¢lativcly small volume o[ slowly mover ~dal bl~. ~ bnin and ~rc~Jlar areas age. Ihcre[ore. usually ~olal~d [gom Ih¢ ~p~ly moving high volu~ str¢am ~rgusing the anterior sc~t. In ~'~ual in~viduai, ff ~ internal ~rolid supply lai~ bilateraUy th¢~ would ap~ to cl~ that ~m~phetal ~rlu~on could ~ suppned by way ol ~cnt flow. "~E SP~D OF ~BRAL CIR~TION." By ~ M.D., N¢w York H¢di~l College, ~owet and F~Ih Avenue New York City. ~¢w Eng~d 3our~ ol Medici.. pages 689~9~ ~t~r 4. 1~62. 29 ~r ~o
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In order, to establish a normal rate of cerebral bl~KI circulation, lests were conducted i~ six adults and one chikl hy retroicradc brachial injection ~low Ih¢ righl axilla and by higk.s~ed ~ngiography, thus providing an op~uni~y f~ ~udy ~ brain ci~cu~li~ in a phys~lo~c sctling. The average Ihorax-I~orax ci~¢ulalion lime in Ih¢ adull is seven seconds. Ccrcb~ul ~raasil usually is accomplished wiihin [our ~conds. v¢l~ily o~ bl~ ~ow ~ quil¢ hi~ through lee anlerio¢ se~¢nl o~ lee ¢i;clcs of Willb and Ihr~gk ~ ~lenor and middle cerebral a~lcr~. B~ain-slem and ~ste;~r ce~c~ i~riB~tion, by contrasl, is slu~h. Reasons fo~ diffc;c~cs a~ ~ ycl u~ica~. ' Flow rates in ¢~c~ are more rapid ~ Iho~ ~ l~ adult. To~ul cc;vieal~e~cb;al ci~c~l may ~ complclcd in ~ lict~ as Bye or six seconds. Hcm~ynami¢ factors arc ~¢vcd to ~ rcs~nsibl¢ for these hlghct vcl~i- t~cs. ~¢ capilb~ F~ ~ adult and child ~ equal in duration -- approxi- m~ly Iwo scco~ "A~ION OF NICOTINE ON CORONARY VASCU~K ~NCE IN ~S." Uy ~yd U. ~adcrs ~d J. P. ~, ~Fu'~cmcn~ Pharmac~o&y, S~ate University of lowa College of Mcd¢ine. Io~a Cky. Amttica~ Journa~ ol ;~h)~.~, Volume 203, pages 621-625, O¢lo~r 1~62. (T.J.R.C. g~nlcc: ~ni) • Ni~tine admini~crcd inBa-arlc;ially in aduk mongrel do~ pr~uccd ~ incrca~ in comn~ va~ular resisl~ncc as ~dlcu~cd by an increase co~ary ~usion procure. II w~ concJu~d Ihul ~]s results (tom sympa- thet~ nervous system activity or rclc~ ol calcc~lamines [rom chroma~n fi~. Ganglia or BanA~oa-lik¢ sl~ures are apparcndy involved. ~¢ ¢on~ractil~ ~or~ of t~ my~ium, as well as ~ronaq ~dusion pr~r¢, was incrca~d wilh inua<or~ary adminls~radon or nicotine or uo~,qephrin¢ and sympal~dc ncw¢ slimulaSon. Co~onaw va~ular ~c¢ wa~ incrca~d b~ th¢~ a~¢nls a~ pr~cdu,cs. ~,is inc,~a~ may ur may not ~ rclalcd to lee ~iliv¢ inol[opi¢ c~¢¢1s of nicotine. ~¢ ultimate effect of inua-aflcfial admb~lfuli~)n uf ,icut~¢. contrary to ~m¢ previous rt~ru, is an i~rcas¢ in coronaw ~CSblanC¢ which would ~ exacted to result in a dccrca¢ in co;opa;y blo~ Ofker Kr~ler; U.S. Public ItcalJh '~HE BUERGER SYNDROME IN THE ORIENT." By Victor A. Mc- ~u,~E and Willaed S. Harrb. Dcpart~nt of Medicine. the Johns Hopkins Uni~rsity ~h~l of M¢d~inc and Hospital Bulletin ol tat iohtt£ ilt,pXi~ iimpitat, Vol. I~, ~¢¢s 241-29[, ~ccm~r 1961. (T.LR.C. McKusick) i. The Buc~gc~ ~ndromc ~ ~cludv¢ ~riphcral vascular dis¢as¢ • ¢ clinical pi¢lu~¢ ~ri~d by ~u¢rg~ ~ ~cu~s in ~¢lalivcly high q~y in Japan and Korea and probably in o~hcr pare of Ih¢ Or~nl. a~ls almosl ¢~clusivcly males. Onet is ~¢otc 35 ~¢aes o~ age i~ a ~ c~¢s. ~ padcnls are al~l wiihnul ¢xcepli~ smoE¢~, usually hca~ smuk¢~. Th~ up~r ¢xleemk~s as well as Ihe low ¢zl~cmilies a~e al~¢cled in a significanl p~owlio~ of ca~s. Thrombuph~¢bilis ~cu~s in ~me cases. Au~ullulion was ~ound u~ul in idenli~yin8 involvemenl o~ lhe lilac and l¢mo~! arlcdcs. A ~¢equcnl ~r~rio~aphic finding in eases wilh involve. 3O mcnt of do: arms was pc~si~tc.cc a.d dilatation o1" |he intc(o~cous artery willa occl,,s~m ¢~f II~c r~ial undror ul~¢ u~lc~Jcs. ~c~iunully a pu~ in a i~r~ur~ling branch t)t Ihc i~ilciosscous a~lczy was palpable a~ Ihc w~isl lifted urlcrio~r~phic;dly i, some. In llzc legs a comp~r~b~ ~nding ~ a ~orutiug haunt5 u~ Ihc ~zoncal urxc¢y communicaliog wile lee ~rmininal ~riiun t~ Ihc u,leri,r lihiul u~icry ~ was'ob~rvcd. "r~ dccp femoral was ~cludcd in Iwo palicnls. 2. in Korea and Japan I~ Ducrgcr s~ndrom¢ ~cu~ predominantly in farmers und laborers, ~rs~s o~ lowcs~ s~i~conom~ slalus. 3. Ol~r imprcsdv¢ cpidemiolo~ Icatu~s are ex~sur¢ and and a low level of diclary ful and p~ozcia consumption.. 4. In a ~ics of twenty-eight ca~s two pzdcnlz ~d ~clus[~¢ d~ in the iliac arteries wile sympl~z~ staxlin~ al the age of 33and ~5 y~ ~ssibly ~condury to Irauma Io I1~ low hack a~ sacxum~ Th~ Iwo ap~ar to ~¢p~c~ni a condition distill from I1~¢ ' 5. in a majority ~ Ii¢ ca~s az~cr~ler~s, emblem ~d Ji~as¢ in the ao~a und iBacs cann~ u~nt for the pr~. Mo~t cases zludlcd apleur 1o rep~c~nl a distin¢l ~tc&ory of v~u~r di~a¢ can le~itimalely ~ Irked Bucrgcr'z di~a~. 6. Hi~lopalholo~ sludy o~ ampu~ted s~ci~ from ni~ Korean males revculcd nonu~ci6c mganizing and r¢canalizing ~cl~ion ~ In o~ chan~cs consistent with subzcute anglilb wex~ ~¢d. 7.. Multip~ taclo~z ~ I~ ~Jes of cases and ~haps even in ~ivid~ which is, within fimiis, p¢og[c.iv¢. , ~ihtr ~r~lor~.: U.X. P,blic I Icahh ~lv~c and the Ei~i Company, Japan. "TILE i~UERGER SYNDROME IN TIlE UNI~D ~AT~. ARTERI~ GRAPHIC O~St~RVATIONS. WITH SP~IAL REFERENCE TO INVOI.VEMENT OF THE UPPER EXTREMITI~ AND THE DIF- FERENTIATION FROM ATHEROS~EROSIS AND EMBOLISM." By Viclur McKusick. Willard S. Ila~rb. O1¢ E. O¢~¢~n and Richard M. G~man. ~parlmcnls o~ ~.ledicinc a~ Radiology. ~e Johns HopUns Un~v¢~ity ~k~l ~f Medicine a~d Hosphal. B~ki~¢¢. Md. Bu~l,~i, ~oh~ ilop~i~ Ho.~pit~i. Volume !10. pages 145-176, Ma~k 1962. Aor(o~rams, ~¢moral a¢l¢~iog~am~, and ~achial a;lerioM~s ~r~or~d in Iwclvc male palatals wile clinically lyp~al Bur;get s~ndrom¢. The avcrag¢ a~¢ of unit was 27 yca~s (ran~}15 to 43). All wcrc smoke,, and in most. remission and xebpsc wc~¢ intimalcl~ rclat~ to salion a~. resumption o~ smoking. 10); hislolog~ malerbl sup~r~in~ lee diagnosis of Buerger s di~a¢ was present in al leasi fc~r (N~. I. 3, 4 and 6) and will ~ ~ri~d ~o evidence or ~clusiv¢ di~a~ ol the aorta and ils large branches supply- in~ lee exlremiliCs was di~overed. No eviden¢¢ ot atherosclcrosis of wo~hy pro~rtions was 31 C £ U I (.
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o ~ " "~h~.and other a~tcrio~aphi¢ Iindints were suiUn~ly similar to d~ in Ko~c~n p:ficnts with d~c Du~cr synd:umc (~cgusick ci ai.. ~,IL d~;~.. Wiclhu ~¢ di~r~ ~ of c~fllially Jn~ammalo~ ~tur¢, that ~ angii~ b a p~m fox hbtolo~ic stay. Ol~er Ir~lur~ Nal~naJ I~tilulcs of Health. "flUERGER3 DISUSE: A DISTIN~ ~INICAL AND PATHO. L~iC ~IW." By Victor A. McK~ick. M.D., WiHa~d S. He.is. M,D., M.D,, and R~n.D. Bl~wcll, M.D., Johns llopkins Hospital and ~h~l o~ Mcd~in¢, Dahlmor¢, Md. Jo&~ ol ~ American Medical A~iadon, Pa¢~ 5-12,.July 7. 1962. . Art¢~ioMaph~ and h~lopathoiogi¢ slud~ of a group ~ 22 patients in Bah~o~¢ provided tvi~n~ I~1 Buerger's d,~a~ is a d~linct clinical ~nd pad~iog~ emily. PreciOus ather~ier~is und ~ysltmic embolism can be excluded as d~n~ ~ibili~s. Although the changes in the vc~cls are inllsmm~m~ in char~cler, it may n~ follow that they repr¢~nt nn c~parabl¢ Io Pa~rlerhis. T~ etiologic factors and Ih¢ pathotsn¢tic mechanisms in Uuergcr's di~ are ill In Korea and Japan. where B~rgcr's disease b relatively mo¢¢ man than in I.~ Unil~ Stales. tx~sur¢ m damp cold and ~ulbly Io trauma ~e~d Io ~ ~ilialing f~to~ in the young male subjects sluditd, nearly all ~ wh~ lived m ~arm villages and worked long hours in ~¢ paddies ~ and f¢¢1 in cold walar, in ~lh the oriental and U~l,mo~¢ casts, ci~r¢~ ~king ~cmcd to ~ a ~tcnt ¢x~crbating and~tuating tar ~ t~ d~a~. "CORONARY VASOMOTOR TONUS IN ATli~O~L~ROTIC ~." By C¢¢il E. Cr~ and Ro~n W. Obl~, ~p~flmcnt o~ R~;ich, SI. Jo~ph H~p~lal. Bur~nk, Cal;~ornla. American Journal ul Phy~i~o#y, Volume 202, ~ 61~618, April 1962. (T,I.R.C. D~. R F. Salisbuq, o[ Si, Jo~ph • An a~herogtnic regimen ~std u~n do~ ;~uhcd ;n ~vtral abnotmallt~ of (~ ~ro~ry c~¢~tion. The st~ctur¢ of ~c a~crics was m~i~cd by cx~ivc athcfomatous de.sits. During control slates ~for¢ t~ admi~tration of v~aclivc drugs, ¢oro~r~ flow ~r of no( propubivc fo:¢c a~ ~n w¢i~t was unvaried or mcrca~d. TIC ability of thc at~romatous ~r~ry Ir¢¢ Io ~cfca~ or dc~ca~ i~s vas~ mo;o¢ {o~as was mark~ly ¢u~d. ~h¢ ab.orm~fifi¢~ ~o;dtd w¢~¢ "~AL CIRCULATION IN H~RT blU~LE ~UDI~D WI~ N~~ C~RANCE M~HOD." By Pcltr F. Salisbuw, Cocil ~ Cross. Ro~n W, Oblath, and P. Andre ~¢~¢, ~parlmtni o[ Medical Re.arch. J~ph H~pital, Burbank. Califo~a./o~nal ol ~pplitd P~y;iology, VOl- um¢ 17, pa;¢s 475-47~. Ma~ 1962. (T.I.R.C. ~amt¢; S~li~ury) 32 Tic disappearance of radioactivity of Na~Ci, injected into the left veniricular walls of dogs, was studied. The xat© of Ha clearance from indi* vidual depo.sils did hal measure coronary flow Ju absolute trams; bewtvtr, wicn, in the cour~ of a single observation, the Ha clearance dope changed. this reO.ccted directional variations of. coronary flow. lncrcucd cemral coronary pressure did not always result in marc rapid sodium clcaranc~ from iu:hcmic regions of Icart muscle. "VENTRICUI.AR PERFORMANCE MODIFIED BY ELASTIC PROP- ERTIES OF OtJTFI.OW SYSTEM." By Peter F. Salisbury. M.D.. Ph.D., Cecil E. Cros~, and P. Andre Ricben. ~B.S. Circulation Re~eo~¢k,,Volume I pages 319-328, August 1962. .L ell ventricular ~nd alrial pressures, left vcntricnlar circumference and Iong,tudinal meridian•| Jegment,itngth, ¢oro~mry Eow, and ¢~rdia¢ oaytsll consumption were measured in'dots under ¢ooditiop whic_k permitted tentional variation of the ¢laslicity of the lefl vtntricutar OUtll0w system, comparison of cardiac performance during steady S.~atcs in_ wbic.h .hem1 rate, stroke walk. and stroke volume were identical but th~ oulllow elastic capacity was varied. , When ¢jecling through n rigid s~stcm, the left ventricle generated larger fraction of the contractile t¢lLtlOn under nuaoto~]e condifiocs, and left vc,,trlcular systolic pzak pressure was increased. Ejections through rigid tubes proceeded from higher diastolic ventrleular prc~,surc~ end larger tcrnal dimensions. The cEon of hearts which ejected through rigid outflow conduits was associatcd with • rcduccd myocardial oxygen consumption. Ol~er Ir~llorl National Heart Institute. "CORONARY VASOMOTOR TOHU$ IN MODERATE HYPO- °I'IIERMIA." By Cec~l E. Cro~s, P. And¢¢ Ricben and Peter F, Deparlmenl of Medical Research, $1. Joseph Hospital, Burbank, Cafifomia. American Jo.rnol oJ i'hTsiolo&y, Volume 203, pages 825-828, November 1962. Ctxona~ blood flow was measured in mongrel dots in open-chest preparations wlth'fixed cardiac output and by-passed right beart. A~c~ial oxygen tension (pO~), pH, and tcml~ratur¢ were measured. The siop¢ o~ recession lines between mean coronary drivk~g p~ssura (,,ordc p.~cssu~c m*nus kft vcntricular pressure) and coronary flow indicated direction•| changes of coronary vasom(xor tonus. During pcriod~ o! blood cooling in non.fail.log hearts, the c(xona~ vessels dilated only when pO~ was permitted to ~all,]but nol whcn it remained slablc, in failing hcaru, moderate decreases o~ bl~d temperature and pOs did not ¢~usc |u;ther decrements of co;chary va.~omotor teens. TIC indicate that diminished pOs and not low blood Ic~npcraiurc was the factor that caused coronary IV. P~ycho-Phy~iolo~ical ,!~tudie~ "CONSTITUTION AND SMOKING IN ITALIaN-AMERICAN TORY WORKERS." By Albert Damon, Department of Epidcmiology, Harvard ~;:hoot of Public Health, Boston, M~s. American Jo~r~l C £ Q I I-
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Physical Aal~pology, Volume 20, pages 67.6g. March 1962. Uccau~ o( inCo~sislcnt and inftcqucnt ~c~nt~ og a~i~tion o[ tobacco smoking with b~y (otto, it was dcsirabk" to study as hOmOgCllCOUS i ggoup -- biologically and cultura~y ~ ~ ~sibk. in Ih~ case 167 adult tunics, aggd 2~59, working in a sm~g fa~lmy, all with pafcnl~ ~;n within 75 miks of Naples, Italy; 151 wcge ~m in tl~ U.ited Slat~. Among the[ 167 men, t~ le~er individuals smoked significantly m~e than t~ ~t~t or fat (bal not mu~u~f~ noel. The bi~ial of eog~lation were hi[her w~n ~n-smoke~ and light smokers were com- pag~ with ~avy smokers than when non-smokers were compared with all ~okefs. ~ as~iati~t, thm~ si~ificant, were not par0culady close, or clo~ e~ugh-for ~dividual pgedict~n, with bisegial c~flicicnu¢ from 0.25 to 0.35. ~e ~int~ was not due to d'fferent diea, since smoking and ~ofi~ intake, total as'well as ~rcentag~ of proteln~ ear,hydrate, total gal, ~tugaled tally acid. ~d ~lyun~turatcd fatty acids were not c~ As re~aed by previo~ authors, ~fum cholesterol Icvcb were sig- n~antly hi~r ~ t~ ~mokg~. Cont~a~ to previous go,as, the were no le~ ma~li~ in phys~ee, no more active, a~ consu~d no mine alcohol titan non.smokers. "~UDi~ ON FIGURE DRAWINg: A REVIEW OF Tile LITERA- TURE ( 1949-19~9)." B~ ~ona W. J~s, Ph.D., and Caroline B. ~omas, M.D., Johns Hopkins Umvcrsily ~i o[ Medicine, Baltimore, Maryland. • ~ P~yc~alri¢ Ouwlerl~ Supplem¢~l Voi. 3~, pa~c, 212-261, Part !1, 1961. (T.I.R.C. g~nlce: Thomas) As ~ of a long-Item ;tudy ~ precu~ra of hy~ncnsion and ~rona~ a~ db~, figmc ~aw~ have ~ ob~ieed Ir~ 7~9 J~ns Iiopkins medi~l sludcnU ~ twelve s~ve c~s. The pre~nl ~r is a review of the figure~rawing literalure f~ the pur~ of pro,'~ing a b~md back- ground lee a. Wo~ect~ ~ries of uudi~ in regard to figure drawings, their ~ming cla~ificalaon and their u~ in t~ appraisal of ~rtonality in a ~u- bil~ ~ healthy medkal studenlt on whom a wide varlely of olher, data age ava~ab~. In f~l~mlng a~kles, comparisons will ~ made ~tween the figure drawin~ of s~kc~ and nonsmokers, of subjec~ wilh and without a ~renlal h~o~ of hy~ie~ and/or coro~ arte~ disea~, with and wilful hy~choksluemia, a~ with diacrenl ty~s of ~y build. ~ ~ev~w of t~ figme~rawing lilcrature [~m 1949 through 1959 ind~t~ an cxoandine ~leg~t ~ the u~ of the Draw-A-Person Ic$1, with ~c~m8 cmp~a~a on t~ rok as a gc~atch t~l. As yet there ts no um- vc~lly accepted gming pg~uge, although many invcstigatms have dc- v~d ~ir own g~ing ch~al~. At kast ~e major ~tudy has dem- onsua~ ~at reliable ~o~ng can ~ achkvcd and that JtatisticaJly signifi- cant correlations can ~ ma~ ~lwecn ~orcs for drawings and othct ~fes such ~ tho~ ~ the Ro~h~h test. Ac~rdingly, ~e authors ~Jlcvc ~t the D~aw-A-Pggma test o~cgs pwm~ of ~coming a ~implc, effective, psy~og~l ~r~ning dcvkc f~ the ~sonality apprai~l of ,COMPARi~N OF SMOKERS AND NON-SMOKERS. I1. TII~ DI~ TRIUU'I'iO.N..O1: ABO and Rh(D)"DI.OOD GROUPS." Uy Dcrnlc¢ I iirschhom CohcJ,, Johns .I Iopkins Unlvcrsily School of ! l~,glene and Public I Icalth, and Cawli.c Iledcll Thomas, Johns l lopklns Untveraily School o! Mcdlcine. llaldmote, Md. Bulleth, el Lhe John~ Iiop~ins IioJphol, Vol. 110, pagc,~ I-7, January 1962. ~ The distributions of the AB0 and Rh blood groups among 1398 healthy white and Negro men claxsified according to smoking habits were examined. Nn significant d~erenccs were found in any of the comparisons among the Negro males. Among the white males, there a~peared to be a significant deficiency of group B individuals among heavy ctgarette smokers and an esccss of group B pe¢sons among non-smokera and ~x:casicmal smoke~S. An excess of Rh negative individuals was found in the white oc- casional smoker group. The diflercnccs, while not marked, gem suf~cicnt to warrant further investigation of the relatio~hip between smoking habits and blood groups, along with other pertinent variables. O~her grantor: U. S. Puhllc Health Service. "PSYCHOLOGICAL. CULTURAL. AND HEALTH CHARACTER- IS'TICS OF AGING SMOKERS AND NON-SMOKERS." By Frederick E. Whiskin. M.D.,Andrew S. Dibncr, Ph.D., and Paul J. Rhudick, P.ILD., the Age Center of New F.ngland. In~., Boston, Mass. Journ~lo/Gerontolotyo Volume 17, pages 69,.74, JanuaW 1962. (T.I.R.C. grantee: Whiski~) • Demographic, health, J~ycho.logica~, and cultural characteristics of 402 aged smokers and non-smokers were examined with queslionnaire tech- niques. ]'here were 153 male smokers and 21 male non-smokers and 126 female smokers and 102 female non-smokcrs in the study group. . None of the hypotheses peru|nine to health attitudes or psychological factors was substanlintcd. I [owcver, such dimensions as inhaling and'attitude toward smoking among smokers sccmcd to be related to certain p~ycho- logical and health attitudes as well as to on~ct and cc~iatkm of lie habit. Most men started s.'nokiug before they were 25 years old. (80%), while only 35% of the wongn had staffed by then; 42% of the men but truly 29% of the women reported.they inhaled; :52% of the men and 37~ of the women felt more relaxed while smoking; 10% of the men and 6% of the women felt smoking was heneficlal, and 29% of the men and 22% of the women thought it harmful. Only about 15% of each group s~id they wanted to cut down their smoking, and only one-third of the men and women believed they could definitely stop smoking if they ~ desired. ' The dimensions of inhaling vcrsus non-inhalin~ tended In s~parnte the smokers into two groups which showed statisticall~ signif~ant diffc~cn~s with respect to the following characteristics: inhalers are more concerned about Shell health, tend to believe that smoking is h.3rmful to them, arc not certain that they could slop smoking, fccl less rclaxct~ while smoking, smoke more non-filter cigarettes, smoke mote of the cigarette, and started smoking at an earlier age, as compared to the non-inhalera. ~ Among smokcrs and non-smokers, cultural |act,~rs were of impe~tance, parliculady in relation to parental atlitudc. Smokers of both ~cxcs had fathers who smoke more often than was the ca~c with non-smokct~. Women 35
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smokcr~ m~ic frcqucntly indicatc'.t parental rcstrlctions on smoking tha. women who did not smoke. An interesting observation which is di~cult to eva~uate is that most ~kets did not re~tt ~ing inflected by ~h¢ publ~d findings of a ~fionship ~ween s~king and ca~. Thb alfi.~ ~ems ~cau~ some o~ ~hc ~s~n~n~ who ~ ~es~ndcd nonclhc~s admitted co~ccm over health. ~is ~nding may ~ in~ucnccd by the fact that ~ op~ in ~c~ral cx~bit more health concern but ~ not nccc~riJy rclate to their smokin8 V. ' Tobacco Chemlstry and Biochemistry "AFFINITY OF POLYCYCL|C AROMATIC HYDROCARBONS FOR ELECTRONS WITH THERMAL ENERGIF..5: ITS POSSIBLE SIGNIF- ICANCE IN CARCINOGENESIS." By Pro(. J. E. Lovclock, National Institute for Mcdiczl Rcscatch, London. Engl~nd, and Prof. A. Zlatkis and Prof. R. S. Dcckcx, Dcpartmcnt of Chemistry, Univcrsity of Houston, Tcxas. Nmure. Fcbrua~ I0, 1962,'pages 340-541. (T.I.R.C. grantee: Becket) In previous studies (l~ovelock, 1960-61 ) ~t was found that most c~sscs of hydrocarbon had litt~ or no affinity for free electrons with thermal c~crgics, altboush tbc~ wern s~vcral exceptions to this rule. This paper reports some preliminary observations on the cloctron aJ~nity of Ictracycl~ aroma~ hydrocarbons, a~d discuss~ the possible relationship hctwccn dcctron a~nity ~d carcinogenic activity with these and other compounds. Th~ results of the experiments Indicate that among hydrocarbons cJ~s o( polyc)~clic aromatic compounds is unusual in jx,'s~cssing many mcm- b~ with a high affinhy (or |rcc erectors. So far, most cx~:rimcntai work and thcot,:tical consid~ratinns of :,~c electron distribution in th~se com- pounds has bccn con~cr.'.~d with their ~ndoubt©d ahi|ity to function as c~ctron donors. This fact has tended to overshadow the essentially ~.mbiva- lent character of the ix.lycycih: hydro~rbons in electron transfer reactions. It was su~r~tcd in the previous studies that the toxicity or biological activity of compounds with high electron af~nlty wa~ attributable to their abUity to function as irrcvcrsihl~ electron traps, so that tl~ norton| transfer o! electrons durin~ oxidative phos~ho~ylation was impaired. Thc possibility th~z carcinogenic activity is a sJ~clal example of this form of toxic action supported by recent cxpcrimcntai work (Allison, A. C. & L~ghtbowo, J. N~u~ 189:892, 1961). The notion th:t an abifi(y to extract electrons from 1heir nnrmnl path in a livlng ccJl is • ncccsr~'y molecular property of a maio: class of chemical ca~cino~eus is spccuL~tiVCo but is relatively accessible to experimental vcri- ~tion ~ • denial "POTENTIAL METHOD FOR THE DETERMINATION GF ELEC- 'IRON AFFINITIES OF MOLECULES: APPLICATION TO SOME AROMATIC HYDROCAR~BONS." By W. E. Wentworth and Ralph S. Decker, Department O( Chemistry. Uoivc~sity of Houston, Texas. Jour~.d ~ ~ Am,:rican C'hemi¢~/$~/~y, Vol. K4. p-~gcs 4263-4266, Nov. 20, 1962. 36 ' t One of tl~:priu¢ipal aims of this invcstlgation is to establish tl~ mcnlal nature of the electron capture by molecules occurring in a detector used in ~as chromatography. 2he interpretation ~ dcvclo~d~ te~ms of ¢quili~mm ~l~cn thc neutral molccu~s and t~ clcctro~ ~.rclatio6- ship between tl~ clcct~on capt~c ~cic~s a~d the electron a~aitlcs of molecules isprc~ntcd, The ¢csults for a ~ri~M ~romat~ hyd~ar~ns a~c ~mparcdto t~ half wave r~uction ~cnt~ls. If oc~a~ a~ptions a~¢ made co~crning the ratio of the pa~tit~n~ functi~s of t~ negative ion ~ the molccu~ to the neutral ga~s molccu~, t~ c~cffon a~nity of the molccu~ c~n ~ cstimatcd. ~h~ has ~cn carri~ out for anthracene and othc~ ar~atic h~d~ar~ns, a~ the results com~rc fav- orably with ~cccat theoretically calculated values. "~UDI~ ON TH~ BIOSYN~IS OF ~. PYRIDIN~" RING NI~TiN~." fly Thomas Gtigth, Kenneth P. Hcllman, and R~ard U. BTcrrum, ~p~tm~t O( Bi~hemistry, Mi~igan State Univc~fity, ~nsing. Bi~hembtr~. Volume I, pages 33~340, Ma~ch 1962. (T.i.R.C. .g~ant~: Bycrrum) Tobacco plan~ wcr¢ fed Ihfcc CJ~-ia~d ~ubstrat~ to ~t~y their aspa~ic ac~-3~ ~th c~trtbutcd rein.rely ~gc quantities O( r~ctjv~ car~n to t~ pyridi~ rin~ w~tcas p~opri~a~-3~j4 did ~t. 2-Cj~ w~ inco~ratcd into t~ pyzidmc ring to a~ut th~ same ¢zt~t ~tial de~a~t~j~ of t~ py~dine, ring of nic~ine fr~ plants fed aspa~ acid-3-C revealed that as~t~ acid w~ not c~vcrtcd d~cctly to the r~ sin~ ~J~ was ~ated in more than a s~glc ~ifion in ~ r~g. th~c~ la~d ~un~'all ~tfibotcd Cj~ to t~ py~olidin~ r~g of nic- otiac. ~c pat~m of h~ling in ~ pyrrolidi~ r~g succeed ~ p~op~i- onatc was coqvcflcd to ~ct~tc ~[o~c utili~t~n for n~oti~ bi~ynthc~b. "SYNTH~IS OF PYRROLIDINE RING OF HICOTINE ~OM SEV- ERAL Ct4-~BELED METABOLIT~ OF NICOTi~NA By Pci-Hsin$ Mn Wu, ~homas G~iSth, and Richard C. BTcr~m, ~cmical La~ratoff, M~higa~ State Univc.ity, ~st ~ming. ]ow~i Biological Chemb~, Volume 237, pages 887-8~, March 1962. Actinic, ptoprionale, glTccrol, and aspanale were util~d b~ r~tica for sym~sis of Ihe pyrrol~inc ring O( ni~e. When ~ta~-I~t~ was mcta~li~d by ~ plants over a ?~ay ~ri~, 95% of t~ Cj~ inco~ orated into nicotine was I~atcd in the pyrrolidine r~g and Ibis was equally divided ~twcen ~sitious.2 and 5. ~c I~at~n Of C~ in t~ pyffolldino ring abet [~ng ladled acc~te, proptinnate, glycerol or aspaaat~ for yawing ~ti~ of time was c~s~tcnt with ~c by.thesis that thc~ ~ta~lit~ wcrc convc~cd by way of colysls and the tr~at~xylic •cid cyc~ to alpha-kcto~utarat¢, and a symmetrical intermediate, ultimately to ~icl~ ~c pyrrolidinc "A~OXIDATION OF NICOTIN~ !i. PRODL~ AND PRO~SED MECHANISM." By F. Paul Gavin and Ro~t H. ~nn¢ll, ~pa~ment of 37
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Chcn,ist,y. Univc~fi|y of Vcrm0nl. Uudington. Tobacco ~ci~nc~. Vol. 6. pages 28-31, February 23. 1962. (T.I.R.C. ~anlcc: Nicotine wa~ va ".ram dislil~d and oxidized by Oa at 40" C. pr~uc~s wcrc s~udicd by ~r chromatography, in~rarcd :~ct~oscopy and gad Fisher lilrafi~ lot wact. About 20% ~ I~ Oa ap~arcd ~ colinin~ a~ ~r 20~ aS oxynicotine, w~reas 30% ap~ared ~ wa~er. An ua- stabk hydro~mxi~ ~ proud. This cou~ split out walu to form cotininc, H:O~ Io form an unstable diradkal (which could Ihcn [cact [urlhcr to lotto higher m~ecular wcighl ~:s and ac¢oum lot ~hc bahncc ~ Ihc O: c~um~ t~n) and Ihc H;O: wou~ I~n react with nicoti~ Io form Ihc ozynicotinc. T~ reaction h ~lkvcd m pr~ecd by a hoe radkal mechanism. "R~IDUAL ARSENIC IH SOI~ AND CONCEH]'RATION IN T~ DACCO." By H. G. Small, Jr. and C D. McCan~. ~parlmcnl of Soil ~kncc, Norlh Carolina Ag~tural Ex~ri~nl Stalion, ~mlh Cmolina State Colkge, Rakigh. Tob~¢o $¢ien¢¢, Volume 6, pages 34-36, March 9, 1962. (T.I.R,C. ~antec: McCan~) ~nicah were.removed in 1952 horn lbe list of [ecom~n~d in~c- tki~s for control of hotnwor~ on tobacco and confiderable ev~e~e ~dicatcs ~at since I~t time t~rc h~ ~cn a sharp dcctca~ in Ihc arsenic content dl cigarcltes. T~ ~jcctiv~ of Ibis study w~c Io cvalualc the ab- ~tion ~ ar~nic by I~ a~ to ~in an estimalc ~ Ihc r~ual Icv¢h of ~scn~ in :¢ptc~ntalivc soils u~d for tobacco pr~uction in North Carolina. ~hc su~ey'i~iu~ all ol t~ major toba~ pr~ucing areas Ih¢ ~talc. A~ in ~il was f~ to zange horn I to 5 par~ ~r million, with an average f~ all areas of 2.a paris ~r million. This value h clo~ Io the 4 parts ~r migioa re~ned by G~eaves,,J. ~ (Bio. Chem. Bull 2/8:519-523, 1913) for a virgin soil andlhus su~csts no incase;able iocrea~ Imm previous u~ o( ar~a~h in ~ ar~nic conlent o[ ~ils u~d for tobacco. The a~ak co~¢ntrat~n found in Ih¢ cured leaf in tobacco grown • e~ ~ils is from 0.~ to 3~ par~ ~r million. The average [or all ~mples h 1:~ pans ~r million. ~I~FLU~CE OF ARSEniC APPLIED TO ~IE GRO~t MEDIA ON THE ARSENIC CONTENT OF FLUE-CURED TOBACCO." H. G. Small. Jr. and C. B. McCaals. ~groaomy ~out~l. Volume $4, pages 129-133. March-April 1962. Fk~ and gt~aho~ enactments were ¢ondecled to study Ibe ab ~t~n ~ a~n~ by ~ured I~co. ~ f~ ucalments consh~cd a ~¢k ~ talcs of kad ~nale ( 17% As) equivalent to 3, 6, 12, 24 ~d 48 ~un~ of ancnic ~r t~¢ appllcd ~ thrcc di~ercat soil ty~s h the spring of 19S7. Ex~mcnU wc~c conduclcd on t~ same silcs in 1958 and i959. but ~ a~iiional As was appl~d, in the ~cenho¢~, tobacco w~ ~own in sand cultures to whi~ was added a nutricnl ~iatioa varies c~at~tiom of ~ablc As as a s~ium a~aatc. Dala from the field ¢x~r~cals ~ow thai Ilac co.~alral~n o( ar~nic in ~e creed Ioba~o var~d from 2 ~ns ~r million where none was applied Io~e so~ to a max~um ol 14.3 parts ~r million at I~ 48-~uad rate. 38 There was consideraide varialion in the arsenic dontent of the leaves between years and Iocalions. In general, the coacentralion was highest in thbse leaves grown in Ih¢ sandier soil and dcc~ea~d as the day and ima conical ol soil increased. Phosphorus fe~ilintion also affected Ihe level of As in leaf, the content being hi~cr where fcrt~i~r p~phorus was applied than wl~e it was omlttcd. The af~nk content ~f the aerial portion o( plants gmwa in t~ ~ecn-. ho~ w~ considerably lower than that of the r~, sub.ling t~t t~ lcv~ of As in ~av~ from field ~owa plants ma~ ~ due in pa~t to ~ lack of appr~iable transl~ati~. • ' "DEM~HY~TION IN THE M~ABOLISM OF By llc[~rl Mcgcnnis, Jr., ~nnox B. Tu~nbull, $orcll ~ ~hwaf~ ~n~ ~kc Tamakl ~ Edward R. Bowman. ~paxlmcnt o[ Pharmacology, teal College of Virginia, Richmond. lournal oJ a/ologicai ~Jlry, Volume 237, pages 541-546, Feb~a~ 1962. (T.I.R.C. ~antee: McKenn~) The mcla~lism of (-)-nic~inc-mcthyl~u has ~cn studied in the rat and the dog. Alter administration to the former s~cies, 8 to 13% of the radi~ctivil~ Of the do~ ap~ared as r~pJrato~ car~n diox~e. An cxaminalion of rite mcta~m o[ (-)-nicotine and the int¢~cdialc (-)- colininc in ~th s~cies ~ads Io Ih¢ conclusion t~t the ~nvetsi~ ~ ~linine to demethykotinmc h involved in t~ formation or carla diox~e~t~. ARcr a~inhtrati~ ol nic~thyi~**, ~tininc and ~ma'(3- pyridyl)-~la~awN-melhylbutyrami~ were ~ted from the ~t~ ~ dogs All of the gad~ctivity of ~¢ latter com~und was f~d in the N-methyl group. As a con~quen~ of Ihh and other ¢onsidcrati~ng aris~g from the hydr~ysh of I~ keto amidc in ~ivo may ~ an in~,m~ia~ in t~ Iormalion o[ the ¢arb~ dioxide-C** ob~ in the studies. Ol~er granler: American Tobacco Company. "STUDI~ ON THE M~ABOLISM OF (-)~TINIHE IH ~iE liUMAN." By Edward R. Bowm~ and tler~rt McKennis, Jr., ~panment o[ Pharmacology, Medical College of Virginia, Richmond. lou~l PhatnugoloXy and E~pcrimcn~al Thcrapculic;, V~. 135, pages 3~-31 I, Mafch 1962. After the ingestion ol (-)-¢ot~i~, Ihc male human excret~ (-)- colininc, hydroxycotininc, and gamma- (3-pyrMyl)-~la~x~H-mcthylbutyr- amid. ~e Iwa mela~it~ were imlalcd [mm u~c and ~nlif~d by com- ~ri~n with authenlic c~unds p;ev~usly hohted from ~g urge. The ~ indicate re(as o[ similarily ~twcen t~ dog and the human in mcla~lism ol (-)~olhinc. In ¢onl~ast, however, no dcs~lhykotini~ was fou~ ~ Ihe ur~ of two.human sublets afar oral adminis*ral~n of (-)- c~in~¢. Hydroxycolinine has ~¢n obtai~ for the ~st time in c~ttalline form. ";rUDI~ OH ~IE RESPIRATORY AND CARDIOVA~U~R EF- FECFS OF (-)~OTININE." By J~cph F. Bother. ~ward R. Bowman and Iicr~rl McKcnn~, Jr., ~parlment of Pharmacolo~, Medical College of Virginia, R~hmond. lournal o] Pharmacoiofy ond Ezptrimtntal Th¢ra. ~u:icJ. Volu~ 137. ~ges 313-318, ~p~cm~r, 1962. 39 O I- I- ff I
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An investigation of some aspects of the pharmacological activity o[ (-)-~olinine, n metabolite o! (-)-nicotine. has demomtrated that, in ~nc~hel~d dog, {-)~dnin¢ lacks th~ ~cat p[essor ~tivity ass~ialcd with lhe parent c6m~und. In ad~do., i~ hax ~en ~how. (hat (-)~odnin¢ h~ a dcprcsmt aclivity wh~ w~ nol a~lb~d by otdinay bilking of atmpmc or diphcnhldrmin¢. ~ prcxncc of ~prcs~r aclivity in the decerebra~ and spi~ dog b consblent with the su~t~n that th~ ei~cct may ~ mcd~lcd ~hrou~;l~ abilily o~ (-)~otini~ ~o pr~ucc, dingily indi~Hy, a ~a~ular mu~u~r rc~xat~n. The quandd~ of (-)-cotinin¢ employed (o. pt~¢ the obx~cd phamm~lugical cEcc~s wc;c in cxc~s of amoun~ which w~d ar~ ~ vivo born ~¢ mc~a~lbm of lethal or non- ~ai do~s ~ (-)-n~ti~. "~ilE ~RRE~ED ~RU~URE OF A KETOAMIDE ARISING FROM ~IE METADOLISM OF (-)-NICOTINE," Dy ll~r~H McKcanis, Jr., ~nox B. Tumbull, ~ward R. ~man and ~rcil L. ~hwarlz, De- portent o[ Pharmaco~gy, Medical Col~gc o~ Virginia, ~ichmond. o/~ American Ckem~coI 5~ic~, Vo]. 84, pokes 4598-4599, Dcc. 5. 19~2. The co~ected struclure.o~ a kcloamide i~iatcd born the urine o[ ~gs and later o[ ra~ during ~ cou~ o~ stud,s on ihe mclabolism o~ (-)-n~otinc was established as the mclhylamldc ot gamma-(3-pyridyl)- gamma~xobulyric ac~. ~is evidence, toFcthcr with ~ synthesis o~ the kczoamidc, provides op~rtunilics for addizzonal sludics on Ihc intcrmcdia~ mct~li~ o~ (-)-nicotine. OJ~et grun~orz Amcdcan Tobacco Company "VI. Plmr.macology "MEC~IANISM OF THE POSITIVE CHRONOTROPIC RESPONSE TO NICOTINE." B), Floyd E. I~aders and J. P. Long, Deparmlen! of Phaeton. culo;y, Univcrslcy of Iowa College of Medicine, Iowa Oily. Jo~rna! ol Pkannacbloey and Ezperimema! TherupeuricJ. Volume 137. pages 206-2 i 2. Augusl 1962. (T.I.R,C, grant~: Long) ' The mechanism of the positive chronotropic response to nicotine was s~udi~d, using isolated cat atria preparations wt~h parasympathetic (vagus) and sympalhetic (postslellate ganghon) nerves intact. The cl[ccls of ~anKli- oneclomy and reserpinization on the response Io nicotine were observed. Inhibition of d~c parasympathelic nervous system with hemicholinium (HC-3) abolished bulb the positive and negative ch~onotropic responses to nicoline. Both of these r~pons~s could again be observed aller rcp~aled wasldng o~cr a I tu 3 hour period. IIC-3 did nm inhibil |he ~csponsc Io sym~pathclic nerve stimulalion nor did it black lhe response IO nicoline ad. minbtration when the yogi were no~ stimulated. Gaa~lioneclomy followed by nerve degeueration or rescrplne admin- isler.cd for 2 days abolished the positive chrono~ropic respon,~ Io nicotine, l.unbcr, it was demonslraled thal there was no evidence of nor~plnephrin~ uplak© by the aida after gaogl~oncclomy and nerve degeneration. I lowcvcr, norcplncphrin© upmk© was suggested in a~'ia from coo~'ol animals and those prclzealed wilh rcs~rplnc. 40 , "l'hc involvcmcn¢ of the parasympathetic inervous system in both lh~ ncj;ativc and posilivc phases of the aldal rcspons~ Io nicotine obvlalcs necessity of postulaling" sympathetic ganglia in' the hcart to e.xplain thc~' actions of nicolinc. "l'hc ability o[ Ihe pa(asy~pathctic nervous syslcm to inllnencc sympathetic nervous syslcm activity ha~ bccn dcmo~tratcd. Olker ~rnnlor~ U. S, Public tlcallh Scrvlce. VII. O~her S~udies "SKIN GRAFTING IN ~ONGREL DOGS.~ ~y David B. pilc~cr. M.D.. Warren E. John~n. A.B., Ro~ Ko~s~, ~.D. and Ju~us H.. J~wn M.D.. ~part~nls of Surg¢~ and Patho~, Univcnltv of Vermont Col- lege of Mcd~mc. Dur~n~ton. Piu~u¢ and R~¢~trucUv¢ $urx¢~. Volu~ 28. pages 67~680. Dcccm~ 1961. (T.I.R.C. ~a~t~: Jacobin) Prcpafalmy to the study ~ lung homolraasplanlal~ in ~gs, the ~rimcntal animal of widest choice, it was nece~ to obtain data on leasibk technique of skin graltio8 and ~e~l~ ~ skin autograf~ homo~rafls in Ihe~ animals as a ba~l~ f~ further transplan~tion invcsl*galion~. Multiple cbclc, 3 cm..in diameter wc~c cxch~ from t~ ~a~ back and chc~t wall of mongrel dolt in ~cas relatively i~cce~ible to bil~g and scral~hing. Di~ of skin born ~no~ animals (ho~grafl~) were ~af~d six pgcpared ~ilcs. and an auto, aft inlo a gvcnth ~ile. as a ~n~ol, and four to ~ix di~ of skin wcge ~tcg~angcd on the ~me aa~al (autoHah~). On gross exami~linn Ihe homo~ahs and aulograhs were ind~l~g- ubhable at 8 days. and by 12 days ~8inning ~gencratioa wts ap~rent the ~mo~alu. Mediah ~u~iv~ ti~ of the ~lt~ was 16 days. All homograhs were sloug~d by 24 days. in addidoo Io a ~dpfion of Ihe ~tcp~ inv~vcd in ~aling or gcjcction, t~ mkro~opk a~ly~h taught Io antwc~ I~ queslions: ( I ) Can one tell an auto, raft h~ a (2) Can one Icll inleclion from homograft ~cj~t~? (3) Can ~e dis- tin~ish viab~ front non-vlable graft'/T~ answer i~ a quailed yet in all cases. Viabilily is cosily dete~ined by ~fshlen~ ~d gegeneralioa of dcrm~ and skin ap~ndage~. "FLYING-S~T INTERFERENCE TELEVISIO~ MICROCOPY" By P. O'D. Monlgumcry and L. ~ llundlcy. ~paa~nt of Pa~o~. Uai- vctsily of Texas. ~uthwcslcm Medial ~h~l. Dallas. ~alur¢, ~m~ 16, 1961, pagc~ 1059-1060. (T.I.R.C. ~anl~: Monlg~c~) The aut~r~ dcvclo~d in their ia~ralo~ aa tll~leclr~k flying-~t ~lcrlc~n~ ~lcv~ion mtcm~ for Ihc rap~ determination ~ ccHu~ dr~ ~. ]~e syslem devi~d has several advan~gcs over prcv~udy dc~ crt~d tcchn~ues: (I) ~e ~ta on d~ mass o~ whole ~ of ~en~ ~lls ~e oblained and recorded by two melh~ eve~ 10 ~oad~ (2) dry-mass images o~ I~ s~c~ca are cond~u~sly d~playcd on ~e moait~ tu~ du~ing ~ cou~ of the ex~rimcnls. (3) ~e v~ual ~n~n the d~-ma~ ~tage ~akcs ~itioning of ~e bri~tcned area ol ~e gas~r q~ile easy, and this ~mdls coal~uous dclc~adon ~ ~ d~ m~ ~c~d ~c~ ol ~c C] u" I C.
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OIAer 8~nlor~: Atomic: Energy Commission. 5outhwcslcrn Medical Foundation, :nd D~m~ ~unyon Mcmo~l Fund. '%N ULT~VIOL~ MICROBEAM TELEVISION SYSTEM." By W. A. Bonnet," University el Texas ~uthwcstcm Mcdical ~h~l, Dallas. Tc~. A~b el I~ New Y~k Aca~my el 5ciendes. Volume 97, pagcs 408~11, June 5. 1962. (T.I.R.C. ~amee: ~. O'B Monlgomcff) "SIMULTANEOUS ULTRAVIOLET AND VISIBLE LIGIlT FLYING S~T TELEVISION MICROSCOPY." By P. O'B. Montg~nc~. vcr~y of ~cxas ~ulhw~lc~n Medical ~h~l. D~llas, Text. Annal~ t~ New York Aeadem~ el ~clencrs. Volume 97, pages 491-497, June 1962. ~ pa~rs dc~fi~ a versatile tclcvisiun system in which an UV cm~dng ~nncr tu~ rFplac, the sourcc and p[imary a~nure el "conven- t~nal ~ micr~am sysl~, and moth,s o[ obtaining simuita~ous iUumination o[ ccllulu ~ns by dilIcrcnt wave lengths el light, which pre~n~ d~tinct adv~tages in biological study. In order to view a s~cimen simulluneoudy in two wave ~nglhs o[ light two scanner tubes ar~ employed, one ~mitting UV light and ~ other visible light. " O~er granlora~ Atomic ~r~ Commission~ Damon Runyon Mcm0rial Fund for Cancer R~arch, ~ the ~uthw~slcm Medical Foundat~n. "PERIODIC FEVER, AN EHTITY. A COLLE~iON OF 52 CAS~." By Hobart A. Rcimaan, M.D., ~part~nl of Medici•c. Hahncmann Med- ial ~l~ge and Hmpi~al, Phi~phi~ Pa. American ]ournal o/the ieal $c~,~, Volum~ 243, pages i 62-174, F~rua~ 1962. Pc~ic [cvcr w~ pro~cd as an entity ~pa~te from other d~dcrs ~ 1948 and fu~r substanfalcd by the d;s~i~ion of ~2 cases ~ ~s ~y. Pcri~ fever ~ ~;rac~riz~ by rc~titive lebrilc cpi~cs ~ antennae nc~ous disturba~cs in prcd~labl¢ cycles o[ days, weeks mon~, ot ~¢~latly, ~ ot~ healthy ~ns. It also may ~cur m ~t~nts with ~ign~t or ~er chronic di~e. It b ~cdhaff, ~8i~ ~t ~n~ lime of life, may last for decades, and m*7 h~v~ Ion[ s~tan~ul ~cm~ss,o~ ~d m*y c¢~. A~ut 10% o[ vlc- ~ms died, usually in • sh~-Ii~c ~tal~. ~hcrc is no satisfactoff treatment ~ the cau~ b ant•own. T~acco played no role in any of the vktims who tcadcnc~s or miFai~. Th~ Ingather wilh evidence of c~cbral dys~hythmi, ~ abnormal ncuruv~ular ~cs~nsc~ suggests the site of mlgin to "HEREDITARY PERIODIC EDEMA. Tile I~ERRE~TION FAMILIAL PERIODIC DI~RDERS." B~ IIob~ A. R~imann, M.D., ho[c~r o[ Medicine and P~cvcntlv~ Mcd~inc. II*hnem~nn Mcdlc~l Col- kgc ~nd Hospital. Phlisdcl~la, P~. Ameeican ]ou~al el i~ Medical ¢~¢~, Volume 243. ~agcs 727-?~9, Jonc 1962. " ' A nU~r.ol [¢llurc$ gu~t ~n imcff~ladon ~twc~ ~r~i~ cdcm~ ~d siz.or mm¢ olh~r ~ ¢ntides disused in this r~vi~w: Each m,y ~ months, ~:~UI:t dlslurb:nccs, ovcd:ppin~ [ca~urcs. g~ h~h ~twcca 42 episodes, long duratio, with temporary or iXrmancat remission0 and similar h[stopathologi¢ and clcctw~nccphalograph*'c changes. . Whclhcr this group of condi|io'ns a~c unified on the basis of a commo~ underlying pwvocativc rhylhm or arc rcgulai-.d by biologic clocks solution by new invcsligativ¢ mclhods, if gcr.ctic factors are responsible, the chances of Wcvcntlng or curing periodic d~5ordcrs by means other than th~ application of cugcolc prlnciplcs do n.ot seem holxful. "TI IE LOW-FAT DIET. FOR PERIODIC PERITONITIS." By Hobart Rcimann, M.D. ,4merlcan Journal oJ (3a~tro~nterolo~7, Volume 38, pages 8:5-90, July 1962. Fourteen patients were given a 20-g~am ~at-dh:t; cpi~des ot pe~lic peritonitis were stopped in four. were milder and farther •part in two. ceased temporarily in three, and wcrc not affected in Six. None of the victims who smoked tobacco noted any influence of it in his disorder' Alcohol lelicved the" symptoms slightly in some. VIIi. Review "THE ACTIONS OF NICOTINE Olq CENTRAL NERVOUS SYSTEM FUNCTIONS." By H. Silvette. E. C. Heft, P. $. l.anon and H. B. Hang (deceased). Departments of Pharmacology and o/Neurolog~.al Science, Medical College of Virginia. Richmond. Pharrnacolo&ical Review& Vol. 14, pages 137-173, March 1962. (T.I.R.C. g~antee: Ha•g) ' Th~ is a lcvk:w o| 184 ~i~ntific papers and testifies to the many lacunae in knowledge on thc ncuwpharmacologicnl effects of nicodno administcxcd to humins and to animals. "[hc pharmacology or toxicology of ¢obacco- snsokin$ and pharmacology and toxicology of nicotine axe not identical. and often ate not cvcn comparablc. Not only does tobacco smoke contain many oth~r ingredients, known and unknown, with distinct pharmacological actions of thc~ own, but the dose of nicotine contained in the smoke is not ~eally ascertainable, though it is often cstimatcd. Since this ~cvicw is conccrnedwith the ncurophann•- cology of nicotine, the results of *'smoking" experiments are not mentioned. except in special ckcumstances, and then only ilr these ~¢m 1o be equivalent to ~csults obtained in contwllcd, quantitative experiments with nlcodne. An account Of "smoking" expcximcnu in gcncnd was published in Tobacco. E~perimemal and Clinical $ludi¢a. by I.anon, Hang & Silvcttc (Williams & Wilkins Co.. 1961), in which must of the data on the •cure- pharmacology of nicoline to aleut mid-19$9 also appears. The present critical review is designed usefully to fill the gap; In gcnclal, small do~s' of nicotine have • stimulating action on the central ncrvous s~,stcm whereas la~gc dcncs dcprcss. This review covcm spontaneous •ctiv,ty, conditioned rc~cxcs, icarnmg, higher cerebral func- trans, medullary functions, ccrcl~llar functions and spinal functions. 43 ~ C) I- I- uo I I-
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Recipients of Grants ' Following is a list og all recipients of grants approved by the Scientific Advhogy Board since initial grams were made in lalc 1934. 1¢ should be noted that some of Ihc proj©¢tt hay© Ixen completed. AND INSTITUTION CLARENCE M. AGRF..e~ M.D.. Cn~diowucular Laboratory. Vclcran$ Ad~nisltali~ ~cnlcr. I.~ tint. Univu~ty of Calit~, L~ AnuI~ llon Rc~iliC~lioa Ccmcr. While ~ T. AHGE~KOS, bI.D., Ph.D, Ass.. elate Proltssor Univgr~ty ~ og Mcd~. ~1~. D. MURKY ~NGEViNE, M.D.. Pro. .~EPHEN M. glul~aty ~borutory. Sl. V~CCAI'I FREDERICK W. BARN~, Jn., M.D., PII.~.. AI~t Proles~or u~ Medicine ~d Pkysidagffol Ckem~try. Jo~t IIopgins Univcrsily ~1 o[ Mcdi. clue. Ualli~c, Md. Medial ~cncc, ~own Un;vclAly, P~ov~c. ~. i.) RALPli S. DECKER. P,.~., SAMUEL BELI.ET. M.D,. v~ion ol C~diology, Philadcl~ia Th~ effect o[ nicoliac on prolcln and amino acid mclab~m in humans The role of hypcrplasia in lls~ue rcspon~ Io chloni¢ daul~ge.(C- P) An invg~lll~lion of the spCCliaJ a,ld chromalolraphi¢ characlcriztics ol aromatic hydtocall00~, (P) ~ Ihg ~¢~n¢c of Ic~rp;~. and Ihc el- (col ot n~in¢ ~ c~onary bi~ flow or do~ with cor~/y in~u~ic~y IC--P) ~ccl+ ol n~ofinc ~ the ~plmloly ~ ¢~¢Cls O{ ~iC0lin¢ ~ human a~ ani- mal plasma; ¢~¢c1~ o( ¢¢i~ul;On ol 44 CILANTE£ AND INSTITUTION HYLAN A. BICKERMAN, ),i.D.. Ass~- ek~t CIJMcM Prolix.or ol Meditln6 a~ ALVAN L. BARACII, M.D., C~umbis UnJv~ty; ColumbiJ Re- mr~ ~ G~dwat~ RICHARD L SING, M.D., P~o/eu~ ol Meddle ~d C~irma~. ol Mid,Int, Wa~t Slate 'Univcttily ~kl~ o~ Mcd~ Fi~ 'i~) O. DOCK, M~. PaLD+ Scnkv I&M~ F. DONNEE. PII.D.. Ptotts~t o{ a~ol~. Ca,t~ l~utt ol T~h- ~ut ~bota~, Chtmistt~ De~tI. mesa, No~' Carolina ~ac¢ Collc1¢. JOSE~ BROZEK. PII.D.. Pralt~r ~d ChaPman. Detriment ol r~ych~ogy. ~ M. a~. M.D.. Ptol¢~ el oly, Unjven;iy of ~uthcm KICliAMD U. IIYEKKUM. V,.D.. ~ O/ Chambray. Mkld~n $1aI¢ 0;+I~I~. ~I LI+I+oI ~ c~cctto! mnokbl oa m~l+ (P) ~c: M ra~cliv~d ~ow ~ ~ wi~ ancr~r~k on s~ ~ m~ ~ h~n F~ matlc ~tudy of mcthylafion reactions plant ti~u~ (C--P} ' , TDE and endrin rcaidu, in ci~cti¢ smoke (C--F) Biolo~cal ch~mclcristlc~ o! men jnd thclr 45 C Lt C
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0 0 LI, 91, "(1'11,1 "|'/IIIV.'~ ,q.'lll~::! "If MOI,£~ZI.LRhll (1NY ~.3',LNYIIO,
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CRANTEE AND INSTITUTION LAWRF.~CE L. lIES', .R, Ja., M.D., ProleaJo, ond Chm'rmn. Dep,wLn~nl o! Ob;tetrlca ¢~d Gynecolo&y, Medical COIIcig O| ~0ulh Cal.ol~nl, Chat!e$loo.. EDnE CURTIS IIOFF. P,+D., M.D., o! HrwololpIcat .Tc~t~c¢. Medical Col- Icic og Vi~linia, RichmomL RU,SSELL t HOLMAH. M.D.. ~or ~d Ilead. Dcl~r#menL ol Pmkol- ogy. ~siana S1~¢ Univcnily ~ o( Medicine. New Orkanu FRFI)DY H~MBIJR~ER. M.D.. dent, Bi~R~ar~ I~filuic, I~ Cam- gOBERT W. HULL. PJ~l.O., A~oc/me PtoleJJor. Dep~lmtm ol 8~dogicnl .~¢~n~¢, Northwe~tun" Univm~ly, Ev- anston, IlL ' JERKY HART JACO~ON, M.D., Di- recto~ ol F.l~cuophyslolO#yo Ncw Ymk Ey~ ud g-r In~rm~¥, New York. JULIUS H.'JACOBSON II. M.D.. c~.'¢ Prolt.,oe oJ 5~tr~y c~. Univ~sity t~ MURRAY ~ JARVIK, P~.D.. ~N~REW PROJECT TITLE Th~ g¢lationship of the m¢ o! tobacco pruduct~ to the outcome o| pregnancy Cerebral autonomic changcs Igoduccd by Iobaeco smoke, nicotine or ¢olinine. s illCl~l~O~jle O[ IiJgUi.illg Patholog~c--snatomk study of cellular • changes in human bgonchi IC) The influence of tobacco smoking on ~utc myo~n~dlal h~fa~ctiua (ca Studig~ on carcinogenesis and, the bio- assay or carcinogcnk a|cnts (P} Comp~rallvn slud~cl ~ off.iS Ol varies tob~¢o ~okc ¢~dc~utcs on uki~ ol m~e (C) ~ystem~ cflocts ~ ~r~ tobacco smoke condcn~i~ (C} r~am~ ictival~ o[ ¢a¢cinogcnic hy~: assay (b) invcsfi~li~ o~ Ihe ~chanisms ~ lclivallon ~d ~n~ ~ iromat~c c~cino~c~ by ~mm~ (P) ~ in~uc~ o( cc~in cnvironmc~lal childi~ A ~ri~ or el~tr~etinojraphy I mc~s Of cvalual~ t~ cfl~l of vu~onsU~t~ dru~ u~ ccfcbraJ 8~ ~ctinal cbculal~n with ~hcr t~iq~ for ~ ~t~ (C) Lung ho~gansplan~l~ Pilot study or habituation to nicotine by mg~s ol ehm~us monkcys (C) To dglgrm;~ to what extent tobacco 'l~l' m;m~cs the ~llo~ or ¢lfg~gCfl~ hyd~ar~s in ~ ~kin and o~¢r tiu~s tO) 50 GRANTI~ AND IN$'~l'i'trrioN ARNOLD R. KAPI.AN. P,;D. Director, i.abo~atory ol Medic'a~ G¢~tic*. Clcvc- land psychiatr~c inltilutc and limpit~l. ELIIIU KATZ. PII.D, Associate Pto[tJsor ol 5~,.dog7. Un;vg~sity or Chicago. ANCEL KEYS. PtI.D.. P.ole~or ol PAys- ~at~ ot pkys~ot~al Ilyx~. Uni- Hcil~ JOSEPH B. KI~NER, M.D, Ptol*~or "" ol M*dici~, Univ~y KENHETII P. KHUD~H. M.D., A~- Wa~.; Ptolts~* ol P~:~aaT. Um- vg~ly Og W~lt~ M~I ~, • ~L~IH L Hew RODERT A. KUIIN. M.D.. All ~ul* MARVIN KU~IiNER, ol P~k~ot~. New Ymk Uaivcniiy C~lglc of ~ololy, ~l~v~ a~sl~t Pro~t~r Ph~I~. o[ p~kolotY. N~lhw¢~crn Uiivcrsiiy mini O[ PuJAoloIy. PAUL S. LARCH, P~.D., Ph~macolol~. ~al ~llclc O~ Vil- ~, gJ~ (~ Mcgcnnis) PROJECT TITLg Examination o! the extent 0~, and co~- llituiional basin f~, cmrdat~ ~- twccn ~ f~lowini: (I) a~c ~ got quinine a~ 6.N.~opyUh~r- (4) f~ d~ik~ Ihc tra*~dati~ og m~tv~ ~to ~0 g~¢ O[ I~O lmkJn8 U~ b~ Patholol~--a~ st~y ~ ccflul~ c~s~ in hu~ bt~ht {C--P) sgctt~ ~ke Effccl of ci|ageit8 smokc ¢~ pulmonary cl~ara~.~ Prep6rntlon for publlcatioa, og s book the b~o~ ,s~U oi ~ 8~ *mkini ~matic u~fmm,~ of n~ ~col~ ~ ~bg ~ 51
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£f £q mp~l• i~. ~ I° primo= ~IO=LrV (:3) (d--i)) lo!~.lqiq pl:lnpil.iuilliUelOll~lltqllul oo liinp!, .~.p giluow|nd l~ue llopiI lelUilulol!~lll~ Id) :mllO)!,u |o ll~illt llln~llxm, pii"~ (d) O~lU ~ mpepliolnl ~ iIi~lO~! ~ IMDI =u~sn *~lellq~ aqo~ ~ ~J~ IIn3e ~l lu!mp lUll ui!~iw ill u! i~lq ll!i.iill!~ ill ~ m Im~l I~q:~iq Ill ~I~ lo itOWl IIlii~!~ ol I~li "l~l~/U! (4) (ml '~m) l~wlUl I!jIl~I Io I!lilll Ill uo ~ 1~1~I io Pii) ~ Is) jo • ~! ~111lll~ ! :l!l!t~l I! "lil II 'll!ll~Oil! "l,lplloH rlmil 'l'4,1olill~ll'l ll,l.~ "f "N '1i!3 li~l:! "t ,~410. II Io ~lllOD
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CMANTE£ AND IN~i'ITUTION WILLIAM S. MURRAY. Sc.D.o ~¢. DONALD M. FACE, PIED.. Joe C¢Ilul, w R¢~*o~ch, Univcrl~ty Ne.br~tl~, Liocoln. MARTIN ~. PROTZEL,, B.S.. D.D.S.. Mllrtland Medical Center, Newark, WALTER REDLS~||. M.D., New York UnivErsity R~.arc~ .~r4c~, Goidwa'r Memorial H,~.pitsl. W¢llar~ New Y~L HOBART A. REIMANN, PI|I)|ECT TITLE "1"1~ productkat ot lenetlcally conlrollcd ummals and tumor's Ior to ~:allh (C)" goad;l~oal ~¢llowshJp tot train,S ~ liuU¢ cullug¢ Igchn;qu~ ~udy ol the Cll¢¢ls O( I~acco smoke constituents on v~iu~ ~ug celia gull~v~lgd ~ vJiro (~) study of slguclurc-acfivity i~$ dru~ which i:gllowshlp~ for study;,,| the culture human luo! liuu¢~ nnd Ih~ cffcctt known nnd po~ble c~rcinoSCniC u~n s~h t~ (C--P) Pllhololi~nalom~ ~udy o[ cellular ¢hln~ ~ h~ln brecht (C--P) AppllcM~on of a new blowsy Icchnlq~ ~ csami~fi~ o( ci~telle ~oke c~- a ~mpe[~ o[ l~i. i¢l~n~ to ttiadardizgd ~i[. ol ~pplicil~. ¢om~r~l/v¢ study O( Ih¢ cflccll of ]- mcihyichol~nthrcng and c~prgite u~kc c~dcn~lc ipplkd to I~ tion~ with ~ol and/or V~ul~r rgs~ngl to tobacco smoking The po~lbl¢ clfcct of tobacco or nicotine in periodic disordcra, a ncwly- recolnizgd |yndrom¢ (C~V) 54 R. |i. RIGDON, M.D., Prol¢~or ol ~hoiogy and Dwector. L~boraJor~ o~. T~ Medal Brash. Galvcsl~. SYDNEY C. RI~ENBERO. P,.D.. l¢~or ol ~lcriolo~. Onlvcnily ~t~m Calif~, Lm Aalcl~ . BEN~N B. KOE. M.D., d~t Pro. le~. U~vc~y o( ~lil~h ~h~ ot M~ ~a Fr~ BE~J~I~ ~ ~UBI~, F~.D., ~- ~ rrolr~ ol Publ~ ll¢~h vzlo~ Wy~h ~~ ~h~" HENRY I. RU~EK. M.D. C~la~t i~ C~d~v~u~ Dbg~, U. S. Pub. $~t~ Ida. N, Y. Tu~ lasthme. PAUL D. SALTMAN. P~D.. P~oIt~ el B~k¢mlJ~. Usivcrs~y Of ~rl Cdiforaia ~ of M~- ALVIN R, ~IIMIi)T, 55 Ea~xk~d su~u (eccup~tio~d), u~b .~.~. ¢hul~ ia human Iwcmchi (C) (D 0 0
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CRAh']'EE AND i/qSTITUTION ~AAC ~CIIOUR, DJ).S.. P..D.. D.Sc. ProI.Jor ol ~ ~to~o#y ~d £m~o~o#~ Iclc ot []¢alhUT, Chk~go. MAURJCE S. SEOAL, M.D., Clinical Prolr~or ol afcdici~t, Tufts Un;vcr- Director, Dt~rlmtml o/ I~aliom ~epulmenl o~ Nulrilioa, ihtvard ClIAILE~ E. $11EIWOOD, M.D.. sity of Rochuicr Schod ol Mcdkiu ud DcotisUy. Itochca~, N. Y. PROJECT I"I ud aa.I I~u~ ~ es~rimcnld sni~ls subjcc~ Io I~s~ smok¢ ~ in ~mal wi~ ~r~in rcs~r~ry dim~ conS- I+ns chloo~ (~S~livc) ph~mu (C) H~ud.J~ ilopk~ m ol mh prms, ~¢ carl;at ~ gchl~ip mk~l m the ~r~ov~ ~ ~n (~P) ~y. ol dmt of T~¢ pu6fica6on and slruclur¢ deisms. IJoa of the chlo~o~cnk n¢id ~ Eap~meulal liudia of unccr ulili~l i new lechakiu~ Io u¢~ J vir~oul 'l~n" ¢aita¢lcd (tom Iob¢cco may in. clio I~c Iormulioa of lunl lumn (C) 56 GRANTEE AND INb'TITWrlON C. iiAIOLD STEFFEE. M.D.. ol I,abo~atntic#." Mcthodbt Ilmplt"t, Mcm~l .~s. Tcu. lACK P. STEOHO, M.D., U,ivcnily ~:ho& d Mcdkin¢. Od~ (~ ~mm ~ McGiU) Ymk Uulvir~ly-~lgv~ M~I C~" TISSUE CULTUIE ASSOCIATION JAMF..S £ P. "rOMAN. P,.D.. Assacilte P~oleuo~ ol #kpiolot~ and cototy. C~--lo M¢di.l School. JANE~ TRAVELL, M.D., Associate P~O- I¢~or Of Clinical PA~mucology. COP ~ll Unlv¢~iiy M~d~l C~1c~¢, Y~k. ~tY, ~ate Univ~r~y o[ Iowa I¢~ o[ M~n~ lowu Cily. $111ELD,5 WARREH. M.D.. Director ol t~o~atodo, CaT~tr Rese~rck ln~i- I"tt, New Llillisll~cl I~llColi~ ~Oe~;LE], PEOJECT TITIZ Studha of ~.olg~dl c~vclopmcul of nlhcrc~'.lumis u re. vc£ul by &ulopff d v,,ci&:nl vk:iin~ Iwe¢~' 8mo~m ~nd lion.noUn PildlO~il~--lllilom~; study d r~lhdlt chn~ in human Monchi [C--P) Correlation or bronchial epithelial c~aalr.s with, comp~ribi~ cllug¢l hi mhcr ~xluu~ patholoj~c-~atomk lt.d~ ~ i~ttgm og llglulllb og 57 o) tO 0 o
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Ie ~o'~lo~d "Q'I'~ 'J.I.VXIA "d NllOf '~m.r~qd Io I~Xl:~ "RJIop~w~m~d ~o
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CTR-STRTE OF FI_ [lie 1"1"~1::1 60043471
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TABLE OF CONTENTS Page Ptefac¢ by Dr. C. C. Little ............. Progr,'ss of Rescarch Cancer R©~arch ............... $ Human Lung $~udies " ' 16 Catdiovmcular Sludie~ ............. . 17 Psycho-phydolo&~ 5ludi~s ....... • ..... 22 Tobac~ Chcmb[~ and Bi~hcmislry , t ....... 22 O~h~ Sludics ........ ~ ....... 23 Absi~acls of Pu~bhcd. Rc~s ~ C~r Re.arch ....... ~ ....... 24 l[u~ Lung S[udics ............ .. 32 Cardi0va~u[at Sludics ...... ,,~ ....... 34 Psych~ph~siological Studic~ ........... 49 Tobacco Chcmi~lty and Oi~hcmis~ ..... . . . 50 O~hcr S~udics . . ' ........... . . Rccipicnls o! Graa~s " 60
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SCIENTIFIC ADVISORY BOARD to the Tobacco Industry Research Committee KENNETH MERRILL LYNCil, M.D., SO.D.~ LL.D., Choir.san Chancellor and Prole~or ol Patholo&y Medical College of South Carolina C'hadcston. South Carolina RICHARD J. BING, M.D. Pro/eJ~or and Chairman. Department Of Medicine Waync State University College of Medicine Detroit. Michigan McKEEN CATTELL, PII.D., M.D. Pro[es~or Emerllus o[ Corncll University Medical College New York, N. Y. LEON O. JACODSON, M.D. Prole~or anJ Cha[rm~n, Department of Mcdicine, Univcrsity of Chicago Dir¢cwr. Argonne C~nccr Rc~carch Hospital ChJcaso, lll~-ois PAUL KOTIN, M.D. Paul Peir¢¢ Projector o] Pathology Univcrshy of Southern Califonda, School of Medicine Los Angeles, California CLARENCE COOK LI"Iq'LE. Sc.D.. LL.D., Ltrr.D. $ciemi/~c Direcwr, Tobacco Industry Research Committee Director Emeril~, Roscoe B. Jackson Memorial Laboratory Bar Harbor, Mainc STANLEY P. RE[MANN, M.D., Sc.D. Director Emerita. The Institute for Cancer Research Philadclphia, Pcnnsylvan~ WILLIAM F. RIENIIOFP', Jn.. M.D. Johns Hopkins Uni~crshy Sohool o| Mcdicin¢ Baltimore, Ma~land EDWIN B. WILSON, lh,. D., LL.D. Prole~Jor Emeri¢~ o! Filal Harvard Unlvcrs~y Cambridge, Ms~schu~c~s ROBERT C. HOCKETT. P,~.D. J. MORRISON BRADY. M.D. ,4~ocia~e $ci¢mi~¢ Director A~ocia~e $ci~mi~c Dk¢cW~ Preface A mon'ograph on cancer morbidity', i~ucd by the United Public ElcahhScrvicc, commented on statistical and cpidc.miolo~icai dam as follows: "In Ibe 'study of cancer, a discas~ that apparently C~n bc induced by a multiplicity of etiological agents, one cannot real-. istlcalIy expect to do more than identify factors that appear to bc frcqucnl|y associated with canccr. The proof of' an etiological rclatiooshlp must then be sought through, more intcmiv~ c.linjcal or experimental studies." This is s.ubstantially the position adopted in 1954 by the Scientific Advisory Board to thc Tobacco Industry Rc.~arch Commlttcc. It was rcallirmcd in 1960 and rcmains unchanged at the prcscat time. it is a position that also is held by many others, including statisticians and researchers. Dudn~ Ihis period significant evidence of ~/arlous po.ib .1~ contributor/ causal factors in lung cancer has been accumulating born both statistical and experimental research. Previous lung infcclions, air pollutants, 3cnctic facl'ots, stecss, hor- monal influences. Viruses, diet, and other po~ibic inffucnccs arc being investigated further and. as thcy a;c, a morc ~uratc pcrspectivc of the whulc picture of lung cancer causation is emerging. "Fhcsc f~ctors arc not cited either to answer or to cvadc the question as so what tok, if' any. tobacco may havc in the,origin of lunlt cancer. They do not and will not deter the Tobacco ind~sw/ Rcscatch Committcc from continuing to support indcpcndcnt research which is tryin& to answer this question.. i.unx C~¢cr OriKi#. i~ Consplez and Obscure The present si,uation emphasizes thc truth of what wc and others have said relatedly. Thc origin of lung cancer is complex and still obscure. There probably arc many contributing factors. However, dcvclopment oI research into various aspects of thc lung cancer program has had to be carried on in ~n unusual and son.times licult psychological climate. This came about bcoausc there arc those who would insist on acccptin~ ~s a proved fact thc hypothcsis that cigazctte smoking rcprcscnts a primary causativc factor in lung cancer. This group e'Mo~bidil¥ |tom cancer in the Un|tcd St~les." Public Hedlh Mo~osrsph No. i)cpseemen! o( II¢~hJ~ Educ~tio,s s~l Weir, see. 195~. Wsshla|toa, D. C.
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C -~Jd )o so~Qxoldmo~ pu~ ~o~s ~I s~l~l~nil~ ~n ~I ~l~q~ "~u~molloj "'~)'~'I'.L ~1 jo s~o~p ~gpu~ ~l~m~ oq~ ol pu~ 'p~,~ ~m~ppV "llU~ml~u I~UO~lnQl~UO~ J~l~ ~u~ ~p IJ~ "s~auea ~ sa~U~ll~:qa ~ql Ol sUO, lnlO~ I~mlU~ lOJ ~Oq iK3J :l~,pm "~lluiIo3 lql InOq~sql ~l~lU~3s ~q p311od3j su *Jn~X Isled ~ql )*) s2u~pu~ aq.l. • ~pem ~u~ s~ ~aJ~oJd '/iac~l,) "sUO~l~nh ~11 jo ~u~pu~l~J~pun ~011~ ~ej e "p~l~wo ~ ue~ so~U~lleq~ Xuem sl~ ol "~l~lU~ "UO~le~ne~ a~ue~ )o S~l~q ~ye,uRop pue ~u~d~a~s ~eq Ol alO]~ IUO~DUn] ~le~llU~ ~m ~e I~. q[ ~eld~a pue ~RI~e l~nm pun • s~oso,umq~ ~1 In XU~tU O~e a~e ~Oq~ ~Otuojqa )o z~mnu /emse)u~l q~m ~Jomnl qlmoaR ~lqqloJluo~un "~ou ol dn 'pun P~ll,UlUO~Un jo ~ud ~ql Ul '~auo ~ou aVI op unql "p~la~]lnun
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The Progress of Research Progrc. ol the Tobacco |ndustry Research Committee program, as developed and carried out by the ~cienlific Advisory Board. is reflected only ia part by the increasing number of papers published by tcciplcnls of grants. Since the 1960 Report, 60 new publishcd papers have appeared, bringing the total to 222. Abstracts of the new publid~cd works arc in- cluded in another section of this Report. Mere numbers of papers, however, do not measure Ihc significance of research progress. A review of completed and continuing research givc~ reason to believe that some Of the year's dcvclopmcnts open more direct paths toward d~scovcries that may be cgpec¢cd to cm~trihute practical mea- sures ~or coping with certain forms of cancer and cardiovascular diseases• This "r~view essays to cstimale the state ol' progress in several fields, to assess the impact of certain findings, and to define the nature of some un- solved problems. The discussion is dlvidcd inlo chesc sections: I. Cancer Research. II. Human Lung Sludies. III. Cardiovascular Studies. IV. Psycho-Physic- • logical. V. Tobacco Chemistry and Uiochcmlstry. VI. Olher Studies. I, Cancer R~earck " In planning cancer research it is h¢lt;ful Io distlngubh cwo diff©r©nt lcvcL~ of attack. A full and final solulion of the cancer problem may bc expected Io come only when we undcrsland the basic biological mech- anisms of cell differentiation and ol the regulallon of mclabol~c and cell division processes. The most fundamental investigations ol the day are at this level, and more effective participation in such long-range and basic research is definitely one goal of the T.I.R.C.'s program. At Ih¢ ~am¢ lime, research ala less basic level can be ¢~pectcd to produce uscful information and sometimes to yicld immediately applicable measures for parllal control or d=lay of .cancer in the human population. Many such mcasmes have indeed been developed in the past. Well.designed eapedmonls at Ihk Icvcl may be successful in apprais- ing the relative effects of many controllable e~lrinsic, as wcll as inlrinsic, factors uixan thc level of incldcncc of pa~licular forms of cancer in animals. Perhaps the besl hope o~ developing control ,,ensures ~o~ some forms o! malignancy in Ihc rclalivcly near future lies in studies of this type. Scientific history provides many cases where inch research not only solved immedi-',tc • problems.bur also produced sci=nlific by~)~oduccs of even greater uhlmatc value. Pastcur'~ discovery of induced immunity may he traced to his origi- nal allack upon the practical problems o1' the beer and wine industries. The $ci©ntific Advisory Board, along with other scientists, has con- sistcntly held that pathogenesis of bronchogenie carcinoma mutt be n complez phenomenon and that real progress toward solution must bc c•- pcctcd through discovery and relative evaluation of a whole s~ries o/con- tributory factors. This position has sometimes been misconstrued'as im- plying that no progress in the control of lung cane.or could I~ etpecled until the whole cancer problem could be finally and fully solved at .the basic level of biological discovery. 'This is far froln the true meaning of this po~tiOtl. TIlE EXPERIMENTAL APPROACli The several reports of statistical associations between cigarette smoking and lung cancer incidence made it logical to develop research to ~ce if smoking could play • direct, prima~ role in thc~ eliolbg~y of the .di~a.sc. To be sure, statisticians worthy of respectful ~ttcntion did point out many anomalies and inconsistencies in the statistical picture. Some even qucstiot~d seriously whether biases of several kinds might not invalidate the rcpottcd rclatinoshlps. These kgitimatc questions about the statistics could, however, bc left for eventual re.solution by qualified experts in the field of cpidcmb- ninny and statistics. The testing of the question conccrnmg tobacco as a possible causative fai:tor, called fro" ©atcnsiv¢ ©x.i~ rimcntal research in the laboratory and clinic. " : The point requiting re-emphasis is this: Even if a statistical •ssoeia- lion is assumed Io be compkt¢ly ~alid, it does no| and cannot demonstrate that smoking is actually a.l'aclor in the eliologylof human bronchogenic carcinoma. it has beta s!town, for example, that thcr¢ is an csccIlent correlation between socio-economic class levels and the incidence of "chronic bron- chitis" in Ilrltaln. No clinician or statistician wou~d suggest fur a moment that the amount of money a man receives per annum'could of itself cautt any discas~, unless hc wet© •cruelly infected by microbes from coins ot paper money. Wc automatically proceed to consldetation of such mat- Iers as dietary adequacy, housing conditions, Kind of clo~hlng worn, nature of employment, level of medical care, amount of rest or cxcrclsc, nature of recreation, cxposurc to the elements and otber factors which may he dO.coted by income and which in turn may inllucncc incidence of the dlscasc.
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o( intIrmIdi-t¢ v;~;i.blcs that may li¢ between the cod ;¢sult (disease) and the cnviro~ment-"~ faclOr orginal[~ lakcn into account. The useful function of 6ndlng such a corr.l.[ion thus lies in the cluc~ .nd hints turned up which m.y I~: fuzthcr and separately validated. *'FaJlacy o] ~llmplacgd ~,oncretenem~" In the pardcula~ illu~Uadon just ;~vcn. t~ im~ssibilky of a d;;cct ~usal rcl~n~ip ~ ~c~dy obvious to prcvcn~ investigators horn m~k- ing pzcmalur¢ or fa~ jnfIrC~z. In the ~s¢ of Ih= r¢~rtId as~iadon ~twccn smoUn8 and lung cancer, 1hc stat~ica[ evidence is actually ~ dif- ferent from that o[ i~ ~c.br~hilis ~luation and ~s not, of it.ll, ~rmiz any marc ~cliz~lc conclusion with rFs~ct to direct causation. Dr. Dcr~ has cal~ th~ ~izurc u~ the .pp~eml~ obvious as an example of the "(allacy o~ mispla~d ~ su~i~ ~t smoki.~ could ~ a pri~ causative factor in lung ~r co~d ~ u~d only ~ a worEin; h~po;he~ix but not as a proved fact. Hcvcrthclc.,.lbc h~bk of using Ibis h~thcsis fwm ~Y Co day zs a gcncP ato~ at cx~imcnta] dcsi~ ~s to have ~duccd some ~[cntists to (argot i~ wholly tentative stzt~. Even ~ an hymens, it ~ctually contained a vc~ ~ious limiiadun: Onl~ a vc~ small pro~rdon of cvcn the hcavicst smokcn ever develops Ibis di~#~ and it a~ ~curs amon~ nonsmokers. This iz actually sfrong evidence that Ihc clinlogy ~ t~ di~o~ is complex and that a humor infl~nccs must act in conceit in its genesis, T~ implication is str~g that t~c must ~ factors determining t~c ~rcc of susceptibility or resistance in individuals. It would zp~a~ to ~ z promising cnlcrpri~ Io ~lcrmlnc what factors arc, with the view oJ utilizing Ihcm in cunt;ul ~ canccr. Yet ~s~bilizy has ~cn ~rgcly ignored in practice., The rclativcly low inci- dence at lung canccr ~ hca~ makers as well as in the general population has ~cn attributed lather prc~mplo~ly to "natural differences in ccptibilky," as ir zhc~ wcrc unitarians or in~cc~siblc to study. Gilliam's recent obsc~alion o~ th~ diminishing rate or i~rcasc io lung conccr ci~ncc suggests the gradual d~ap~ar~ncc of a pa~iculad~ susceptible ~pulazion. One way u~d 1o sludy the hy~hcs~s that cigarette smoke ~ghl ~ a prime ¢aus~live ~ac~or in t~¢ genesis of lung ¢anc¢~ wa~ animal llon. ~hc mo~t di~ctly Wrli~nl of t~ ¢x~rime~ts were t~ humerus sludies in which ani~.als of ~vc~al s~c~ were made to i~1¢ frc~h, whole cigarclt¢ ~.okc at frequent intervals over.long ~r~ ~. time, ohcn durin8 I~ w~c nalural span at li~¢ ahcr wcan~g. ~¢~ Ix~imcnls co~sblcndy failed to produce squamous ccl] carcinomas at i~ ly~ t~l arc mint prev- alent in human. Th¢~ failure, in v~w o~ ~e humor, ¢xlent nod duradon ~ Icsts by many ah~ and IX~¢icnc~ invcsli.ga~rs, milltzlcd a~insl z~ zur- mi~ that tobacco smoke could ~ a prima~ factor in the ind~l~n ~ cancers. However, z~ prob~m of s~cics differences in zu~cplibility could ~ ra~cd, and general ignoranc¢,o~ size effects ¢vIn ~ grong ¢arcino~cn~ agcnis on the lung lis~s ]cft the rea~ns for negative results uncc~zin. Further wo~k h~ bcl~d c~ar up zhc uncc[tainlic~. ]1 was ~Bica] to extend lh¢¢ zlud~s to investigations in wh~h reals wcrc made to inhale ae¢os~s or fumes of ~lent, known carcinogens. including mclhylcho~nlbrcn¢ and ~,4-~.zyprcnc. SuFh ¢~imInlS on rals by Kuschncr wc~¢ also negative. Again, I~ ~sulls c~ld ~ in ~veral ways. ~¢ e~cient lung cleansing mechanisms (including mucus flow, phaG~yl~ actJvily, and ab~xpzion, mc~aholbm and excretion) Ih¢ bcaldzy animal might not ~it a contact time, or effective dosage, adequate for carc,inogcnic .ction. ~e problem of s~cics differences in s~cplibilizy could ~rhaps still b¢ rated. Ihough Andcrvonl had I~g ~for¢ shown thai ~uamous lung carcinom.s could ~ induced in C-57 blac~ mi~¢ by transfixing thrca~ im- pregnated with 1,2,5,6-di~nzantbracenc Ihrough the lung. ~is had onslrazcd thai mouse lung cells arc biologicall~ capable of trans(o~alion into ~li~nl dssuc ol this histological lye. Ri;don and Shubik ~zvc shown that larG: d~z of carcino;c~ic dr~ar~s ;nt;~uccd into she tracheas of ducks and hamslcrs ;cs~clively in oil solutions will produce cancers of various ly~s. Similar cx~rimcnts using zohacco smoke condcnsalcs have ~ailcd 'to pr~uc¢ ca~¢r. ¢x~rJ~nls have. however. [u~lhcr confirmed the fact that ]un~ at ~v- oral animal species azc hiologlca]ly susccplihl¢ to molignanl change when do~s at known carcinogens arc su~cicnt and conlacl time is long e~gh.
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Andervont's studies ~ the~ caledon by gu~hncr ~ing ua~nion intr~u~d ~ ad~o~l ~tor of trauma •long wi~ ~cr~ ~n~t ti~ and intcd~rc~ with neural clcansing m~isms. T~ rclalivcly high inci~ of ~uamous ceil ~cinomu ~ thc~ cx~rimcnts ~cw attention to the ~blc ro~ of trauma a~ ~rhape of attempted regeneration ~ su~pdbility of ~¢ lunK to Carcinogenesis. Sub~qucntly~ ~ ~fi~ of studi~ sho~cd that a humor of radioactive ~d ~nt chemical sub~nc~ can induc~ cpidcrmoid lung ca~rs in ru~ and mice. The~ studi~ ~e not dirccUy illumina~ng wi~ res~ct to ~ cdolo~ of cp~crmoid lun; cancer in man, ~cau~ ~cy were carried out on anima~ and t~y employed very ~wcrful agents not widely cn- coumcrcd by human ~ in ord~a~ I~e. The studi~s d6, hewers, dis~l any douo~ a~t ~ck & s~ su~eptibility. M~anwhi;~, cli~l and cpi~miologic~ studies el h~an ~ubjccts by a humor of ~vcnigato~ ~intcd towazd the ~.ibility that damage to the lung, followed by rc&cncralion, mi~l ~ a prcdis~s~g factor in huron lung' cancc~, W~thc~ ~ damge was due to tu~rcuJos~ l~ions, infarction, or m~han~Jl ~ju~. Winlcmi~ lon~ ago ~intcd out the frequent ~currcncc of ~vcrc mctapl~as i~ the lun~ of ~r~ns who died following inEu¢~ in t~ 1918-19 cpi~mic and had ~1~ altc~liOn to thc~ "precancerous ap~ar- an~." ~vcral, ~vcstilatoa had attempted to p~ucc lung cancers in an~Jals by rc~atcd ~flucn~ infections but, thoug~ mctaplaslic changes wcr~ pr~uccd, no t~ly invasivc tumors dcvclo~d. Cancer Ezperlme~ J~hh J/lru~e. Uy combining repeated ini~ucnza infcctio~ wizh inhalation of syn- Ih~c sines, Wi~lcy, Eotin, Fewer ~od Trividi have obtained invasivc and mctasZadc ~uzmous cell carcinomas in ~he lun~ ~ C-5~ bl~k mice at a substantial level of i~i~nce. Aimo~ aZ the same zi~, Martin and his colb~rators showed a syncr&istic action ~twccn ~vcrzl vi~s and a s~- ci~c c~mical carcino~n by obtaining ~umo~s when combined small d~s of vies and chcmi~h wcrc given. Given ~para~cly, al I~ ~mc Icvcls, ~hc~ agcn~ laird to induce ca~r. Stanton al~ has rc~cd ~c induction o~ ~uamous cell lung car- cinomas by chemical ca~cinogcm administered intravcno~ly into ~ats in wh~h ~rcas ~ lung infarct~n had ~cn pr~uccd. ~c~ r~nt evils arc cited to i)lustratc the rapid dcvc~p~nt of ~th~s for study ~ ~ cell carcinoma h animal lungs. These methods provldc a basis for evaluating the relative cffecr~ of many oihc'r ¢x~insic and inlrinsic factors on the rate and level of incidence of brmtchogenic carcinoma in animals. By suitable design, it should hecomn po~ble to evaluate the ¢l]ccts of age. ~cx, nu~'idonai slatu¢, cxcc~ or dcti- ci©ncy of hormoncs, stimulation or deprra~sion of the rcuculoc~dothr.Jial system, cancer promoting agents, various types of trauma, irritants, mucus compositio~ and abundance, activity of cilia, cllicicncy of detoxificatlon mechanisms and many ¢khcr factozs. Te~l~ Coniinue on Tol~co'Smoke Tests of tobacco smoke in this cxperlngnt•l blologic~! sysgzm hay© not yet b~:en completed. So far, the.indications groin the~ and many other tests of !he activity of tobacco smoke, arcthat the smoke is much t.on feeble to play a role in the cdology bf lung canccr as a dircct contact carcinogcn. This does not ncccssarily cxcludc tobacco from having any role at all, nor is any such role established. More ,,westig•tinns arc necessary on the sug- gestions o~ possible indirect, contributory roles for tobacco. As. thc cxpexhncntal systems described ~'•dunily permit the rclativc cvalu•tion of all thc possiblc cxtcrnal and intcmal influences llstcd above, it should become possible to dclcrminc whcther and to what extent tobacco smoke can ¢onlrlbulc. whether as irritant, p~omoter, modifier of ciliary activity, inllucncer of nutrition or by r-ny other means, it is a task of'con- sidcrat,;c magnitude, but the mcans now seem to be at hand. The fortunate •specl is that, as the contributions of the various suspect factors are cvaluatcd, methods of nullifying or blocking some of them may become apparent. Of course, the problems of specks differences and rele- vance to man will remain to he rcsolvcd. Hopefully, clTcctivc mcihods of reducing thc toll of human lung canccr may bc~;omc cvidcnt hem this type of work. ~ CURRENT CONTRiilf/TION.$ FROM T.I.)~.C. PROGRAM Thc program of canccr rcscarch supported I~y T.I.R.C. grants pro- duccd several significant dcvclopmcnts during the 7car. The suggestion th~,t some transmissiblc agent is produccd by certain tumors has come from further study of the increased concentrations of deoxyribonucleic acid (DNA) in tumor-be•ring r•t~ in tissues distant from thc actual tumor. Extracts of lung. kidney, liver and spleen of rats hearing thc Walkcr 2:56 c•rclnoma nnd the Jonson sarcoma havc been found to in- corporate thymidinc.H) more rapidly than those from normal rats, lndicab ing • posslblc inllucncc hem the tumors. L F C C.
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In three different laboralories, cxposurc of cultured cells Io smokc and non-smoke ga.scs was :tudiud with d©seriplion o1' morphological changes, alterations in growih rates, and modification o1" modal values of chromosome numbers. E~Tccts of irradiating human areola, ceils have been similarily scribed. Since morphological .changes and ploidy o1' chromosom~ lion arc not simply or dirccily diagnostic ul" malignanl modilication, it is expccled Ihal fulurc sl~dies at Ihc cell and lis~u¢ cullure levels under T.I.R.C. :upport will p|acc increasing emphasis on changes in Ibe dynamics o! the living cell. Furlhcr quanlitativ¢ cylnchemical sludies on the r,:lalion'of DNA Io various pathological condition* also point Ioward Ib¢ conclusion thai deviations from normal in amounl and distr~bu|ion of' DNA arc specifically diagnostic of malignant Iransformalion. bul rather of growlh o~ regeneration regardless o1' cau~:, or o| DNA virus infeclion. ~o Lun& C.an¢~r~ i~ Mice Expo.~d Io A new summaq~ sevicwcd the histological, cytological and cytochcmi- cal study of lhc trach¢obronchial tree and lungs of mice exlmsed to ciga- rctlc smbke. It confirmed the pre:;uusly ~cporlcd variahilily of response. ranging from absence ol signifw.aol hLstol0gical change, throu~;i mild bronchitis with swohcn cpi|hclium and mild hypcrplasia, Io severe bran- chilis with a typical basal cell hypcrplasia, squamous cell mclaplasia and occasional dysplasia or "carcinoma-in-situ." lnvasivc carcinoma was found. The cx.trcmc variability o1' response, reGardless ol' dose and duration oir exposure, poinlcd |o conlribuling faclors, such as lalenl virus infections. characlcrisfic o! the individual animal. Lung-conlinucd studies with Ihc while Pekin duck have culminaled in production o1" non-m¢lastalic ncoplasn~ ~1r varied lypc in tl,: lungs o| birds given mclhyleholanthrcn¢ in polyso~balc 80 by inlra|racheal inh,.~i(m. To- bacco smoke condcnsatc$ similarly inl'uscd have hal p;oduc~:d lumors. BIOA,~SAY METllODS Numcr~)us studies have Izcn suppor¢cd by granls in Ihc oblain a mole cxac~ quantitative mcth~ u( Ics~ing (or ~cb~ivc over-all "carcinogenic ~lcncics" o~ various subsla~cs and mixtures, i~luding Iobacco smoke and On a slricfly thcorclic~ basis. "carcinogenic ~lc~y" b hal an in- berenl pro~rly o[ a chcm~al subslancc. Rather it is Ihc rcsuil of an inlcraclion of ~mc kind ~wccn ,the host. "Relative polcncy." thcrcforc, implics comparbon of activily within some fixed or standardizcd biological syslcm. Each such system will produce ils own scale, sinc'c there are wide varialion* in ~caction both among and within species. If several scales based on diffcrcnl biological phcnom©na, olhcr. Ihan aclual lumor production, arc set up, Ihcrc is no guaranlce thai any parallelism will cxisl between them in the r©lalive positions assumed by the various agents Ic~slcd. I! a degree of parallelism should occur among several such scales, it snighl encourage confidence in d~cir significance, especially il' one at least is based on actual tumor production~ 'Obviously a m~:lhod more rapid a~id controllable than mouse skin painting, and requiring only very small quantities u[ tcsl ~ub~ta~.c, would bc of greal practical value in speeding sescarch. In the T. 1. R. C. granl program ovcrlhc past half dozen years, a ~core o! mclhods have bccn tried out in ¢h¢ atlcmpl to lest [or IhC ~¢laliv¢ "carcinogenic potency" o! Iohacco smoke and oilier substances."Such in- formation would, it was thoughh help assess the hypo|hcsis thai such amok¢ conlribulcs'lo human cancer as a conlacl carcinogen and help determine where emphasis in research should be directed. None of ilw.xe earlier allcmpIs proved lu be salisfaclor)" fur rclalive qua~'*ilativc evalualion. Most,. buI not all, gave complcldy ncgalivc rcsulls. But even though not wholly Salisfaclory, thcse many studies produced an overall impress|on thai ¢ooacco. smoke ol" normal churaclcr, in ils Icnuous stale, is ioo weak a earcinngcn. ilr il is ~u: al all I'or human:~, to acl in this capacily as a Generator o1" human lung cancer. Enr,eurnglng Resull~ in Three Area~ Now Ih¢ bcn¢li|s o| Ibis work a~¢ coming Io feuilion. The research for marc salis£',clory I)ioassay mclhods l,as cn~cred a n¢w phase which appears cnc~mr;~giqg ah.og Ihrcc line~: I. A method ba~cd o~ the activity ol °'c~i~cinogcnic ngent~" in cnhancin~ Growlh ol Iransplanlcd tumor and~ normal skin grafts ha~ been ~hown capable ol~ q.amitadon, and un "~ctivity ~or a large scrics o~ highly pu¢iGed polycyclic ~ydrocarbons is in conslrucllon. 2. Furlher ~landardizalion is in pr¢~.:ress l'or a prolozoan assay [or carcinogenic hydrocarbons, ba~'d on P, rus,ecim, eu,dm,m Io ultraviolcl and rclalc~J radiation follow- ing exposure Io Ihc hydrocarbon* in high d[lulion. A second potency scale is al.,co Ioh¢ c~mslruc|ed by II~is method, with use o[ the ~am~: ~amples of highly purifcd hydrucarbon*. C I- I C.
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• 3. A third projected sc•k: is to bc based upon animal skin tumor production by •n accclcrated mcthod, if plans materialize. The relative evaluation o~ various "unknown" ~ubs|ances on these ~ales is contemplated in due course, when back~ound informa- tion bccomra adequate. ConJerence on lIi6a~say and Many of the matters outlined •bore wcrc di~u~d in a round tabl~ confcrcn~ on Ma~ ~. 1961. in t~ o~c~ of the Committee. B~sides mem~zs ~ t~ ~tific Adv~ Board and staff, the [o~owing guast ~icnth~ participate: DR. T. D. DAW. U~ve~ity of ~ ~1 of Mcdkiaz~ ~, ~sland DR. WALTER E. H~ON. Nal~l ~er I~itute, Bclh~da, Md. DR. FREDDY HOMDURGER. Di~R~agch lmtilute, Inc., Cam- bridge, DR. ROBERT W. HULU Nonhw~n Univ~nlty, Evamlon, Ilk DR. CHARU~ J. KE~SUER, A~hur D. ~tfl¢, I~, ~mbridge, DR. WIIAAAM ~ POE~ Univcnity o~ Pit/s~rgh, Piltsburgh, Pa. DR. MURRAY J. ~iI~R, NarWhal Cancer Imtitule, Bathed•. Md. DR. CON~AN~NE & ~EPHANO. 5tephano B~Ol~r~. Inc., .P~iadelphia. DR. HAROLD ~WART. National Institut~ of Htalth. Bcth~da, Md. Mg. G. F. TODD. T~acco Manufacturers' ~anding Committee, I!. Human Lung Studies Among studies on pulmona~ |unctioq and physiology was • signifi- cant contribution in the mcasurcmcnt of "airway rcsistancc" by the mcthc~l of body plcthysmography. Inhalation of cigarette smoke both by normal l~ons and palicnts with various lung diseases, whether habilual smokcxs or nonsmokers, produccd • mild bronchoconstriction lasting from 10 to 80 minutes in most individuah. The effect did not appcar to mcdiatc through nicotine or other volatile substances and could be prevented hy isoprotcrcnol. Data wcrc inadcquatc to warrant relating of this cffcct causally .Io initiation or aggravation of chronic pulmonary disease. ' A rcvicw~has appeared describing experience in the cooperative study of p~lhV)Jo~gic~l anatomy of the human.b~onchial tree and lungs which the Sclcntific Advlmry' Board initialed in 1954. About 3,000 cases wcrc in- vestigated..' yichling 8.590 slides from males and 3,661 from females. Participating were 12 pathologists in dil[¢rcnt locations around the country. The review rcptu'ts c|tfi.'tly on problems of diagnosis and claretfie•lisa. The study is now being cxtcndcd under .auspices ol the' Unite~! States Public ilcalth Scrvlcc. A morc detailed" report by one of.the participants in the. cooperative study has indicated that only 48 percent of ;hc cases could be coasidcscd normal and fewcr of these occurred among smokers than among non- smokcrs. Results o! such studics indicatc the m~tny problems .in defining pathological changes and lnterprc|ing their significance. • IlL Cardiovascular Sludies Several of the cardiovascular diseases have bccn reported by investi- gators in epi~miok)gy to Ix: associated with the use of tobacco, ~pCcially cigarcttcs. As in the c',,usc of the othcr association, these reports have given intpctus to additional studies on the epidcmiological level as well as to many of a clinical or cxpcrlmcntal nature. The objcct has bccn to determine whether the associations arc Uuly meaningful and whether they'reflcct any contribution by smoking to the etiology of thcsc diseases, or whether the link with smoking is only h)nuitous or indirect, through intermediate cam- ann factors. Many Other Fn¢'lora Jlso Bring StudDd Among othcr factors under investigation in sludies o| cardiovascular di~a~ development ~rc heredity, cmolional cmstilul~n, strc~ and ~c individual manner of reacting to stress, physical activity in reht~n to caloric ~tak¢, ~clatlvc ~y weight, mcla~lk characteristics, thyroid activity and d~lary habils, cs~cially with tcs~cl to I~ amount a~ ki~s of fat c~sumcd. ~x and ethnic origin arc al~ involved. Rcccnt pro~lcss Ja ~vcral ccmcrs su~sH that a disunion may nccd to ~ drawn ~twccn thosc influences that nffcct the gate of progres- sion of chronic va~ular ~gc~alivc p~c~s s~ch ~ al~clc~mh, and tho~ that may help prccipitalc acute cpis~cs st~ch as my~ard~l infarc- tion. the mechanisms of which still elude full cl~idation. Evidence emerging fn)m the Tobacco ImluH~ Re~h Commiltce program and cl~whcrc su~csts that the prevalent ty~s of chronic va~u~r dcgcncral~n arc nol sJgnificanHy in~ucaccd i~ rate or dcg;cc by the ~ri~ic administration of nicotine in small amounts over a hag ~ri(~ or by the m~ralc practice of smoking by avcragc ~nons. Still ~u~e are b C b 0
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the mcchanisms that ptccipitatc -n :~cutc cpisodc in pcrsons with advanccd underlying va~ular di~ase, who arc consequently more vulnerable to all kinds of s~r~s. Effo~s Io solve ~h~ p~oblems al tl~e cpidemio~ic~l ~vcl arc fraught wi~h many di~culdc~ Presumably Ihc dcgrcc o[ va~ular degeneration in. human ~in~ can ~ accurately dclcrmincd only at aulopsy by analomic mode. Though accidental deaths c~slanlly provide ~mpics which cu~ across all lines o[ a~e, ~x and race. Ihe problem o[ acquiring Ihc needed dala on li(¢ habils ol.lb¢~ vicdms, by rctr~ctive mct~s, is [o~midabl~. . Pro~cdve studies, while ~i[ling belier access Io in[ormadon abou~ ~onalhy, dict. smoking. ~y build and the like, ~ nol conduce Io acquisition o[ analo~c information in a unive,al or n~-~lccl[vc, random manner and Ihus ~nd u~n vaguer clin~al indicadnns ~ cardiovascular ~lholo~y. T~y mu~i, moreover, for practical reasons, u~ ~)pululions con~d to Ihe older aSc ~roups. Despil© di~culdcs, a pathol~ic-analomic study of human artcrics. recovered trom acci~nl victims, is ~ing sup~rl~d. Pcrsisicnt and in- genious cfforls are made Io acquire and vaGdalc as much dala as [clr~clively. a~ul the ~rtinenl characlcrblics and lifc-habils of the subjcc.. To c~mpa~c ~ppmachc~ techniques and ~ndin~s in Ihis f¢rc~cc was ~ld du~in~ Ihc ~car to which ~icnlists involvcd in s~ud~cs involving similar Icchn~ucs and problems wcrc b;ou~hl tu~cthcr. Co~]eren~e on Alheronrler~.l~ This confcrc~e was hc~ in the o~cc~ of Ihc Tobacco Indus~ ~arch (~mmhlce on May 26, 1~61. In addition .to ~iaff and ~mhcrs I~ ~icnlific ~dvbo~y Doa~d. Ihc [Nlowing mvcsll~ulori pardcipalcd. DE. WII.I.IAM G. Bi~DEHKOPF. Hew York SlalC Dcparlmcnl o[ Hcahh. AIh~y, N. Y. DR. TIIOMA~ R. DAWIIER. U. S. Pu~ic Ilcallh ~vicc. Framing- I)A. IK~ GORE. Vclcrans Admini~lraliun II~pilal, W~ Ma~.. and Hazard Mcdlcul I)~. (;1 (~IA ~AI.I.O and ~R. MICH~I~I. i.YO~S, Hew York Univcr~hy C~1~¢ o~ Mcd~inc. New York Cily ~R. liEHRY ~. U~ll.I.. JR.. and MRS. MYrA I.. I .~isiana ~ale Univer~ily ~h~ ~ M~icine. H~ OIIcuns. I.u. DR. GEORGE V. MANH. Van~hili Univcrsily ~h~l ot Meriting, ~a~vill¢, Tenn. DR. SEYMOUK Ii. RINZLEK. Ncw Yo~k tlospilal--Corncii Medical C'~,l~:r. New York. N. Y.. DR. WILBUR A. "[IIOMA$. Albany M~licul Collcg~, Albany, N. Y. DR. ~I~()XC;E E. WAK~Ri.IN. American Ilca~l A~ial~. New Yu~k Cily An cpidemiological study on u large ~pubt~n of ,ring jccl~, including ma,y n~asurcmcnts and functional ~ls, providcd no evidence el la;g¢ or ~i~[~nl dillcrc~cs in circulatory ~vity Gruu~ u[ habilual ~nwkc~s and non,makers. Th~c was Utile evidc~ce'of dcl~rloeul~n ul ~ardiuvu~ular "liin¢~s" in ~lo~e~s ~rl~mb~ work Iicavy s, loker~ had consbtcndy Iowc~ ~cludv¢ ~y wei~h~ and hi~hcr haud oxygen cunsumplion. D~lierenccs in ~ell~g bl~ p~ur~ either no.>igl~ilicunl u~ Itndcd to b¢ lower aniun~ smokcrl..' I~¢~au~ ol ~¢~rltd dil[~rtnces in ~hc relaliv~ incidence ~. ~mic houri di~ca~ unlong the Ihrcc major cdmic grou~ O[ South A[~, a sludy wu~ made amon~ ~ .~alihy.¢cprc~malivcs o~ th¢~ groupS. Co~ra- lion w~ Given w ~moking habit, inco~, t¢cupal~n, d~t, unlh;o~lr~ measurements, u;t¢~iul p;c~u;cs, and tolal bl~ choks~ol well as dislrihulion or this lipid ~lwccn alpha-and ~la-li~p~otein; No ~i~n~can~ r~lalion~hip Was found ~lwccn smoking and ai¢, ~c, nature of ~cupuli~, height, weight or degree ol o~sily, k .hilly con- ~i~lcui dillcrcncc wa~ [uu~ in t~ disiribulion of cbol~icrol ~lwCen Ih¢ alph;~-and I~'la-lipnprolcin (r~clions. however, and Ih¢~ di~cren~ p;~rallulcd hy dill¢¢cnccs in the custon~ary dietary [ai inlakc. II was there- Io¢c p~o~d Ihal smoLinE may cxcrci~ an indi[ccl influence by in~ Ihe ~lcclion of Io~s IhrouGh cllccls nn the laslc ~ns¢. sludic~ Wuvi~d some preliminary cv~dcnc¢ that smokc~s may pr¢~ salty. spiced and hiGh-fal 1(~ ~nd may cxwricncc a diminished ~nsiliviiy to I,illcr In a Iong-lerm pro~clwc sludy designed !o elucidale Ihe o[ h)'~len~m and coronary di~a~', il has ~cn reposed Ihal while ma~ medical sludenls who arc Ihc ol[spring of Iwo p~r~nls a~cclcd ~ilb I~ di~ca~s, arc ~i~nil~cantly dil[~cnl from 11¢ offspring of two unaffccicd parcnls. On Ihc uvcragc. I~ sons o[ the al[cclc,d parcnls arc 10 heavier, mo~c [¢c~utnlly have h~W¢c~de~lercmla. ~w higher resting ~y~lolic bk~)d prc~urc levels and a¢c more likely Io ~ ~moktrs. Whi~ Ihc~c dil[¢rcncc~ arc nol g,cal. Ihcy arc colnpatib~ with Ihc hy~l~sis ol m.hifaclor~d i.htrh;mcc. "l'hc~ uh~c~vations ~ccall the ~sibilily smoLin~ hahil~ may r~'llccl prc.cx/slin~ consdlullo~al faclO¢S, ralhe¢ Ihan ~¢cs~rily conlrihuli~ cau~ally Io pr~uclng lhc difltrcncts. l ! ( t l
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Tha obscrvation, from animal studics0 that nicodnc may ~clca~ cp~cph~i,c and no[cpincph~inc [~m dc~u and thus ind~ly the m~i~tion ~ fr~ (a~y aci~ (FFA) ~to ~ ci~culati~ (win t~uc fat ~its, prqmptcd a simila~ study in a limited humor of human jcc~ T~ smoking o~ two ci~rct~s was found to pz~u~ an clcvado~ ~rum fr~ fazzy acids. The ;cs~n~ was not ~clatcd zo age, ~x, general smok~g ~biU, ly~ ~ cigarette or prc-smoking level o( FF~. Total cho~c~rol w~ not z~cct~. Hon-~oking controls subjcclcd to othc~;~ ~n~ai pr~cdures a~o cx~co~cd a m~c~atc but smaller Su~ mobgi~Zi~ of ~ was In have ~n cx~c;cd zs a no~mal pz~ ot ~ rcs~ ~ z~y J~css ~ I~ sym~thedc ~ous system. ~s su~,'il'~uJrcs quzntJla~vc evaluation in xclzlion to the effects ~ all other ~o~s of s~c~ t~ dcz~m~c wbc~cr such cQccts arc o( any ~al si~i6cancc ~ ~ a~r~rot~ ~c~s. ~canwhHc. a d~cnt ~oup of jnv~dgato~ has shown ~at Jn ~s~bso~vc s~, the human as well as ~ ~g hea[t cx~rac~ a con- s~ntly hi~cr ~c~tagc ~ ~cc o~c acid than of any o~r frcc fstty ac~ prc~nt in a~tcrial b~, It had ~cn dcmonstraCcd prcvi~sly cncr~p~ucl~n o~ ~ hc~ ~n~ largely o. ~a¢ty acid An~l stud~ ~ va~ul~ patho~w, thou~ much more c~ily con- l~ol~d, arc ~dcd by pr~ms o~ s~cJcs d~Hcrcncc~ and di~cultics intcrwctation nnd oppl~adon to human ~ings. However. fu,hcr studies have ~cn completed wJth r~bbJts fed cholcstcrol and cotto~ccd o~I. nic~inc, or a combinat~n of all three, in compa~son with ~,crols. A previous ~udy had [c~cd an apparcntly synergistic c~c~ n]codnc in s~cding and inlcn~fying the p~l~on ~ ~iphe[al to~ changes and cardiac d~ma~e, wi~ ncc[osis, by t~ a~hc~o~cn~ In the Wc~nt cx~i~ot, however, the ~pheral circulalo@ chan&cs wcrc minimal and cardi~ nc~is ab~nt. Since crgonovi~ had ~cn used . Wcv~Jy' for Ic5ts to a~ cardiac functional status, it was a~d to the rcgimcn, and the nccr~ic condit~ wcrc again oblain~. ~csc necrotic cffccU ~rc now attributed by the invcsCi~ato~ to the additional action o~ ~[gonov~ in the combinntion. EHccls for~rly co,side~cd ~o l~ cho~stcr~l d]cC, with or withom nlcodnc, have d~in]shcd accordingly. R~n~ to Cl~et~ ~moklng by ~oro~ Pmienls ~c my~i~ rc~n~ to cigarette smoking in pat,cnts wilh ~wn di~a~ has ~cn m~ur~ b~ cat~t~ techniques. ~cvions stud,s had shown that smoicing enhances myocardial blood flow in no~mal sub- jccts. Hear! talc was acccl,'ratcd in I~th groups by smoking and .',rtcriai pressure generally rose, but these changcs |ended ¢o he more pronounced in the coronary group. A uniform incacmcnt of Ic[I vcntricula, work was also more pronounced in the latter. Myocardial oxygen usage was virtually unchanged. The coronary subjects did not Cxi~cricnce increased myocardial blood flow dur~g smoking, perhaps on account of the "fixed "coronary resistance" alleged to exist in such patients. There w~s no evidcnc© o1' myocardial ischemia during smoking, however, evenin the coronary group. A study of Bucrgcr's disease among young men in the Orient pro- d~Jccd evidence that this disease is dLstincl from the ~,therescJerosis or embolism of" II~ pcriphernJ vasculaturc chat o,:.curs more commonly in the United States. and where actual'existence o( a distinct Bu©rgcr~a syndwmc has been questioned. While all the 62 patients ob~:rvcd were smokers, the sludy suggested that the etiology and pathogcncsis of the condition probably complicated. Whether the essential lesion is truly an angii~is re- mains to b,: proved. Pipe and cigar smoking have L, ccn shown to produce circulatory clTccts (a drop in skin temperature, inc:ea.se in pulse rate 8rid blood pressure) similar ¢o but less marked than those found following cigarette smoking or tobacco cltcwi-g. Ballistocardiographic changes wcs"e Icss than those I'ollowing chewing, hut Krca|cr than those I'oUowing cigarettes. In an ell'oft to throw light on the physiology of .rclative h),pcrrcactivity to smoking by certain healthy young adults, in terms of blood pressure, heart rate, or cardiac o.,tpul, the clTccts of preliminary smalJ inlravcnous doses of hcxamclhonium, mcphcntcrminc or of • sah-solutlon placebo wcrc studied, individual dil~crcnces in h(~ncostasis wcrc revealed but the changes wcrc not readily grouped and Ihe results were too varied for simple class~6cStion o! subjects. Fundamenlnl $#udiem oI C.ardlo~rular Numerous contributions to study of the cardievas~ula~ system ,~ong fundamental lines wcr© mad© during the year by rcciplcnts of Tobacco Industry Research C'ommitlcc support without im,~|cdiatc bearing upon the effects c~lr nicotine or snmlcing. Others contrihuled new or improved tcchnlques for sludy o~ this system. A nolable s~rlcs of such papers centered around the metabolic tivltics of the heart muscle under various cond~tioes and in/~uences and of the relations between biochemical cvcnts and (~rug actions, and the resulting mnchanical and other (unctions. Others dealt with the rationale
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of Ueatments as .based upon biochemical considerations, and with methods of measuring coronary blood' flow and of assessing coronary arlcry insuf~ciency. A beginning has also been made at the cult.ire of normal rabbits' aortic and myocardial cclh in vitro. Various nutrient re©din have been tested and the relative growlh potenlials of ~cw:ral cell types dctctmlned. Objcctlves are'to observe metabolic activilieS as they may be affected by various ex- traneous, substances, including nicotine. Ther~ contributions are important scientifically to the fu.rther study of cardiovascular diseases and abstracts o! all such papers are included in this report. IV. P~Teho-Phy~iolofica! The general objectives of previous reports, and a continuing program is in the process of expansion. Current reports include a study of relationships between constitution and other, characteristics and smoking in a group o! subjects all of Italian family origin.s from tl~: area near l~aples. Lean men were found to smoke more than stout ones. but the diets were tint significantly dilTcrcnt. Slighlly higher serum cholesterol was found among smokcrs, but significant dif- ferences wc~c nol observed between smokers and nonsmokers in ~nthro- pomctric mi:asurcmenl, in physical activity or in alcuhul consumption. An analysis of the smoking practices of a group of Harvard m'cn in comparison with those of the general population has also appeared, as a by- product of a more intensive study of smoking as rclatcd to body build. V. Tolmcco Chemistry ar, d lJiochemi.~try A u:ries of studies on mcchanisms of biosynthesis of Hirotiana alka- loids has reached publication as culminalion of a long-continued program of study. Mechanisms of mammalian and bacterial metatmlism of nicotine and related alkaluith have bccn traced through additional stages with full identification of intermediates by exacting methods. Several new con- stilucnts of tobacco have been identified. Scvcral years ago the question was raised whether the former use of arsenical insecticides might have contaminated the ~oils of tobacco growing areas with consequent Iong-sustaincd increase in ar3~nic absorption by tobacco plants. A three-year study of this subject, reported previously, showed thai such ~oil contamination has not occurred to any significant degree. A new rcp(xt on methodology of u:mi-micro analysis for a~cnic in plant material and in soil~, now published, will facilitate any future studies of this natron. .. Vii Other Studies " Other studies include reports from .the continuing inv~tlgation of nicotine pharmacology which cmphasizcs espy_ "ially effects.upon the nervous system with. an ultimate view to cluci~a~ sing some of Ibe bases for the use of tobacco by humans in the context of life situations. Tobacco use has been found to have no influence on the occur~em:e of episodes in so-called "periodic" disease. A notabk event in 1961 was publication of the comprehensive moao- ~aph, Tobacco. F, zperimemal and Clinical ~udie;, by Dry. Lawson, Hang and $ilvette of the Medical C011cgc of Vkginia. This 800-pase book, whose complctlon was assisted by the Committee, should greatly increase the accessibility of sclcntific literature in the ficld and thus stimulate and facilitate new research, while contributing significantly to the development of better perspcctiv~s. The book is a comprcbensive account of the world literature, based on study of more than 6.000 articles peblhhcd in about 1.200 journals. It has been widely and favorably reviewed. Other comprehensive reviews, of the literature on the effects Of tobacco on specific organs or systems appea~cd during the year. The lheraturn on lung cancer from 1930 to 1960, was reviewed by Rigdon and Kirchoff. who prcvlously had publishcd a review of the period 1900-1930. The later article, containing 455 rcfcrcnccs, noted that various hctors have bccn studied in the etiology of lung cancer, including tuberculosis, influenza and other chest discuses, occupational e~posures, almospheric pollutant~, and tobacco. It concluded that the cause of human lung cancer is unknown. . Medical Stud~nl F¢llo~,hlp, Since 1953 Ihc ]'obacco ioduslry Re,catch Committee ha~. upon recommendation of the Scientific Advisory Board. been supporting a pro- gram designed to stimulate intcrcsl in basic ~csearch among medical school sludcnts. This program was again in effect during the year amo.ng the nation's accrcdlted medical aml osteopathic ~hools. The importance of such a program was recognized'in the April 1961 rcpurt of the Prc~,idcnt's Conference on ! leafs Disease and Canccr. This report said Ihal basic research mu.,~t be supported, as Ihe chief source of new knowledge and urged that more young people of outslanding ability be recruited into the health field. Under the fellowship program of the T.I.R.C.. students, in comulta- tion with their advi~rs, select the subjects they v~ish to study. Deans of the schools choose the fellows, and the work is don~ during summer or other off-term times under the supervision of cxpcricn~cd researchers, in the last seven years more than 500 young persons have re.ceived fellowships offercd by the Scientific Advisory Board. 23
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Abstracts of Reports Each reciplcnt of ~ Tobacco lndust~ Research Committee grant-in- hid is resi.)o, nsible for the initlul presentation or publ~ation of the results of ~s rematch in ~itntific ~e.ngs or ~ appropriate ~icnfific journaLs. Fo~ow~g art a~ract~ approved by the" authors, of research tc~tts. with acknowledgement of sup~gt Item the T.I.R.C., t~t have applied in gienti~ ~urna~ ~ncg Ihe hat gt~rt of th¢ ~icnlific Dirgctot and tMough ~'m~ 1961. ~c name of t," m ~icnt~t to whom the T.I.R.C. ~ant was mad~ is ~ven in parcnthc~ where r~ubcd. Copies of ab- ~rac~ in previous Rc~ are avaihb~ u~n request. The~ a~tracts have ~n ground un~r ~x headings: !. Cancer Research; ii. Human Lung Studies; !1 I. Cardiovascular Studies; IV. Psych~ physiological Studies; V. T~acon ~cmist~ and Bi~hcmistty: a~d Vi. Oth:r Studits. ' I. Cancer Research "TUMOR-HOST RELATIONSHIPS STUDIED IN VITRO: EXPERI- MENTS WITH CFA, L-FREE SYSTEMS." By Leopold R. Cereccdo. Sister Marian Jo~ Smith, and Jesus Vicenle, Dcparlngnt el Biochemistry, Fordham University, New York Cilia. and Department of Biochemistry and Nutrition, ~chool of Medicine. University o! Puerto Rico, San Juan. ,4rclffves o! Biocltemi~try and Biopky~ics. Yoi. 92. [,ages 4g4-486, March 1961. (T.I.R.C. grantee: Cegccedo) Pest.Dose o/,r'J~f~'t I:~geVIOUS studies by the author, have shown th~'t in tumor.bearing rats thegn is an increase in the deoxyribonucleic acid (DNA) concentration of certain ti~ucs at a distance I'[om the lamer. These eft'cats of the tumor could alto b¢ shown in vitro when the incorporation of thymidinc-H] and adenine-C" into the DNA in slices from tumor-beating animals was corollated with that in the lissues of control animals. It was decided to investigate whether the stimulatory cll'cct of the tumor could also b¢ shown in cell-free systems. Procedure: The incoq~oratiun of thymidin¢-H) inlo DNA was studied in high-spcFd suwnatants of extracts of lung. kidney, liver, and spleen of not'real rats and of rats bearing the WalKer 256 cagcinoma and the Jensen sarcoma. Fi, dings; An increa~d incoq~ration was observed in the supomstants of the liver and the spleen of the tumor-bearing hosts as compared with that in the normal .controls. "l'he cflcel of the Jcnsen tumor on the incorporation ,was more pronounced than that o1' the Walker carcinoma. This increased 'activity~Was also Iound when the incorporation of the thymldinc-lP was studicd'u~'tbe supcrnataut fractions o| the tumors themselves. It is rca~n- abl~ to assume, thai some lector produced by the tumor and transmitted to these tissuei by way of the blood is involved in this phenomenon. Ot~ar gt~nlor~# U.S. Public ilcalth Scrvic© and the Damon Kenyon Memorial Fund. "TILE EFFECT OF SMOKE AND NON-SMOKE GAS,~ ON CELLS IN CELI~, AND'ORGAN CULTURES." By Phi!ip COoler. M.D., FACS, and irene P. Goldring. Ph.D.. Department of Surgery, Albert Einstein Col. lege of Medicine, and' Bronx Veterans Administration Hospital, New York. Surgical Fotumo Vol. 11, pages 72-73, 1960. (T.I.R.C. grantee: Cot)pot) Purpose o] srudy~ Studies have already been ~,compli~hgd on the I~" siblc ell'eel of cigarette smoke on lung. in viva, or on tissue tdicas, in vitro. The present study was initiated to investigate the elt¢¢t o/. various agents on'cells at a c~llular level. Procedures~ Smoltc from cigarettes, cigarette paper', or onionskin paper was injected into mammahe.n cell cultures. C0nttols included timid' ~ul- turns exposed to atmospheric gases, carbon monoxide, illuminating gas. and o~her non-smoke gases. The gases were injected alter a growth period of 24 hours into fla~ks containing an original inoculum of 100.000 ceils in 2 re. of.NCTC-109 synthetic media In which 10 percent horse ~'rum had been added. Three cell volumes (0.~, !. or 1.$ c¢) of smoke ,,~.r¢ injected: total cell count el each culture: was made alter an additional 48 hours. Daily microscopic ohservalion~ were made. Cells in n Ro~ igrfusJon chamber were obw.rvcd directly after 15¢ iniection of cigarette og cigarette paler smoke. Cigarette smoke was inlcCtcd into embwonic rabbit lung oggan cultures. Lung orpn cuitur©s o! 18 day old rabbil embryos, grown for 24 hours in synthetic media, were exposed to $ cc~ of cigarette smoke, and s¢ctlon~ were prepared from the tissue after an additional 48 hours. ' Fln,i~l~s~ All smoke gases tested altered the growth eur~¢ of Ih¢ cultures .~ignificantly, and a reduced cell population resulted. Tk¢ changes induced by cigar¢lt¢ papor or oni,~nsU, papor smoke Were more pronounced than that produced .by cigarette smoke, Non-smoke gags teslcd showed no sig- nificang clTcct. C¢!~ grown in a porfusion chamher became enlarged, tSowed surface "blebbing ~, and incgcased cytoplasmic granularity and vacuolation. The embryonic lunl~ organ cultuxes showed ~.rresl of growth and degenera- tive changes in the t~,u¢ after exposure to cigarette smoke. The ¢~cct of smoke gags, ovar prolonged igriod~, may conceivably produce chronic inllammatory changes in the lung. , . " • "A P~,OTOZOAH ASSAY I:OR CARCINOGENIC HYDROCARBONS." By Robert W'. |lull, Ph.D.. Department of Biological Science,' Northwestern University~ Evanslon, II!. P~oceedin&~, International Conlerence o~ Pro- tozoolo&7. Prague, Czechoslovakia, Aug. 24, 1961, P.urpo,e o]. ,#ud.v: Although the basic mechanisms of photndynamic ac. ~on are stdi .unkno.wn, exploitation el the phenomenon of response el rrotozoa to ultravlolct andrclalcd rsdiation lot use in the detcetlon o| hydrocarbons in high dilution can have comiderablc utility in the area of cancer research. Procedute, Solutinn~ of hydrocarbons in water a~e prepared by either of two methods. The ciliatcs in an amount og glass-clis~illcd water equal to the volume of hydrocarbon solution are added Io P~,rcx spot t~l plates or standard slides containing the suspensions. The ~iliates are concentrated ~o as to provide between 20 and ~0 ciliatcs par dcprcsfion. The ciliates
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routinely used are P~ro~ecium caudalum I~own in asenlc media or in media containing Aerob~x~r ~rog~tx. Contro~ in t~ test arc ciliatcs handled in ¢xaclly I~ ,me manner c~cpI [hat zhc hydr~ar~n is ~c cilialcz in Ihe hydrogen zus~nszons arc held ia Iolal darkness ~r one ~ur or more a~ zh~ cx~d IO light ~ known quality and ~c linm inle~v~h ~[wccn o~t Of ex~x~e and imm(~ility Of 9~ ~rccnl o~ the cilJa~s is recor~ ~c clr~is Of various known light wave-lengths ~twc~n the mzzJm~ baclu~jda] wavc-~nglh and vJsJbJc light wc~c examined. ' . Fi~din~z Th~ work doo¢ m date deals wi~ sta~a~tion Of z~ a.ay ~¢hniqu¢ ~ ~¢gas~ i~ I ) repr~ibilJty and ~ng¢ o~ ~nzizivity, 2) ¢~cc~ o~ ~ q~i~y Of I~ ixradiaz~g [i~. 3) lh¢ effect ~ various o~ ~x~suxp o[ Ih¢ ~liat~ ~ ~ ~ ~un~ p¢i~ In i~adiatj~, and 4) vanabo~.~p ~dtJvity in a ~ ol diffcmnl h~dt~ar~z, some Of wh~h mam~ tests to ~ ~rcinog¢~¢ show a ~c¢ kill-time in the a~j • ~ do h~dr~ar~ wh~ ~rcinogenicizy his not bec. established. This assz)' p[cdicls that corgi, of th~ c~u~ I~tcd wiU ~ found to cg~zivc casc~og~ Iz c~ ~ c~nclu~d from the datz now zt hznd t~t thb z~zy system b ~nsitive znd reiJzblc ~ the dc~ccdon o~ ~]yc~clic hydr~axbons in high di]uz~n. ]z can ~ anticipated z~ lu~r chzrac~ri~don o~ ~he Icsz may prover a~zze pr~don ~ carcinogenic ~zc~y Of Ihe ~ydr~r~ns. ~c~e ~s al~ the v~ ~zl ~ibi"ly zhaz this assay zystcm mzy provide m~ns ~or uir~z allac~ ~ I~ baz~ m~h~nisms Of chcmiczl ca~cin~cncsis. OF DEOXYRIUONUCLEIC ACID OF CEL~ TO VARIOUS PA~IO- L~ICAL CONDITIONS." By Cecil~ Leuchlen~eBcr, Ph.D., and ~uchlen~r~er, M.D., T~ Children's. Ca~er Re~reh Foundation, • ~ ~d il~ chemical ¢om~silion ~s~um~s pa~icular ~i~nW~nce in ol ~nc tact mat a chan~c in luncl~n and'morphology Of a cell ~s more o~ less • c caption o~ ~rly~g and often p~cccding chemical alteration. Simultaneous mo~hological and chemical invcsligation at Ibe single<ell ]cvc] mJ~" I not onJy Ihmw light on clJo]ogy and palhogcn~Js bul abu migh; help gr~dy in Ihc ~tcczioo and un~rslanding Of distal. In parlicular. s~c~l atlcntJon Io the Mudy ~ dcoxyxi~nuclcic acid (DNA) in ~boormal co]is and ia~lls u~r pathologic conditions ~cmcd recoiled in view o~ im~rtant r~c o[ DHA ~or cell life and cell ~ntinuily. iU quantilativc stabilily undc~ ~md co, idol. and ils cl~c ~¢]azionzhip zo z~ zones. Pr~edure.~ Du~ing Ihc last 10 yeats the quantitative ~hav~r or DNA ~n co}Is has ~fn cxlc~ivcly ~vcsli~zlcd by m~r~clrophot~ctry mlcric~c~e m~o~o~y in rcla~on Io lout ~a~lo~l priests: (I) surg~zl st~cu. (2) turn. (3) v~us in~cctm~, and (4) i,[c~ilily. ~udyiog ( I ), dop w~c zub~lcd In j~u¢ctomy ~ cho~cyzi¢clomy, and cells of liver and adrenals were analyzed for DNA conlenl. In IIz¢ case of • (2), human ~precancc.rous and tumor Iis~ucs wcr~: sludicd and contrasted wilh normal human tissue. Under (3) dilfcrent t#l)CS of human and other cells inleclcd wilh dillcrem DNA-conlaining viruses were examined in in Ihe hosl and in lissuc cultures, and in (4) morellhan 32,000 sperm cells from over 200 men and from over 10O bulls were aaal),zcd for DNA contenl. ~'~nllingl~ (I) Analysis of more Ihan 7,0(X) individual ¢~lb from llvus and adrenals from 17 do~ showed Ihat DNA con~ent remained unchangr.d after surgical sires/, although n considerable elevation of eyt~osine was noted in liver cells and in cells of Ihe adrenal medulla ~/ter surgery. (2) 11 wu found Ihat all normal tis~ucs, no matter what their origin or metaboJic function, contained cells with t similar baxi¢ mean DNA content, where~ Ih~: DHA conlcnt of precancerous lesions and malignant tumors was found Io be increased and revealed n much larker u:atler from cell to edl, The dcvialing DHA dais cannot Ix: considered a specific criterion for' malignant "Uansformalion of crib. bul may be explained mainly on the basis of growth and milotic processes ~)rcsent in most tumors. On the other hand, con~lancy of DNA in normal lissu¢l indlcstcS titan an increase and lar.~e ~atler DNA in such li.ue must bc looked upon wilh suspicion of mah ..g~ncy, un- re. regencratlon is to be cxpecled. Benign cells disclosed etsenlia[l~'• n~nnal co~nlant DNA quanlity. (3) Study of dilferent lyFs of cells infecled with dillercnt DNA-containlng virusc~ b~ shu in the host and in ti~ue cultures revealed a peculiar combination of intranucicar bizarre conglomeration of DNA ma~ses a~u~:Jalcd wilb slriking increase and variabil|ly nf DNA. This ahno~l specific ,espouse of cclb In an infcclion wilh n DNA-conlaining virus w,,s noted i~fcspcClive of lhe lyp¢ of such virus. (verruca vulgaris, adcnovirus, tic.), of Ihe speclcs and types of cells infected (human, insect, nufmal, or cancer cell), or whether the cells were slill i~ ailu or e~tplanl,:d in lissue cul|pre. (4) In contrast to the remarkably constant and uniform haploid DNA content in sperm from fertile human males and hulls, the DNA conlenl in Ihe sperm from infertile males was frequently variable and sijinilicanlly lower Ihan that from fertile ones. in addillon Io the various lyi)¢l of human lumorl sludied, the relation of DNA In spontaneous and b'ansplanlcd animal tumors was nl~o invcsti- galcd. Principally there wcrc no essential dificrenccs bclween Ibe DHA behavior in human and in animal lumors studied. This similagily of DNA response deserves special consideration, bccaux some of the animal lumor~ studied were lumors wilh a known vi~al cliology, namely Rous ~arcoma of ihe chickon and Polyoma tumors o| mice. Olher ~rnnrOr~: U.S. i~b|ic lleallh So.ice, Brush Foundalion, Elsa E. Purdue Foundation, and Franchcslcr Fertility Fund of Cleveland, O. "A CORRELATED ilISTOLOGICAL, CYTOLOGICAL AND CYTO- CtiEMICAL STUDY OF ]'HE TRACHEOitRONCHIAL TREE AND LUHGS (JF MICE EXPOSED TO CIGARETTE SMOKE." By Leuchlenbcrger, Ph.D. and Rudolf Leuchlcnbergcr. M.D., In~liiul fitr Ail~;emeine Bo|anik, ETH, ZUrich, Switzerland. Ac~u Medico $c.,ndinuvica. Volume 170, Su!pplemcnl 369, pages 102-118, 1961. On Ih¢ basts of Ihe data presented so far, it tppears Ihat exposure cigar¢lte smoke w~ evoke allerado~ in Ihe bronchi of some mite ;umo C F C b Q I-
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ma~izcd •s fo~ows: I. No significant histological chan~es. :l. Mild bronchitis; swoUcn cpithclium frequently ~oclatcd with mild hypcrplasia. 3. Severe bronchitis and pcribronchitis; •typical basal cell hy.p~.~rplasia, squamous cell mctaplasi• and occasionally hbtopathological ch~n£es consistent with the terms "dysptasi•" or "carcinoma in sit•." One or more of the above changes may he obscrvcd in the sam© animal. • Although, oa the evidence of thcs~ findings, one m,'~y be templed to co~lude that there i~ • direct cause-effect relationship between ct&arctt¢ smoke and the cpithslial lesions, there are mainly two findings in our study which impose caution against drawing such a conclusion: I. A striking difference of respo•se is encountered from mouse to mouse which occurs I~&ardlc.ss of whether mica were exposed to relatively. low doses of cigarette smoke for • brief period or a reintiv¢iy high dose at cigarette smokc for • long period. In each of th~ groups, over 50 percent of the mice did not show any btonchlal lesions, while 2Spore©hi showed mild and 20 pcrccnt dyspisstic Ic.sions. 2. There is abs~nc~ of • rdalionship between dose ann length of ex- posure to cigarc:le smoke and frcqucncy and severity of icsin.ns .produced. Iris evident that, in spite of the considerable increase in Icngtl~ ol exposure and number of cigarettes, the rcl•tiunshlp between Jnicc showing no s!g- nificam changes and mice showing mild and scvcrc chart.get in the b~onchtal tree did hal alter appreciably. It is indced astonishing that, among the last group, no invasive brouchogcnic carcinoma has bccn ohscrvcd although Ih~ mice had bccn exposed to enormous quantillcs of clgarctte smoke. and, whenever po~ibic, for n~ariy their whole life span. The wide spcct~Jm of findings and th~ independence of dnsc and du~a- tins of exposure to cigarette smoke would ~¢cm to dellaCt from the ira- parlance of cigarette smoke as an injurious agent invariably affecting the major bronchi and would, rather, point to contributing factors characteristic for the individual animal. Among the many possibl~ ho~l factors, viruses dcscrv© special consider•elan -- the marc so since they occur with a certain frequency in mice, sometimes in a latent form. and are capable of producing respiratory lesions and prollferation of bronchial epithelium. There are two main lines which wc are investigating at present. The first is concerned with the detection of latent viruses in mice prior to ex- posure to cigaxcttc smoke. The sccond is concerned with the ¢llcct of cx- po,suze to virus in addition to the exposure to cigarette smoke. "COMMON HUMAN VIRUSES AS CARCIHOGEN VECTORS." By ChrL.,to~llgr M. Martin, M.D,; $igmundur Magnusson, Fellow of the Squibb Institul~for Medlcal Research Foundation; Philip J. Goscienski and C~¢rald'F. Jlansqn, National Institutes of |lealth re.arch fellows; Scton Hall Coll6gc of ~cdicine, Jersey City, N. J. Science, Dec. I$~ 196,1, panes 1985-1986. (T.I.R.C. grantee: Martin) PutpoJe ol alu~¥~ It has been • continuing paradox that carclnogcns strongly implicated in human tumorigenesis, Ihough prc:,cnt in the human envknnmcnt in only ~'ace •mounts, ordinarily will induce neoplasia in animals only when administered in rclaliv¢ly large amounts or with various physical or c~mlcal "co.cam.inogcns." Spccu|ation on pu~iblc natural co-carcinogens led to considcmtion of thc' possib!c rolc of common, non- tumor viruscs. P~o~tdurel= StudieS were performed in vivo o~ 280 male Swiss white micc from a colony proved frcc of polyom• virus ~nd .which were reported to have a low incidence of dt nova tumors. Pairs~of known heroical cur- cinogsns and common viru~s in diilcrcnt combinations wcrc administered by injection. The viru'ses used (vaccinia, ECH.Q 9, Coxsackic ~ and poliovirus 2) were harvested flqids of fully infected ~su~ cultures of monkey kidney; by the routes glvcn, they evoked negligible'mortality morbidity. The carclnogens injected and theh" rFspoctive do~s0 judged to b¢ t~ small to induce tumnrs, were I(X) mi~rogr'-,ms each' of 9,10- dimethylbena:,nthraccnc.l,2 (DMBA) or of 2-an~huofluorcr~ (AF), and 75 micrograms o! 1,2;.5,6-dibcn~nthraccne To dctermin© 'the role of immunizatkm, half 'of • group of 108 •d- ditlonal mice were immunlzcd against vacclni3 vkux and half hozcn-thawcd monkey kidney cells prior to administration of either vnc- clnia virus or frozen-thawed mcmkcy kidney cells plus either DMUA oc propylc0,¢ glycol. ~'/ndinggr Muligna.nt !•mars occurred in $ groups of mice that received carcinogen-v|.'us paws, and in no o~her 8roups. There wese :5 .m•lisnant tumors each among 16 mice injected with DMUA and vaccinia virus, 9 of which were living at 3 months, and among 12 mice injected with DMBA and poliovlzus 2, '7 of which survived ¢o 3 months. There were :2 ~tumocs each among i:2 mice iniectcd with AI: and ECHO 9 virus, with "/living .at 3 months, and anmng 12 mice injected with AI: and Coasackie U, virus, of which 6 survived to 3 months. Four thymomas -- tumors known to arise dt nova in this mouse strain- occurred in the 161 mice alive alter 3 months. After 8 months, the only tumors ob~rvcd in the immunization pcrimcnt mice wc~e 4 iymphomas in • group of 8 mlcc that' were not immune to vaccini• via'us and were given vacclnin and DMBA intra- pcri~oncally. In vitro studies: C"arcinol:cn.hinding by Pol~virus 2--•~proximatcly 10,0iX) molecules I~r vir,.r ti.~sue culture. 5()% of infectious do.~- was dcmonsirated in vi~ro, with the use of DMBA-9.-~Ie, The ~csults a~rm in v~vo intev, ctlo~s of vhuscs and carcinogens previously described by other investigators, and are consistent with the sci~lrt by D. V. ~i~:lcy ct ah (P~. A.A.C'.R. 3:278, 1961 ) of enhanced chemical carcinoi~¢~csis in mice repeatedly exposed to respiratory viruses. If such interactions occur in nature, it may prove po~sible to reduce pins.l• currently ascribed to chemical c•rcinogens by immunization against • VKU$. "CHANGES IN MODAL VALUES OF CHROMOSOMES AFTER IR- RADIATION OF HUMAN AMNION CELLS." By Masahi~o Mizutani. B.A., •rid Y. H. Nakanishi, Ph.D., now at Hokkaido University, Japan; Yasushi Ohauki, M.$., now at Pasadena, Cal., Foundation for Medical Rcseagch, gad C. M. Poatcrat, Ph.D., Tissue Culture Lubo~•to~, Depart- meat of Anatomy, University of Texas Mcdic•l Ilra~ch, Galveston. C~
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Cemlerence in Re~earch on the l~adiolherapy ol Cancer. pages 56-69, April 1961. {T.I.R.C. gran~c¢: Pomcr~t) Pur~,s~ o] ~tudyt ~ylological ¢znminalion of i~rndiatcd cells of wholc or~msms of many workers invitc sludi~ in this field, with ~h~ us¢ of cell cullu~, of s~ssiv~ gamma ~ad~lion on the m~l chromosom~l hUmOr. o~ a human amnion Proceduret A human amnion ~11 ~in with a modal value of ~lcs was cultiv~lcd for two days pg~r to irradiation with I~ r of g~n,na gays hem a rad~cfiv= cobalt s~gc=. ~e observation of chromosomes was made with t~ u~ ~ ph~ gonlgast Findlnga~ The ~puhtinn of human amnion cel~ ~howrd ~vcre injury f~ lhe radiat~. On cullivatio~ healthy l~king c=ll~ howgver, they now had T~ chrome,s. R~tition o~ lh= tg~atmgnt on th~ new ~ublio= gg~ucgd the m~l val~ o~ chromo~me~ to ~I. Furlhc~ daclion of th~ valu= did nut ~cu~ after irradiation for.the third and even [~ the gOu~lh li~. Ollmr human a~ion ccll~ wet= irradiated gout limc~ during S0 ~y~ withal ~king ~u~ultuggs. TI~ most f~cqucnt chromosome numbgr at lhe =levonth ~ub~uitur= o~ the =stablished ~ubli~ 7~ to 71. ~e ~topping of ~ m~al value at 71 invites further studies con- coming this ly~ of "SOME COMPARATIVE EFFE~S OF SMOKED PAPER. TOBACCO AND CIGARW~ ON CHRO~OSOMF~ I~ VITRO." By Akio Awu. Y~u~hi OhnuEi, and G M. P~ersl, Pasa~na (Cal.) Medial Rc~rch. Texm Rep~ts on Biology ~ad Afedicine. Vol. 19. ~I~-52S, Fall 1961. (T.I.R.C. Rllows: Awa and Ohnuki) Mitotic and cM~al analy~s were carricd out in the IIL-C strain cells expend direclly to the =rook= co]~cted from (A) whol~ cig- a~cttc~, (B) tohacco aleut, and (C) pa~r ak)nc. M~phu~gical obsc~a- lions revealed lh~l ~r smukc induced ~vcrc vacuohzatlon o[ lhe cyto- p~m together with py~tic nuclei in most ccll~. In contra~t, little evi- dence of ccllular ~mag= wa~ ~hown by execute of smoke gram whulc cigarette and /rein t~acco alone. • ~ere was a ~cgeag in the tale of the mitotic index and a c~sid- crabl~ increa~ in t~ num~t ~ abn~mal divi$inn~ as a Result of lho lrcat- ngnt with each ~bstance, ~art~ularly wilh pa~r smoke. Contr~clion ch~,m~m,cs was noliccd In ~m= mclapha~s =x~scd Io smoke from w~l~ cigatctles and groin tobacco. In contrast, pa~r =muk~ pn~uccd high incline= of chro~me ~kincs~. Th~ mitotic abnormalit~s and the shift in the m~al chnJmu~omc num~r of the IIL~ ~traia are briefly di~u~d. Ot~er ~rnnlor~ U~. ~bl~ Health ~. "PULMONARY NEOPLASMS PRODUCED BY METIIYI~HOLAN- ~RENE IN Tile WIII~ PEKIN DUCK." By R. H. Rigdon. DepaRt- ment og Patholo~, Univgr~ity og Te=a~ ~cdical Branch. Galvcstun. R~ararch. Vol. 21, pages 571-5~4, May 1961. l~rpoae o~ atud~t The re~p~ralo~ t~acl in the duck is timilar in many way~ to lhal in man. In prgv~ou~ =t~riments carcinomas and ~tcon)as ~currcd in t~ g~pirato~ aagt of whir= Pgkin duck~ ~vgn an intra- t.rachcal injcctlon of mcthylcholantht~n© suspended in polysosbate SO. Mot© clclailcd investigation was cunsldcgcd desirable. /)eo~,e.dur,~r Sixty-six ducks wcrc given 3-mcthyi~olanthrcnc suspended in a I jxrccnt aqueous solution of polysorbatc gO, ;~nd 25 were glvcn only the polysm'bate. A ~mall catheter was placed in the trachea through external larynx, and one 25 ml. injection of the ~o~ution was given within an interval of 2 to :3 minutes; 250 mr. (d' methylchc41anthrene was given to 22 ducks, 125 n:~:. to 28, and 62.S mr. to 16. The ~);rds were ,~acrificed or died at varying Intervals, and the respiratory tracg removed in tote examination. ~ ' Fin.diarist .No. I.umors occurred in birds receiving polygabate alon~, but Strlateo amytOlU In the liver, and local areas of necrosi~ in signaled appeared in some of thc~ ducks. ~lany neoplasms ~curgcd in the tory tract of birds rcccivlng meth.ylcholanthren©, th© firsl appearing ~6 days after |njeclion. S0mc ot the lumors were neurofibgomas, and others werg ganglioncuromas, h©mangiomas, squamous ceil-like c~arcinomas, adenocar- cinemas, and unclassified types of tumors. Frequently a ~ngle tumor zhowed a variety of histological patlcrns..No metastases occurred. Mcthylcholan- threne crystals per~tsted m the tract for long periods. Since amyloid and ~ u~ular necrosis a~)aoeared in Ircated ducks and the controls, the.s0 eft'eels o not ap~pear specifically related to mcthylcholanthgcnc. The problem o|. antyioldosts in the duck is now under study. . Ol~er grnntor~ U.S. Public |Ica]th Scrvicc. "L~.SIONS IN DUCKS GIVEN METHYLCliOLANTIlRENE." By R. Rigdon, M.D., and S. M. ]VlcAncily, B.A., Unlvcraity o1' Texas Medical Br-',nch. Galveston. Arci~ive: o/PoO~olOgyo Vol. ?2, pages 455-464, October 1961. (T.I.R.C. grantee: Rigdon) P~rl~o~e o] shitty: In a previous caper|merit neoplasms developed in the resptratory tract of white Pekin ducks following a single inlratracheai in- ject;on of methylcholanth~enc. "l'hc present study was made to ob~gvc the pathologic changes occurring in the respiratory t~acl preceding the develop- ment of ncoplaso~. Procedurt; Twenty millilitcn of a so|,tion of $0 mr. of methylchol- anthrcne in polysorhatc was in~cctcd by tube into the trachea of 20 ducks 56 days old; 2 of the~e birds were killed 5H ho~rs later. 2 after "/days. 2 after 13 days, and 3 died on the 26th and 2?th day. One was killed on the 35th day and 10 were killed on the g4lh day following the injection. Ten other birds 40 days old were given 6 to 9 daily injcctions and 10 others wcrc given 10 rag. for ? to 16 times; all ducks given multiple injections either died or were killed at intervals of 9 to "/2 days following the first injection of the carcinogen. The respiratory tract includir', only the lower laird of the trachea was removed and several scctinns taken |or histolog~c study. Findin%:t An acute and chronic inflammatory r~'action occurs in the lung of white Pekin ducks following the inlratrachcal injection of mcthylchol- anthrcne in polysorbale $0. Assnciatnd wilh this inflammatory reaction is regeneralion, hyperplasia, and rnctaplasia of the brtmchi'-,i epithelium. Mcta. p.la~a occurs as early as ? days after treatment. Hemangiomas. adcnocar- cmomas, and fibgosarcon~s arc present in the lungs 72 days following the O (£)
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I~rst of i 6 in|raerachcal injections of the carcinogen, in view of the presence of ~quamous metaplasia a~ thc ab~c ~ typical ~uamou~cll carcinoma~ in (~ lun~ o~ ~hc~ ducks ~hc question is raised rcfc~ab~ Io the ~lho~ncsis of ~c~ ncop~sms. Mcthy~holanlhrcnc c~s~a~ mechanically obstruct (he lumen or Ihc small ~o~i resulting ~ atclcc~s~ and sub~qucndy pul- ~na~ ~b~is with an ~ated pulm~a~ cmph~ma. !!, Hurrmn Lung Sludies "ACUTE EFFECI'S OF INHALATION OF CIGARE'~FE SMOKE ON AIRWAY CONDUCTANCE," By Jay A. Nacl¢l and Julius !1. Comroc Jr., Cardiovascular Research inslilutc. University oI California Medical Center, ~ Francisco. Journol o/'Applied Pkydoloey, Yol. 16, pages 713-? 16, July 1961. (T.I.R.C. gran~c¢: Comwe) Purpose o/slmfy# Prcv~ous ~ud]cs of ~C acu~ ¢flccU O[ inhalation o[ cig~c~lc s~kc on "a~way mis~c" a:c o~ ~ublful si~i~ancc, .a) ~a~ wine ~ ~ ~lh~ ~d rcquhc an ini~al ~¢p ins~ra,on, winch we ~w k~w may it~ d~ca~ a~aD ~stancc, and b) bcc~us~ non~ o~ ~ ~sl~ ~=d ~rway r~nce al~c but ~athcr a combination factor. ~cl~inj d~u= r~is~ce and volun~y mu~ular c~oet. Accom- in~y, wc u~d I~ ~y plclh~aph [Tchniquc t~ ~tain a ~nsitivc mc~urc~nl of airway rc~ atone. . Pr~l~rez Ea~ subjccl ~t in the c~ 9~lilcr ~y wcmysmo[raph for a few minutes. I~ pantcd ~ough a ~owmctcr for several ~conds. dufJn~ wh~ lime his a~ay rcd~an~ was measured at flow ralcs of O.~ lltcr ~r ~cond. We I~ cl~d ~ shutter ~twecn the ~uthp~cc and the ~wmctc~ a~ mc~mcd Ih= subject's th~acic gas volume (TGV) mo~raphically. F~ch lest co~tcd ~ four con~cu(~ve measurements of ai~ay resistance ~d TGV. We caku~d all ~ta as airway conductance " ( I/rc$islancc)~GV ~ co,oct for variations in lun~ wlumc du~in~ Ics~ing. ~c t~cd 48 jbbjccts ~h~ lungs wcrc ncrmal, i~ludin~ maic and female ~o~ceE~and ~n-~c~. and 22 ~dcnls wJlh a d~agn~Js ~f pulm~na~ cm~y~m~, as~h~, pul~na~ ~br~s, ~arco~Js. o~ mitral ~lcnosJs, all F~n~ag#~ ]n the healthy subj~ there w~ no Sight,cant difference Iwccn mal~ and fem~ sm~c~ and ma~ ~n.smokcrs. but ai~ay con- ductancc~GV was si~i~cantly higher in female non-smokers in t~ control ~ale. Wc studlcd the acute =~t o~clgarcttc smoke inhalat~n in 36 hcahhy subjects (21 smokers and 15 ~n-smokc~) and 22 smokers with cardio- puimona~ disea~; t~ ai~ay c~uclance~GV ratio dccrca~c~ aflcr the inhalation of cigarctlc ~okc in ~h ~oups. ~e c~ccls wcrc ~d~alc; l~ n~an dural~n of c~cc~ was 35 minutes. Inhalal~n ~¢ccnl i~prolercnol acgosol ~vct~d or prevented the cllccl smoke in~lal~n. T~ ~c~¢~ In conduclanc¢~GV cau~d by inhalalion Our study indica|es thai mild bwnchoconsuictioa, insulqic/cm io caus~ symploms, occurs immedial¢ly in most individuals after inhalati(;n o~ cig- arctic smoke, lasU 10-80 mlaulcs, and rc~cur~ wilb a ~cond c~ga~¢ll¢. Wc su~esl thai I~¢c arc insu~cicn[ and ina~uaK¢ d~la al pr¢~nl Ko wa¢~anl ~¢~lJ~ Ihe "b~onch~onstriclion" o~ ~okmg ¢au~lly Io lhc iniliali~ a~ava~ion of chronic pulmonary ~a~. • ~ OJker gr~ior~ U.S. Publ~ Health ~wlce.' "~E PATHOL~iC ANATOMY OF ~E BR~NCHIAL TREE AND LUNg." By Slan~[ P, R~mann, M.D.. Direclo~ ~crilus. i~li~ule for Cancer Rc~atch. Ph,ladclphia, Pa., and Mem~¢. ~ienlifi¢ Advisow Boa~ Id I~ Tobac~ Indugry R~rch Commit~¢. JrcHve~ ol Palk~oXy, Vol. Analomi¢ Study Group) Twelve c~dc~cd palholo¢i~t~ from vad~ Faro ~ I~ Unked und¢¢l~k a sludy of Ihc palho~F~ analomy of dm bwnchlal trc¢ and lun~ in s~cimens ob~a~ed [rom ~oul,~ autopsy ~w~e~ and surgical ~cidons. The oHocl was to calaloguc ~anges; silos and inc~nce in t~ orga~ in rclat~n ~ a~, ~X, ~cupa~ion. ~lac¢ ol resi~nc¢ ~d work, u~ and cau~ o~ ~a~h. ~ c~,~ca[~ u~d were: normal, hy~lasia, ~uamo~ me,apiarY, alypical ~(apla~, c~cJn~a In zlm. Almul ~.~ c~cs w¢¢¢ invcuiga,~ ~icldlng 8,590 slldes from 'males and 3,~1 sli~ fwm [ema~s adj~gcd ~uilab~. ~¢ ~r~r li~ yoked ~ag¢¢ements, many of wh~h c~id nm ~ ~ci~d. In a~il~n conferences. ~¢led slides were cbcolatcd and many pai~b~im examined II~¢ir own slides a ~¢ar or so aflcr Ihci¢ ori¢inal diag~s. ~m¢ o[ I~ limilafions of Ihc ptaclice u~ pall.dogie analomy w¢~¢ disused. From raw compilalions Ih¢ ~¢sull~ w¢¢¢ equiv~al. Rigid llalisllcal appmisab wc~¢ made and w¢~¢ publis~d in ~par~ pa~rs (E. B. Wilson ~ M. H. Burke, 1957.~). II was ~own Ihal a c~rahv¢ xludy b in p¢~ms in which large amoums ol ~la musl ~ collcclcd a~ in which basic pr~cdures in a particular d~ipli~ can ~ col~lively asscs~d. . "A ~UDY OF THE TRACHEOBRONCHIAL EPITHELIUM AND CHAHGES RE~TED TO SMOKING." By K. R. C~ms, M,D., ~nald V. Walz. M.D.. ~. Kchh Paler, M.D., and E. D. Warnu, M.D., ~parl- ment ~ Pathology, V¢lceans Adminis~allon Iiospilal. Iowa Cily. O] ihe iowa Slate Medical ~iely, VoI. 51, ~geS 137-140. March 1961. (T.I.R.C grantee: Warner) Pur~ o] ,t,dy: Of Ihe tint 91~ automat at the Hospital during a ~ix-y~ ~ri~ bronchog¢nic carcinoma w~ dia~d in 139 ca~t (15 ~rcent). The purer of this pa~r is to di~vgr the ~grcc ntetap~s6c changes ~¢ur~ing in t~ br~hial epit~lium and to whether or nol the~ changes are related (I) to previo~ m~in~ (2) to t~ ~vcJopmcnt of b~onc~geaic ca~c/~a. ~r~edure~ Fihccn represcnlaliv¢ ~cli~ oi I~ l~achea and t~ sma, bronc~ wcr¢ ~¢lcd in ¢~h of 140 aulopsy ca~s proved for sludy, including 26 palien(s wilh carcinoma of the lung. ~¢ were ¢bs~¢d as nmmal, hyW;p~da. ~m~s ~lap~a. m¢lapl~a, ~rcinoma in silu. and carcinoma. Thcr¢ were )I
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O) 0 0 CO 0
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I I Purpome oJ study# In a previous study the early response to cigarette smoking was ass~,iatrAJ with enhanced myocardial b~:xl flow in norms! subjects. Whether a s~n~lar situation occurs after 'the known peripheral hemndynamlc rcspoas.c..s have Ixcn established and maintained required .e.a- aminat|on. To assess t);¢ potential roJc of tobacco as a.¢ausc of myocard,aJ ischamia,.thc resp(mse'to smoking in patients with coronary artery disease has hccfl contrasted ,kith that occuzrins in control subjects. Pwm'~,durea: The study group compriscd g subjects with coronary artery disease who had i~cursed an acute myocardial infarction at least one year ~rcviously and 6 control subjects who had recovered from acute benign illnesses. All the patients wcrc habitual smokcrs. After an overnight fast. the patient was catheterized through the coronary sinus and rir, ht atrtum and a needle was placed in the brachial artery. Resting cown-',ry blood flow was determined in the rccumhent position and the patient began cigarette in- halation at 4S-second intervals. Two standard non-filter cigarettes wcrc consumed in shunt 2:5 .minutes. so that the initial increase of pulse sate and pressure was largely maimaincd during: the subsequent J2'mlnutes of nitrous oxide inhalation. Upon cc.~',stinn of mhalatinn, cigarette smoking was re- sumed at the same rate and was maintained th~oughont the coronary blood flow sampling. Heart rate, arterial pressure, and a left vcntricular lead wcrc monitored throughout the smoking and wcrc relatively constant during procedure. . Findinl~,r During Cigarette smoking both the coronary and control groups had significant acceleration of heart rate. A uniform r~,e of artcrlat prcss;,re was sccn in the lat~cr and, with one ¢xccptlon, in the coronary group. Furthcr, there was a tendency for thcs~ hcmodynami," chan.ees to t~ pronopnced it, the coronary group. All control subjects had an incre~ in cardiac index as did nil but two in the co~onary group. A uniform increment of 1¢f¢ vcn|ricuJ~ work during smoking was also me;re pronoupced in the coronar~ group. "]'hc attendant changes in coronary blood flow were not significan! in c[thcr group. . This phenomenon, combined with an unaltered myocardial ,oxygen extraction, resulted in a virtually identical myocardial oxygen usage as m d~.ontrol slate. There was no cvid¢oc¢ of myocardial ischcmia in the coronary ~;uhjccts during smoking. Failure to find increases of myocardial blood flow and oxygen usage in the coronary subjects during cigarette smokln~; may' pJausibly be related to the "fixed coronary resistance" alleged to ¢xist in such patients. That the abnormal coronary vascul~ture is not responsible becomes apparent from the similar response in the subjects without evidence of canonry disease. O~er Rrnnfor~: U. $. Ppblic Jlcalth Service. American Heart Associa- tion. ~ichig:,n Heart Associ~tlon. Life Insurance Medical Research Fund. Abbott Laboratmics. and the Burroughs-Wcllcomc Fund. "STORAGE OF CATECHOLAMINF.S IN THE HEART. EFFECT OF AMINE OXIDASE INHIBITORS." Dy KVohei Kaku. M.D., Athat*a'-ins Chrys~hm*, M.D., and Richard J. Biog. M.D. Ame~ic~ Journal ol Cardi. o/ox.v. Volume 6, pages 1109-111 I, December 1960. "FACTORS AFFECTING MYOCARDIAL STORAGE AND REI.EASE OF CATECHOLAMINES." By Kyohai Kako, M.D., Alhanasios Ch~s- 36 ohou, M.D., and Richard J. Oing, M.D. Cixcu~llon Reze~rch, Volume 9, pages 295,299, Ma~ch 1961. The factms affecting my~ard~l sto~age and relea~ of ~tccholamin~ were invcsliga[cd in t~ two stud~. T~ addition of dihydrox~ph~y~- nine (Dopa) [o the ~rfusion fluid of a heart-lung preparat~ markedly incrca~d the cathccho]amine concentration of tha imlaled bean. In vivo, zhe combination of ipronia~d and Dopa had zhc same cffccl; while ipxon- iazid alone failed to influence my~ardial amine ~ncentralion. In animals prcttczted with Dopa and i~ro~azid. significanl dccrca~ in my~ardial ¢atecho]ammcs.~it is likely t~t stimula- tion of the adrenal medulla and s~mpalhetic nc,~ve '¢ndin~ by nJcot~¢ clcvatcd calccholaminc i~vcls'in b~, with zub~ucnt stora&e in t~ hca~ and olhcr or~znz. "M~AflOLIC A~IVi~ OF THE INTA~ ~RT." May 1961. ~ difference ~ compo~iti~ of bl~ col~Fted from ~ a~tc~ and /win the cmona~ sinus is determined by the pr~c~es of intc~mcdiarx mcta~llsm in the heart muscle ~11; bul.~ca~c of sto~agc ~ subs~at~ and their interc~g¢ in bea~ mince, tho coro~artc~vc~us ~cflccts only a balance and ~rmits no conclus~n~ as int~rmedia~ mcl~bollsm in the heart mu~ cell. T~ llmilation~ of such bi~mlcaJ ob~rvatio~ arc e~mpliE~ bx studi:s on ehe nlt~ogen cquillbrlum of ~c ~y. This fu~ni~cs infarction on the balance hclwccn dietary W~cln and its rclat~n m Wbtein b~kdown or pwtcin sxnlhc~is; hut such studies t~ll nothing 6f the ~te and dcgr~c deami~ion, lr~m~mination, ~cas~xylation, 'or ot~r inte~m~iar~ ccss~s u~ .pwtcln mctabollsm. II is tlm~cfo~c cs~n~ial to combin~ mcta- I~lism b;dance ~tudics with investigations of ccllula~ mc~li~. ~is ~c- ~Jr~ is p~ima~ily ~nccrncd wilh in rivu studics of mclu~iism of the normal art, t~ anoxic ~art, ;rod tl~ die, tic ~art. "EFFE~ OF ATRIAL AND VENTRICULAR FIBRILLATION AND VENTRICULAR TACIIYCARDIA ON CAROOHYDATE META- OOLISM OF TIlE tIEART." llX Michael Klarwcin, Ph.D., Klohci Kako, M.D., Alhanasio~ Ch~sohou. M.D., and Richard J. Bing, M.D. Circulation Re~euvc~, Volume9, pages 819-g25, Julx 1961. Changes in the ~atio phosp~las~-a/to~l phospho~la~ music, as wcll as ~he mX~ardial concentrations of glycogen, gluco~-~ phosphate (G-6-P), lactate, py~uvatc, f~ucto~-i,t6~iph0sphate (FDP), dih~dw~)'acclon~ pho~phat~ (DIIAP). wcrc foll~wcd du~ing a~tificialix duccd vcnt~icula~ ~achyca~dia, vcnl~icula~ fibrillation, and atrial ~bril~l~n. Thc~ cx~rimcnts wcrc ¢o~r~d ou~ with and wit~ .ut sup~rt of the co~X ci~cululion. W~n co,unary circulaxion was n~ maintained, active phusphor~ incrc~d, t~n dlminishcd in h~art mu~le during all three conditions, similar to chan~cs ~c~rtcd in skc~tal mu~le. When cmuna~ circulation was maintai~d, no changes in ca~h~d~atc in~crmcdiatcs or in phos- p~l~o~-a aclivitx were ~cco~dcd. Thc~ rcsuhs ~munstrute thai the 37 L F C F F C
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mclabolic clm~gcs cncountcrcd m hcarl musclc during thc~¢ arrbythmia$ are Ihc rcsull o[ anoxiz. "REC~NT PR~R~ AHD PRF~EHT PROfiLEMS IN THE FIELD OF SH~K." Panel Di;cu,ion by Richard L Uing. F, dsration rr~¢dings. Yol. 20. pages ~2-73, 3ul~ 1961. The chang, in my~dial mcla~ during hemord~ag~ sh~k not i~;ed ~cur~cnc~ bul fofiow the general ~ttcrn of my~ardial anoxia resulling ~rom dim~ished corona~ bl~ flow. On Ihe ~is of cx~riments ~dormcd on Ihc anoxlc heart during vcntriculas (achycardia a~ .fibrilla- tion. il ~ ~hlc Ihal ~hang~ ~ ph(~phoryla~-a activity al~) occur in he~t music during sh~k. W~thu the enzyme phospho~ructokina~ is the rate-limiting enzyme ~ heafl .music during hemorrhagic sh~k Remains to ~ cs~bfished. • "CO~R~I~ PROTEINS OF IIE~RT MUSCL~ IN M~H." R~hard ~. Bin~ M.D. and K. Knko, M.D. Circ.~a~;,~s. ~lun~ 24. pages 483~90, August Ig~l, Part I!. The contract;fity of actomyosin b;n~ prc~rcd ~rom hca;t muscle pztlcnts who had died ~ ~n;csfivc failure was diminished as compared ~ p~cpar~ f~om n~mal hear~. ~is ma~ have ~cn the rcsult of defec- tive protein synt~sis. ~c inc;ca~ in ~art ~atc was correlated w~th the ~tJvst~ of ph~pho~l~-a in hea~ music sad with changcs in cnrb~- d~atc m~mcdlat~ (l~tc, G-6-P and sl~co~cn). Hcan rites over 3~ ~r minu~ wcrc as~iat~ with a transient in- ~ca~.' follow~ by a ~crc~, :~ ph~p~ryl~-a activity; glycogen m;n~d, wh;k lactate sad G~P inc~cascd. The oxi~t;o.-~cductJ~, i~fcs~- Sial in ~an m.~l~ ~camc mo~c negative. In the ab~ncc o( my~nrdinl ;nozia, thc ~cr~ ~tc o~ stimu~tion of the hc;rt pr~uccd no t~o~ in citer the ~nCat~n ~ carbohydrztc intermediates or the phospho~i~-a activity. . Allcratio~ in fusion of t~ heart that ~c into play u~ rapid changes of cardiac activily ~e I~ result of the integration of sevcral divcr~ bi~hcmic~! ccllu~r ~eactions. The contractilc proteins arc but fol~wing the lcad of the cellular ckmcnls c~a~rncd with the pr~uctio, of ~cr~. "EXTRA,ION AND REL~SE OF INDIVIDUAL FREE FA~Y ACIDS BY THE H~RT AND FAT DE~TS." By Ma~tin E. Rothlin and Rkhard J. Diag, ~p~tmcat of Mcdlcioc, Wayne State University Collcgc ~f M~ici~. Io~ o/C~nical Inve;~ixalion. Vol. 40. pages 1380- 1386, A. gust 1961. Pur~, o] ,udy: It her previously ~cn demonstrated that in thc ab~tivc "state c~r~ pr~ucli~ of the hca~ dc~nds iargcly on fully ~M metallic. AI~u~ I~ general turnover rate of individual FFA has ~cn studied, ~ invcstigatio~ have ~cn undertaken to di~ovcr their fate in the ~art mu~le. ~c prc~nl sludy dcah with the my~ardial traction of individual FFA, i~luding its rcicasc by adi~ tissue. Pr~dur~,: Hum~ ~ticna frcc of metabolic di~rdcrs, none of whom was in congestive ~a~ ~ailurc, and ancsthcti~d dogs. wcfc studied fast~g ~a~. Coro~ vcno~s ~ of man and dog was obtai~d by cathctcrization of the coronary sinus; simultancously, arterial blood was collected from the brachlal artery (man) or front the femoral artery (dog). Dlood from the saphenous vein (dog), which drains largely subcutaneous tissuc,'was also collcctcd. Frfc fatty acids wcte dcterminedin the va:ious blood spcclmclts. Fimlinl(Jz in the postabsorptive state, the human as well as the dog extracted a conslstcatly higher perccntagc of frcc olcic acid than of any other FFAprcscnt in arterial blood. This acid was also rckascd at • higher rate of fat depots of the dog. These findings suggest a high turnover rate.of frcc olcic acid. It appears likely that an exchanl;c between plasma trigly- ccrldcs;md frcc fatty acids in heat1 muscle, rcsUltmg from lipoprotcin lipas~ activity, may be responsible. OIh,r (rranlor*# U.S. Public Hcallh Scrvicc, A~ncrican Heart Assocla- lion; Mtchigan Hcart Association, Life insurance ~cdi~al Research Fund, Abbott Laboratories, and the Durroushs-Wellcom~ Fund. "RF,HADILITATIOH Ilq HEART DISEASE." D# Richard J. "inf,.~.~. Detroit, Mich. Archives oJ F.nvironmen:,~! lt¢allI~, Vol. 3, pages .o - September 1961. Rchabilitatinn in congestive failure and coronary heart di~t~ is dis- cussed. Proper diet and moderate exercise arc impoflant and return to work is helpful to. the paticnl. "CONGESTIVF, |iF-ART FAILURF,. ITS PHYS]OPATHOLOGY AND TRF~q, TMEIqT. WITii SPF,CIAL RF,FF,RF_3,iCI~ TO IHTRACTADLJ~ IIEART FAILI IRE." ily William H. Morse and ]~icha~d J. Lling. Waync State U~iversity College o| Medicine. PojIgraduole Medicine, VoL 30. pages 293-300, October 1961. The relationship between the physiopatholol~ic factors involved in heart failure and the manifestations of the disease ts not ckarly understood. Clinical signs and symptoms a~c caused by distu~banccs in clcct;olyte.and water balancc. Speculative theories have bccn advanced concerning the role in heart failure pla~ycd by cardiac metabolic disturbances, changes in thc molecular structure of actomyosin, excretion ol aldostcronc, r©lcasc of antidiurctic hormonc, and l)crversion o! the normal mechanisms of both fluid volume and sodium regulation. Treatment of congestive failure is still chiefly em~)iric, consisting careful regulation of soc~ium and' water intake and •drain,sir•lion ol digitalis and diu~clics.. "DOPA UPTAKE AND CATECHOLAMINI~ CONTEIqT IN HEART AND SPLEEN." Uy A. Wcgmann, K. Kako. and A. Chrysohou, [kpart- mcnt of Medicine, Wayne State Univc~sity College of Mcdick'~, Detroit, Mich. ,4mcrica~l Jouraa~ o/PhyJiofo&y, Vol. 201, pages 6"/3-676, October 1961. (T.I.R.C. grantee: Ding) DL.Dihydroxyphcnylalaninc (Dopa) was inlused in mongrel dogs under various condilions in ordcr to study its uptake and influcncc on the Rio;age of no[cpincphrinc and epinephrin~ in thc heart and spkcn. Ho in- c:casc in content ofthcs~ catccbolamincs in the heal1 and splc:r~ could Ll
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de~cclcd afler Dopa inlusion. Apparcn|ly the ra|c o| conversion o1' Dopa i..n.to norcpinephrine dc~s not depend on the supply of ehe substrale. MYOCARDIAL MI--"rAIJOLISM IN PROGRESSIVE MUSCULAR DYSTROPIIY." Uy J. |~. Sunderm©yer. S. Gudbjarnason, V. E. Wendt. P. O. Den Oakker, and R. J. Biog. Wayne Slate University College of Medicine and Harper Hospital; De|roll, Mich. Circulosion, VoL 24, pages 1~348-1355, Dec. 1961. • . The cardiac.oulpuU were clcvalcd in all of eleven paEcnts with pro- ~jcs~ive muscular dystrophy tludicd by the aulhors. Dil[crcnccs in oxida- tion-recluctinn p0ten|ial hetwccn arterial and coronary venous blood were positive, suggesting glycolysis in Ihe heart muscle. Slimula|inn cg ~lycnly~s by inorganic phosphalc was sug~eslcd by the relationship between inorganic phospha|e concentration in blood and the myocardial glucose exeracdon. ThL~ suggesl~ the po~,~bility of uncoupling o( oxidative phosphoryladon in the myocardium. - "COMMON CIRCULATORY MEASUREMENTS IN SMOKERS AND NOH-SMOKERS." By Henry Dlackburn. M.D., Josef 13ru~k. Ph.D.. and Hcn.~ L. Ta)lor. Ph.D., Laboralory of PhysJulogical Hygiene. Univcr~ily of Minnesota. and Medical Department, Mueual ~crvicc Insurance Com- panics, St. Paul, Minn. Cireu~ion, Vol. 22, pages I 112-1124, December 1960. (T.I.R.C. granlc~: ]~rozck) Purpoee o/,lu,'~y; He convincing theoretical or experimental basis has heen' established th~s far to explain the higher cardiovascular mortality rails in' smokers than in non-:mokers ~hown in ~veral cpidcmiological sludges. The prc~nt pape~ is concerned with resting pulse rate and blc~d p~cssur© and ch'culatory r©acdons to ~cvcral prcar, or stimuli in male smokers a~l non-smokcr~. • ~roc~,e~,re; Four sludy gronp~ comprbing 1,093 men agcd 17 to 67 wcrc examincd: gioup A, 286middle-aged business and pro[c,iona] men; group ~B, 1~9., male university students; group C, 414 railroad employees; and ~roup ~D, 234 cily Arcmcn. Replies to slandardiz.cd qucslionnaircs regarding smoking ~werc~.grouped under never smokcd, occasional smokers, ligh| ~mok:n (under 10 cigarctlcs daily), modcralc smokcr~ (! I to 20). heavy smokers (21 or more ci&arc,cs daily), and stopped smoking for at least on~ year. Findlng~, Rclalive body weigh! was consisicmly lower in Ihe h~avy cig- arc,© smokers compared to tho~ who never smoked, l]asal oxygen con- sumpdon was slightly higher in smokers Ihan in non-smokers. Pulse tale during work and recovery was signi6canlly higher in one group of middle- aged men if patho~glc cases in the group are considered. In "normal" populations, somewhat presclec|cd for absence of hypertension, no (creoles in resting blood pressures were found between smokers and non. smokers, in chc broader studi~s, involving samples of the working popula- lion. smoking was associated with lower systolic and d;aslolic press,tea. Young studcn! ~roups. with short duradon of smoking habil, showed signil~can| differences hetween smokers and non-smokers. The a~iations found do no! provide evidence (or large or impor|an! dil~crcnccs in circulalory reactivily between i~roups o[ habitual smokers and non-smokers. There L~ litd~ evidence for deterioration o( cardlova~cular "l';tnc," in smokers .performing work Iesls. The small magnitude .o~. the dil[crcnccs |ound in circulalory mcasurcmenls, plus certain ~ourccs o! nias. prcclud© ~crious conslderalinn o[ these I'actors as underlying causes of the mcrea~d morlalil~ raic ~mong smokers. OI1~ unanswered q0es[io~s are the im~ria~c of mdlvidual ~cspon~s and hy~nsilivi[y ~o smoking, and the si~ificancc o~ ~cu{c preset and o~her effecis ~ ~mokin~ on ~r~ns "EFFE~ OF tlYPER~SIN OH ARTERIAL PR~URE, H~RT WORK AND ~RDIAC OXYGEN UTILI~TION." Ey [v~ E. M.D., ~ub P~gieler. Ch.B., and Jer~ B. ~hmi[lhe~r, M.D., the a~islance o[ J. H. Ha~en~hicl, M.D., ~nd o~c~, D~v~on page~ 123~-1241, Hovem~r 19~. (T.I.R.C. ~ap~¢¢: Ha~cn~bicl) ~ur~e o/~/u~y~ The cffcc~ ~ acule incr~ in k[[ ventdcu~r pr~ sure ~rk on corona~ bl~ now, my~a~d~ o~ygcn, In~ udli~lion ~cqu~rcd inv~igadon. In particular, t~ere was ~ eor le~mg cx~imcnlal plan in which many obsc~ad~s c~lo. M made on • few amman, each ~rv~g as ~ own ~nlrol. ~ ' ' Prore~lure~ T~ drug Hy~n was u~d, sin~ i; ap~a~ ~o corm~nd complelely wi~h I~ nalurally ~cunlng angio;cnsib, and b an aicnl which migM incrca~ le(I vcn[r~ular prc,urc indc~n~n~y o~ any i~rcase in vcnlricular stroke work or heart ~alc..Young healthy dogs were u~d subj~s in paired ~ri~ ~ ~se~a(ion. compar~g the ~angcs Ir~ th~ [~rsl Io Ihe second conlrol Fr]~ and comparing Ihe d~e~c~c~ found changes o~c~cd ~rom Ihe cnmrol to I~ d~g-in(usion cx~imcnL The various cardi~ynam~ and ~la~Ec (unctions w~[c ~kulatcd and F;mJ;~ge~ ~e siGni~canl hem~ynamic chang, induced 'by t~ d~g were incrcaxd mean aricrial prcuur¢ and increa~d le(~ vcntrkula~ work. A grcaler ~rd;ac ~late ulili~l~ during I~ Hy~rlensia infusion was only chan~ in card~c mc~a~Esm. T~ oxygen le~n in le[~ vernacular venous bi~ w~ nol rcduc;d during I~ aclinn o[ the dru~ The 6ndings ap~ar Io ~up~n I~ thesis Ihal coronary res~lance is re~laled Io insure adcquale corona~ bl~ oxygen and lacla~e trans~n (or the o~ cardiac oxy~' and lactale metabolism. Alcohol o~ II~ Nadonal Aca~my o[ ~Jcnccs-Ha;ional Rc~ar~ Council, Ciba Pharmacculical Pg~uc{s, I~.. and ! ica~( ~s~iation of Pennsylvania. "PRA~ICAL LIMITATIOHS OF ~iE K~ M~OD FOR DE- ~RMINING COROHARY ~L~D FLOW BY IN~ARED AHALY- SiS OF B~D NITROUS OXIDE." By ivan E. Forte. M.S.. Louis Po~;cler. ~.D., Je~ E. ~hmil{hen~r, M.D.. Hunler Heal. M.D.. and J. H. llalken~hiel. M.D.. bivisi~ of Re,arch. ~nke~u Hospital. Phila- dolphin. Am,ricon i/~or~ Jour~,~. Vo]. 61. pages 81-87, January 1961. P,r~ae ~J a~y~ ~c pcalcsl nccd ~ the area of diagnos~ ~;udics in palicn~ wi~b cor~ary ancq d~a~ b ~hc dcvclopmcm o~ a prcci~ w measure corona~ arterial b~ Aow in human~, a lack of wh~h
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to .ha.v= been an important limiting faclor in the selection of patlcnta for, eno, hence, the survival rat= or tho~ undergoing endartcrcctomy. ~f:vmas~a~oe=,r/'r.e: Preliminary to_altempfing development of a simplu method ur.mg coronary, blood llo.w .a.pp.fica.bk: to_bo.[h intact animals and man, . .~.~ ,rs~ necessary ;o ~..am mc hmitaaons or the Kcty-Yan Slyke nitrous ox,oe manometric as wca as [hc direct infrared analysis Icchniques. The obiectiv¢ was |o .tablish Ih= reproduclibili~y o! an experimental design in _wh_~.h.!hc y.m~ anita. ~ were us~d.r.c~a, redly, using the combined anesthesia. Firullng:r (I) The blood analytical technique using Ihe princlplc of infra- red absorption is praclical, time saving, and comparable in precision Io the • manometr/c method. (2) During steady stales the Kety nilrous oxide is quantitative and repsoduciblc, and, at Ihe present lime, is |he bcs! mech~d of measuring coronary blood flow Jn/ntact animals. Olher [irnnlo;a: U.S. Public |I©al[h Service, Committcc on Problems of Alcoho/of the National Academy of Sciences-National Research Council. Ciba P~armaceulical Pt'oducts, Inc.. and llcan Associadnn of ~ou|hcastcm Pennsylvania. "MEASUREMENT OF CORONARY BLOOD FLOW USING RADIO- ACTIVE IODINE COMPARED WITH NITROUS OXIOE." Uy Ivan E, Fort~, A.B,, M.S., Jerry t=. Schmitthenncr, M.D., and Hunter S. Neal. M.D., with [he assistance or' Joseph H. Hafkenschlel, M.D., and others. Circula. ~'on Re.~¢arch, Vol. 9, pages $47.$$I, May 1961. .P,.rpo#. o/,~u,i'y= The t~eory on which this study is based is tl,at after rejection into ci[hrx tie pulmonary artery or left ventricle, the first ac|ivatcd blood to reach the ~ight vcntti¢14; on rocbculation rclurn,, by way of coronary ves.~Is. The answcn sought arc, (a) is it possible, by injccting a radioactive bolus, to record an isotope-dilution curve in t~ blo~l of tl|c coronary sinus draining the I¢[¢ ventricle, and, it' so, is this dilution rcflcc|cd in the proximal pulmonary arterial circulation curve or in a p~ccordial curve, and (b) if such curves arc meanin~ful, how does myocardial blood afl;)w a.nd !Is r.atio to c~rdi~c ou.tput compare with blood-flow values recorded moss slmuttancously by the nitrous,.oxidc dcsaturalion method? The prc~nt report dcab with qucadoa (a) alone, , ' Proeed.re~ Coronary blood flow was determined by scintillation counter in an=stheti~d dogs Ixfore and alter injections of radioaclive iodine. The first two experiments attempted to oblain isolopc-dilution curves while con- tinuously injecting a radioactive sodium iodide solution, which proved un- satisfaclory, and the next t'our experiments involved rapid i~jcclion of boluses through a catheter in the dislal pulmonary artery, In lhe neat eleven experiments, the resulting curves were compared with those obtained by the use of a call.:tar in the aortic rool or left ventricle as the site of injection, Fi~,limxa~ An isotope-dilutlon pettcrn was obtainable in only tl~:¢c of cighl dogs lesled. These results e~c interpreted as indicating thai Ihe radio- !sotoi~-dilution method for the dctcrmmalion of eorona~j blood /low is |mpracticabl© in Ihe dog wilh present inslsumcmation because of [h¢ in- ,h=rcnt unccr|ainty and Lh© technical difficulties involved in the methods adopted, Olher grnntor,; U.S. Public llealth ~crvice, Committee oo Problems of ~lcohol of [1~ National Academy b~ ~=s-Nati~ai Re~ar~ Cou~il, Ciba Pharmaceutical Produc~, inc., and Hcan ~Jatlon of ~ut~rn Pennsylvania. '~HE ROLE OF EXERCISE T~S IN THE DIAGN( SIS OF COR- ONARY AKTERY INSUFFICIENCY." By I. F~, M.S.. J. H. sch;~l. M.D., J. E. ~hmitlhenn~r. M.D., H. N~I, ~.D.. and Daugh~rly, M.D.. Cardiac Clin~ and R~rch Oiv~,. ~kcaau pi{al, Phi~ad~p~a. Jm¢rican ~arl Your~l, VoL 6~, pages 7~&762. Jun~ 1961. Pur~¢ o] sIudyt Bccau~ of I~ lack of info~l~n ~ ary paramclcts in the early rccovc~ ~;i~ after my~rd~ infa~l~n; treadmill test was applied to.a few patJcnU in or~ to ~c:tain w~t~r auch tc~ti,g is feasible as a general pr~cdurc to ~tcrmi~ the ~tc of covery and what ambulation therapy ~houM ~ Proeedure~ Eight healthy volunteer ~lc tubj~ aged 3~ to 60 wet= tes~d at a work ~d of 370 kilo~am-mcte% ~g m~ut= (or I0 mMutgs a treadmi~ ( 10 ~rcent gra~ at 1.7~ mike ~r hou~ for I0 minutes). Aftcr a 2~minut= rest ~ri~, the subjects' un~cnt ~hcr i~m~utc pt¢~s=l~ ii~e I~ ~r~. Various cardiopulm~a~ pa.~a' mcl=~ were ~or~d. ~imilar lasts w¢re then carted on al yawing wo~E~ I~ with 3 ca~dial ~licflls and 3 patients wi~ prima~ hy~t¢~ion Inking drugs and were compared with I~ r~ulxs wish healthy ~bjcc~ . Find;mg~: Prclimina~ studi~ ~ 8 ~al[hy subjecls show that t~ s~n~ ~ vcnlilation, oxygen uptake, and heart gate to trgadmi~ vaqlng ~twgcn ~ and ~ Kg.M./miu. ~ li~ar and repr~ucib~. Pat;thiS recovering Irom in acute my~ardial inla~ction were obeyed to ~ ab~ to Iolc:atc an =zerclse work ~ad of 370 gg.M./min, up to 10 minutes, if ab~ Io ~ ambulatoq. Testing at these work ~vels in ~kcled pali~ls ~ows Ihal Ihc treadmill walk ~n ~ ~fformcd wilhoul undue apprehension, excessive [ncrca~l in heart ~ale, or marked ~T-~mcnt di~ pla~menl in the ~ri~ 6 w~ks Io 6. moul~ after my~ardial infarction. Ol~r Irnnlora~ U.S. Public Hcaitl~ ~rvicc, Commill~ on Problems o~ A]coholo~ the Nalional Academy o( ~icn~s;Nalional R~a~h Council, Ciba Pharmaceutical P~ucls. i~., and Hca~ A~iation o~ ~ul~cm Pennsylvania. "CIGARE~E SMOKING AND i~tiEMIC H~RT DISEASE." By D. Dronle-Stcwarl, ~.D., MRCP, ~rlmen[ of Medicine, Univcnity of Ca~town, and Gr~ ~huur Hmpilal, Ca~lown, ~ulh Africa, form~ly at Univ¢~sity ol Minnc~ia. Br~lisk ~edical Jo~l, pages 379-384, Feb. 11, 1961. (T.I.R.C. granite: Dr. Anc=l Keys o[ ~e University ol Minn- csota). (To ~ read wilh companion pi~es in ~m= Journal: PERCEPTION IN SMOKERS AND NON-SMOKERS." By L. H. K~I, M.D., (~.U., Monica J. Pekin, B.~., Dip. D~I., and B. ~.D., ~RCP, ~gcs 384-387, and "SMOKING AND F~D PREFER- ~NC~." By Pcrrin, Krui and ~ronlc-Slewa~, pages 387-388.) ~ur~ae ~J aludy~ ~vcral cpidcminl~gical stud~ have ~c~lcd I~ical rcblionship ~[wccn I~ ~eva~ o~ i~hemic henri di~a~ and ,~. 0"~ 0 0 F C F U C
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o cigazcttc smoking. O, caaminin~ the association one is immediately con- fzontcd with two major ~o~ibilittcs. Firstly. has the smoking of a cieaz¢¢te a direr ~ct bx ~dcrm& with clthcr coz~ bl~ ~w or h¢~z~ ~ondly. ~ t~ cflc~ indiz~t in thai ~tb cj~zc~tc ~mokin& and i~hcmic h~rl di~ mortalilyare ze~led to a thud and common factor? Pr~edur~ Da~ wcm ablated [~om 6~ ap~rcndy hcaJIhy ~ulb African m~cs aged 2~ to 5~ who were actively engaged ~ d~ciz ~cupaduns. c~¢zn~g t~iz ~me. ~¢up~fion. smoking habits, and customary dict. wJ;h particular em~ ~ ~¢~ of ~ ~at conlain fat. such ~ meat. dai~ preach, e~, m~arines, oils, etc. Anth~o~mct~ic measurements were rccor~d 8~ ~st¢~ chem~atly determined in the bl~ scram. ~h racial ~oup w~ divided into three ~com~ elates, but the economic ~alc is such c~t the hJgh-~co~ Uanlu would overlap she economic JcvcJ of the low- and mcdium-incom~ Ca~ Co~rcd. and I~ hiSh-incomc Colored w~Jd ~ on an economic par with the Iow-i~ome ~uro~an. Cig- arette smokers were analy~d ~paratcJy f~om pi~ ~l~kCfS and ~lh were ~sJfied into heav~, medium and li~t smoking groups. Fi~dingJ: No rcJa~hip cou~ ~ found ~lwccn smo~in~ and a~c. in- comc,'~cupation, h~ght, wci~lt, or dcgr~ of o~ity. ~ arterial pzcs- so,ca of h~ s~m I~dcd 1o ~ dighdy lower than tho~ of non- smokcn, but t~ diffcrcn~ wc;c not si~ific~t. A highly difference ~ow, was t~ ~tr~ution of cholcstc~ ~twccn th~ alpha- and ~ta-li~ptotcin fr~. ~ held Uu¢ at each age range, for each race. ~nd for c~h/i~me subgroup. Such differences wcrc paralklcd by dif- .~rc~ .in th~ cust~ta~ d~ia~ fai ~tak¢. but thc~ dif[crcnccs not ~t~t~ii~lly ' ~ findings ~ noK ¢x~ude the ~ibihty that increa~d to ~hcmic ~rt ~ in hea~ cigarette smoke, could ari~ from the bl~-p~,urc chang~ during smoking. On the other hand. the mechanism ~or ~c inczcascd su~cpdbility ~ the smokers c~ld ~ratc via the changes m ~rum lipid found. ~¢ fi,t companion study showed that the ta~t¢ thrcshnlds for were significantly hi~r ~ ~okua than in non-smokc~, while no c~¢s ap~a~cd for sweet, ~ur. o~ sail. ~¢ age of the ~okcr. and rims p~csumably the duration and am~nt of sm~ing. ~th advcr~ly al[cctcd the ~nshivJly to biter The ~cond compan~n slay showed that non-smokers prefer bland f~ and ~ fairly high pelion of s~kc, prefer salty and spiced Smokc~s ~m¢ marc fat than ~-smokcrs, but t~ di~crcnccs a~¢ small. Hca~ smokers co~umc significandy marc ~at spa ¢~s than do non- smokers, and the lattu ¢o~u~ mr¢ fat in the t~m of cakes, ~w¢¢~ and ch~olate. ~x dict prcfcrc~J may account fm t~ diff¢~¢~es in ~rum cho~stuol ~vc~ thai have ~ ~¢~ncd in su~c~s on smokers and non- "DUERG~R SY~DROM[ IN TH[ ORIENT." By Viclor A. McKusic~, M.D.. and Wi)lard S. Harris. M.D.. Johns Hopkins Universily ~1 Medicine. Baltimore, Md. Th~ ~nc¢l, pages II 17-1 ] 18. May 20. 1961. (T.I.R.C. 8ranlc¢: Puv~ o] ~udy: ~ pr~plion .~at in the Ozicnl the clinical and patholo~,;cat plcturc i~ ices obscured by a high frequency of and ~[om~l~ di~ than in W~t~, countri~ prompted a study of th~ Bucrgcr syndrome Jn Japan and K~ca. Fr~e~ures~ ~nc~eady 1957 ~ Pr~bytczhn M~I C~cr at ~iu. Kor~, ~s admitted 62 patents with the dia~n~is ~ Bucr~r'~ d~a~, all mal~; 28 of tt~ who rcs~ndcd to ktt¢ts.wcr¢ studied as was a control g~oup of 28 Kmcan ~s. All but ~ of i~ 28 ~ficnB were f~m~s ~ farm' wmkcm who~ d~t c~stcd minly ~ r~, ~k~d cabba~ vciciab~, ~ya-~n cake, and says ,ucc. ~11 were smokers, smoked heavily. ~rum cholesterol and fast~g bJ~ sular ~v~ diflu sign~cantly from th~ of the conu~s. Y~i~ t~ 6 ~ica~n[c, Japan revealed that m~t un;v~ity mcd~ ~ic~ lamit Iu to t3 annually with the Bucr~¢~ syndrome. T~ age,-~x, and s~ial ~d status ~ t~ pati~ arccs~ntially the ~ in t~ Korean ~t~ntJ. F~Ji ~J¢[¢ ~p~a~ tO ~ in ~Oung m~S in t~ O~ient obi[tcr~tivc va~lar dis~ which ¢linicaJJy apd cp~miolog~Uy, ~rhaps h~tologi~lJy, d~ not ~v¢ t~ ¢~a~tc~ of or multipl¢ cm~l~m. ~ stlolo~ and pa~o;~,is "m~ ~ ~pj~tca. ~at the ¢~nl~l I~oa b an an~itb rcmaJ~ W ~ ~rovcd. An~;l~ or not. ~e ~thogcues~ is n~ unde~t~ but ap~a~ to dsffcr from tha~ of o~r "NORMAL RADBITS' AORTIC A~D ~YOCARDIAL CEL~ GROWN IN VARIOUS CULTURE MEDIA." By T. Kokubu PoI/ak. Dovu Medical Re,arch Cca~r, ~wr, ~I. E~rim~n~ X,~,~c~, VoL 24, pages 41~23. ~p~m~r~1961. {T.LR.C. ~an;~: Po~ak) Pur~e o/~tudyz l~ prcparalion f~ stu~' of t~ c~lS '~ c~a~o derivatives on a,c~Jal and my~ard~l I~sue ¢u~lur~. it was ncc~ establish optimal conditions for in vitro growlb ~ va~ular Pr~dure: ~gmcnts of a~e~Jng. Ihor~ a~d a~ominal aorta and of heart papilla~ mu~ were removed from adult rabbits as ~fl ~ after death, fined in sterile Jsoi~Jc ~li~ ~lul~n. and cut ~to ~c fluid medium wa~ chan~cd tw~c a week. Micr~op~ ~fvat~ns ma~ cvc~ other day for a~ ~r~ weeks. Five ~p~atc nutrient wcrc ~s~. Findinga~ Undi~crcn~iat~ fibroblam from ~a~ ~cw ~sl; ¢¢~ ~¢ndin~ aorta [~cw ~ticr dmn cells from l~r~ ~ a~al son& Rabbi~ ~¢um promoted cell growth ~s~; hor~ ~rum and human ~mm cnha~cd growth mmc ~han ch~kcn ~rum. CcUs grown in chin ~rum di~ercd mo~holo~i~lly from cells ~llurcd in media with o~r ~m a~ilivcs. Growth m medium wilhout any ~mm rc~mbl~d cl~ly ~ults obtained with chickcn scram. For pr~fical reason, ho~ suited ~[ as additive to nutrient medium for ~ vhro cuttozcs of rabbi~' cazd~va~ular Otker ~ranlur: Hat,anal 11~ I~titutC.
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"CIRCULATORY EFFECTS OF PIPE AND CIGAR SMOKING." David L. Simon. I~D.. and Arnold Iglaucr. M.D., Univcrsily of Cincinnali College of Medicine. Cincinnaii. O. Amrrican J,urnul o! Medical .Tcirnc¢~. Vol. 241. pages 22-30. Januaff 1961. (T.I.R.~. ~anlcc: Si~) Pur~ o/~u¢ly: Much al~nliOn ~s ~cn dcvolcd Io Ihc cffccl smoking ciga~ctlcs on Ihc circubt~n but ~clativcly It,It infornmlion has ~¢n availab~ on II~ ¢ircula[off aclion o[ pi~ and cigar smoking. [r~e, il was dcci~d (o ~thct ~la ~ the c,culat~y ¢hangcs ¢au~d by smoking regular com~rcial a~ low nicolinc cigars and pi~ tobacco and to comp~c Ihc rcsulls with o[hct studies on cig~rcl~c smoking nnd ch~win$ I~a~. • Pr~edureat A group o[ 2~ habilual male smokers ranging from 21 to 69 ycan in agc,.o[ whom I~ smoked cigars and 10 smoked pi~s, wctc ~ludied during regular and sh~m smoking ~ri~ under identical conditions. Bali~ardiograms, bl~ presume, pu~c ral~s and skin Icm~ralurcs were studied ~rin~ and abet Ihe ~oking ~ri~ Flndlng#~ ~ u~ual ¢l[¢¢U o[ tobacco smoking on the circulation fou~ (drop in skin Icm~ralurc, incr¢~ in pulx and bl~ pressure), but were n~ us marked.as Iho~ ~ually Iound following ci~reite smoking or Iob~o ¢hewin~ ~¢ incidence ~ changes in the ball~l~ardiograms was ~ss Ihan thai [gund [~owing c~wing Iobacco, bui grealcr Ihan that round Ilowing ci~t¢l~ smoking. Circulatory chang~ were slightly ~u fi~lh~wing " . ~w nicol~e cigars a~ pi~s when ~mpatcd !o s~ndard cigu~ and pipes. Sham smoking did nol pt~ucc circulatory changes. ~11~ CIR~LATOAY R~HSE TO SMOKIHG: TIlE fiFF~C~ OF SMALL DOSES OF H~XAMETilOHIUM AND OF MEP/IEN'rER- MIH£ OH TI I~ PA~ERH OF R~HS~." By Caroli~ Ucdell Th~m~as. M.D., a~" Edmond A. Murphy, M.D.. l~pa;imcnl o[ Mcd~inc, J~lns Hopkins Universily ~h~l oI Me~cinc. Bald~re. Md. Journal ~q Diseases. Yol. 12. pages ~34-543, Hovcm~r 1960. (T.I.R.C. Pur~n~ o/eludy~ During a slanda~d ballisl~ardiographic smoking lest among heallhy young adulB, so~ subjccls sh~wed hy~rrcaclivily o[ Id~l pressure. ~a~ talc. or card~c ~lpul m var~ comhinalions, while olhcrs wilh ~mi~r smoking habils ~wcd litllc change or ~vcn a negative respond. In o[dcr Io Jnvcsli~ie [urlhcr Ib¢~ ~iv~ual differences, il ~cmcd whi~ ~o a,cmpl to ch~g¢ ~c ~nx Io smoUng by m~ifying Ihc physio- ~gic slal¢o[ I~ sub~cls with d~ffc~nl p~rma~logic ~ubs~anccs. Pr~e¢lur¢ez Ob~rvatJons were made on the ci~culaloff rcs~nsr smoking a sin~c cigarcKc ~ollowing small do~s of hcxamclhonium. mcphcnlcrminc, or o~ pla~ (bolonic s~ium chlori~ ~lulion). ad- minis~crcd by inlravc~us injcc;ion. These subslanccs wcrc given in random o~dcr in ~ ~rics of xcparale double blind I~$ll. ~vcfl ~althy while male suhj¢cls had 8 Icsls apace on different day~, 3 with e~h ~ the aclive pharmacological prcparatio~ and 2 whh I~ placc~. "rhe aim was Io pro- duce minimal measurable effccls. Si~c ~ns~livi~y varies from suhjccl suhjecl, lee apprnprialc d~ had ~o ~ [~ by cx~rimenl. Findin~: A[lcr injec~n o[ I~ pla~, Ihe average citculalo~ ~csp~se to smoking one cigarctt© was similar to that in a larger scrlcs previously reported in which no injcc6on was given. From the duplicate placebo an estimate o[ the av~agc variabilily o[ ;hc~ Iclli ~uJd ~ made. Hcaamethonium did not influence lbc mean ~cs~n~ to ~oki~g ~ar ~s could ~ judged by a pai~cd com~ar~n with ~ placc~ tcs~. ~a~t ra~ w~ furt~r (Ih~h not si~t~cantly) incited, a~ ~is might hav~ ~ expected slncc both h~methonlum and ~ok~g. tend to i~crc~ the heart ra~e. When ~ ~phen(c~e sulfate ~ tcs~ were cornered, however, ~th the c~nge ~ s~olic p~ssu~ and cardiac oulput after smoking were significantly altered by mcphentermlnc. The ~hc~ va~blcs wcrc not thus a~lcd. ~ constancy within I~ divJdual ~ the measurements obtained after a cigarette ~ smoked, previously rc~rted as tl~ "cciling phenomena," ~ impaired but n~ ~t~cly oi~" hcd by small do~s ~ t~. d~u~. In ~ rcs~ct the "ceiling nomcnon" rc~mbl~ a ~rd~va~ular hom~stat~ mc~an~m. in conclus~n it ap~azs that this cx~ri~n~a] approach 8cvca~ dividual di~crcn~ ia homc~t~, but that thc~ chang~ Mc not readily Hound. At prc~nt (~ rcsul~ ~cmt~ various ~d t~ complex to ~rmtt a simple cl~ificafon of ~ubjcc~ which could ~ u~ for ~recning pu~s. O~ker ~r~for~ Veterans Admlnlst~t~ CO~OHARY ARTERY DISEASE." By ~roline~ Bcdcll Thomas. M.D:, Johns Hopkins University ~h~l of Mcd~ine. B~lt~ore, ~ ol ~h~ ~vo~ System, Vol. 22. pages 3P~5, Ap~ 196 I. • I'ur~Je.~J ~.dy: In a long-lc~ pros~ciiVc ihv~cigation of th~ cursors oJ ny~rtc~ion and cofona~ di~a~, studi~ arc ~ing made ot the ~currc~, natuse ~nd in(crrclalionsh~p o~ ccr~i~gcnctic, physiological, metallic and psycholog~al charactcr~l~s in healthy Johns medical student. They a~e ~ing followed over the ypars to determine which (actors or ¢onstcllallons of faclors arc most frequehdy a~iatcd whh early on~l of dlsea~, it is I~ au(hor's hy~t~s~ ihat multiple facto~ play a determining role in the ctiolosy o~ these dis~d~rs. Thc exact form of di~asc a~ age of onset in a given individual is thought to dc~nd on the nature and num~r of fac(~s in h~s own genetic inhcsita~e in combination with the pasliculaf environmental sffcs~s cnc~ntcrcd as hc g~s through ,It. Pr~edureJ: The c~r/cK~l~S of 2 cxifc~c ~ps o/slu~n~ wcfc cxamincd ~ ih~ with 2 d~nilcly aK~tcd parcnis end t~ wl~ parcn~ arc ~th ~fcc from hy~lcnsi~, co~ona~ di~, ~slty and diaries. Among ~43 white ma~ medical ~tudcnU ob~cd in the first ;l~s sludicd. I~ gave a ~sto~ ~ hy~cnsion ~ ~th par~ts, I ! ~ athcr with corona~ di~a~ and a mother with h~c~ion, and 3 rc~tcd Ih~ both paints had co~ona~ di~a~. After-determining that the under scrutiny were similarly distributed in thc~ 3 small grips, the sludy was exlcndcd to t~ numcfous (aclors ~illclcntiating I~m (fore the "nor~l" group. ~ndln~e: ~c ~lsprlng of 2 ~rcnts aKcclcd with hy~cns~n cor~a~ di~a~ arc signi~anll~ diKcrcnt in a humor ~ wa~s from I- (.
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offspri.g of 2 udaffcctcd parents. On the average, they are I0. heavier, more frcquenUy have hypcrcholeslcreniia, have hi~hcr rcsling s~s~o]~ bl~ p~urc ~vc~, and arc mo~c I;kcly zo ~ ~kc~s. ~c off- sp~mg ~ 2 o~ pa~cnis a~c dislingu~cd [or Ihc;~ o&n cxccssivc wcighl and al~ have hlg~ c~ol ~c bro~ implical~ns ~ chest sludics arc ~al Ihc offspring ol dif. fcrcnl kin~. o~ human mat~ hnvc slg~candy d;~crcm physiolog~al, mcia~)~ a~ ps~ulo~ characlc~isdcs. Ihal Ihc differences usually arc ~l ~c;~. bui that they arc compatible w;(h Ihe hy~lhcsis of muldf~clodal in~rit~nc¢. AI~. I~' abi,ty to prcdicl high .su~¢plibifity ~o and/~ ~rona~ a~ d~ in a giv~ indiv~ual may well dc~nd u~n ~ idcnd~ad~ and ap~a],! ~ a conslcdallon ~ ~aclors radser titan u~n any s~gl¢ ~a~cicrislic. W~n ih¢ prehy~r~cnsiv¢ or prccoron~ indi- vidual can ~ idcnl~cd wi;h p(~bion, thc pros~c~ (or the prevention of t~ di~dc~s w~! ~ b~ght. O£her j~nfor~ U. S. Publi~ Health ~ice and Vcteran~ Adm~n- "CARDIOVA~U~R. i~ERA~ION OF NICOTi~E, ERGONO- VINE, A~D HYPER~OL~EROLEMIA IN TIlE RA~IT." Hy ' Duanc G, Wcnz~l, Ph.D., Jam~ A. Tu~nc~, M.D., ~ott W. Jordan, M.D., and Jasb~ Sin~, M~., Univcnlty of Kan~s, ~wrcnc~ snd Kansas City, K~n. Citcu~udo~ 8~ze~ch. V~. 9, pages 694-699, May 1961. (T.I.R.~. P~r~ o~ ~lu~ lt'~ im~lanl to d:l~min~ ~.iblc cauls for the ob~c~vcd ~[cr~cti~ of n~ot~ and ~ hy~r~holeslero~mic dicl in th~ m~diai and th~ ~ripherai va~ular c~ccts encountered in ~abbi~ Pr~ure~An fhltiai cx~imcnt employed 4 groups of 12 female a:bino N~w ~aland ~abbi~: an un~catcd control ~oup; rabbits receiving i~]4 m~g./~y of ~icotin~ ~ drinking water; rabbits rcc~ivlng I ~o~lc~ol and 5 ~nt COtlOn~cd oil in I~ di~t: and a fourth group ~c~ivin~ nicotine and the cho~tcrol~otlonsccd additives. Various circula- ~o~ a~ va~u~r readings were taken at interva~ and compared to ~cat~t I~vc~. After 24 weeks the anima~ were sacrificed and the hcarts and femoral a~e~es were examined. Be~au~ of tim lack u~ murEcd pat~logi~al chang~ in t~ choi~lc~l ~nd nlcotinc~holeslcrol hearls, addi- tional groups of rabbi~ were Icsl~ with crgonovine injected ~cause of i~s value in d~o~t~atin~ altcration~ in the cl~ctr~ardiog~am indicative co~a~ di~a~. Fin~ing~ Throughout the cou~ of lhc inilial cx~rimcnt, th~ ~riphcrsJ circu~lion was dcprc~, the syst~ prcs~u~ elevated, and the coagula- t~n ~at~ s~cd~d. PectOral patho~gi~ chang~ wc~ minimal, and are~ cardmc necrosis obeyed in a Simila~ p~cv~us study were a~nt. In o~dcr to. ~tc~i~ t~ cau~ ~ ~is ap~cnt di~cpancy, a ~ond ~oup ra~its was ~imilady I~calcd except that c~onovi~ wa~ added to Ihc dict. ~ 24-week hlstological examinal~n this li~ ~cvc~lcd cardiac nccmsls all anima~ receiving ~c combined n~otine~holcstcrolc~gonovinc I~catmcnt. ~ c~t had not~en ~tained wi~h ci~ nicoti~ ~ cholesterol o~ with ~dnc and c~ol O~her ~o~ Univer~ty of Ka~as General Rematch Fund. 48 IV. P~yclso.Phy~;ological "CONSTITUTION AND SMOKING~" By AI~ Damon, M.D., Ph.D., ~par~¢nt o~ Epldcmi~o~, }tabard ~I ~ Public Hca~, B~n. Science, ~g~s 339-341, Aug. 4, 1961. Pur~se oJ,~tudy: ~he deletion o~ ~lerminanls of I~O ~oking would help m undcrslnndin~ and ~.ibly prcveming ~ ~ as~ialcd wilh smoking. SJn~ the ~ ~ t~a~ may va~ from cultural ~odp ~o anot~r, it wa~ consi~cd dc~ab~ ~o study subteen a common cult~e and a similar bi~o~cal b~k~ou~, a~ who ~ atitut¢ a restively homogeneous ~roup. Pro~dure~ Such a ~p has ~cn un~r inv~d~tion sin~ 1956. 1958 it c~mpri~d 167 male factory ~kc~ w~ pa~ents were "~hhin 75.miles of Haplcs. Ilaly, Of the workers, 151 were ~m and ra~d near Doston. Mq~.. a~ I~ other 16 nca~ Haply, 7 coming to ~e U. before t~ age of 10 and 9 when they were I0 or ~dcr. ~oking ~bi~ were grand ~ 5 catcg~ies: ~vcr Smoked, r~e o~ ~cas~al s~ke~s, ~ra~ smokers, ~vy smokcm, and vc~ hcavy smokers: more I~n30 circles or 10 cigars or pi~ ~ily. Standard tcchniqu~ wcrc followed for p~ct~,'f~ somat~yplng, and fo~ ~ cholcs~c~i u~ bi~ pfc~urc dctc~mi~dons. Dieta~ ~ta were ~cd throu~ ~ 45-minuic'Jntc~w, etc.. and activity was Ha~d in 5 catcgot~s ba~on estimated exertion ~th on a,d off t~ job. Findi~gs~ ~ results show a cops~tcnt a~d ~tatist~alJy si~ni~t tcndc~y for ~an men lu smoke more than stout~ ~at (but nol men. ~ ass~iali~ was not t~ result of different d[c~. si~ s~k~g and caloric intake as well as ~lake of com~ncnt f~ were in~ndenl of each ~hcr. The prc~nl ~ndin~ confirm rc~ts by ~rs of slightly higher ~rum cholesterol amon~ smokers. Contra~ to p~cvi~s findings, smokers in this stoics were no less m~.~ulinc in physique, wc~c no morc active, and consumed no more a~c0hol Ihan non-smokers. "SOME HARVARD ~EH AHD THE SMOKING ~HABi~." By Carl C. ~l&cr. Ph.D., Pca~y Museum, Harvard Unive~hy, Cambr~ge, Ma~. llurv~d Alumni B~llt~in. Feb. 4, 1961. ~ pa~ of a more intensive s~udy of related biological factors to,coo ~oklng by Harvard men. a survey was ma~ of the smok~g ~biis of the class of 1946 thr~sh qucstionna~c, to which 927. o~ gl.4 of the mcm~, rcs~nded. Twcnly-five ~r~nt were clarified as n~- smokcrs, compared to 18 ~rccnt in the U. $. ~pulalion; 59 ~rcent were currcnl regular sumkcrs; and 16 ~rccnt were for~r regular smokers w~ di~linucd the habil f~ vat, us rcu~, a~ul Ihc ~mc as t~ ~donal av~aL~. Whi~ 18 ~rccnt of the regular ~okcrs in t~ U. S. sta~cd smoking ~f~c their sixlccnlh birthday, only 3 ~rccnt ot the Ha~vard ~n Ma~ed so early. ~e avcraKc smoking h~to~ of current smokers was 15.6 ~ca~, while the average durai~n of ~oking fo~ ~c cx-~crs was 11.4 49 O) ,~- 0 0
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suggesting that the period 1954-55 was lh¢ time in which many smokers "broke the habit." Among cur~cn~ smokcs~, 60.2 ~nl smoke ciga~cllc~ only. 12 ~t ciga~cttcs ~ ~, ~.9 ~ccnt ~ga~cttc~ and cirri, and 2.8 ~ccnl all t~cc toba~o fmmJ; 9.4 ~rccnt SII~G pi~ OliJy, ~,9 ~r¢¢~[ only, ~d 3.9 ~rccnt ¢ig~s and pi~. For the U. S., ¢t'ga~cttc only ~mokc~ ~p~ 76.3 ~r~nt ~ all smokcss and combi~d ciga~ctt~ and ot~r forms of smoking t~ 94 ~rccnt. • ~ Hazard men arc ~ hcav~r ~okc~s than the national, avcragc: 9 ~rccnt of ~ ci~a~llc smokc~ consumc ovcr 2 packs doily, ug~ing ~ccnt for ~ ~. S.: ~6 ~nt c~umc ~twccn I a~ 2 packs doily, against 27 ~cnt for ~ U. S, ~c H~vard sm~c~ t~nd to ~ found mo~c f~cqucatly, in tl~ of busin~s contacts and administration, editor, educators, and mu~um c~atoa, etc., whc~as thc~c arc p~o~ionally more non-smokc~ among cngincca, surgeons, cl~gymcn, Icachc~s, and Jibe•Hans, ~c pipe smokers arc m~c frcqucntJy found among s~carch ~Jcntists, cultural administra- tors, hwycrs, college pmfc~rs, and sch~l t~c~. V, Tobacco Chemistry and Biochemistry "BIOSYNTHESIS OF ANABAS[NE AND OF NICOTINE BY EX- CISED ROOT CULTURES OF NICOTIANA GLAUCA." By ~aHc L. Soil, R: F. D•wson, and D, R. (..ristmaa, Department of Uotany, Colum- bia Univcrslty, Ncw York, N. Y., and Drookhavcn National l~ooralory, Upton, N. Y. Plm.; Phy~lolo&y, Vol. ~5. pagca 887-894, Novcmbcr 1960. (T.I.R.C. Uantcc: D•wson) "Tile BIOSYNTHESIS OF NICOTINE FROM NICOTINIC ACID: CHEMICAL AND RADIOCHEMICAI: YIELDS." By R. F. Oawson, D. R. Chtistman. Eel. L. Soil, and A. P. Wolf. Department of Botany. Columbia University, New York, N. Y., and/~rookhavcn Jqational Laboratory, Upton, N. Y. ,4rchive$ oJ Bioc~mi~fr¥ and aiophysicz, Vol. 91, pages 144-J50, Novcmlxr 1960. "BIOSYNTHESIS OF THE NICOTIANA ALKALOIDS." Uy R. F. Dawson, Department of Uolany, Columbia University, New Yolk, 1'4. Y. • 4n,erican Scientist, Vol. 48, pages 321-340,. September 196U. ISotopic tracers applied Io the study of tobacco alkaloid biosynthesis bav¢ re :aicd that nicotinic •cid is a common precursor of nicotine and anabasinc. Nicotinic acid contributes the pyridine ring to each. alkaloid, whilc ornithine and lysine contribute the py,olidinc and pipcridine rings, respectively: Nicotinic acid is probably reduced I-6 prior to combining with thc precursors of the p~,rrolidine and piperidine mocitics. This conclusion is supported by the fact that hydrogen.isotope labcl on the pyridine ring of nicotinic acid is transfencd in sJlu Io the pyridine ring of nicotine from all positions on the pyridinc ring czccpt number 6. The occurrence of the postulated 1,6 dih~,cko intcrmedialc helps to explain the otherwise chcm- JcaJly di/l~cult displacement of the carboxyl group of nicotine acid. There is no indication in these cxpcrimcnts of Ihc nature of Ihc circumstances which compel the plant to synthesize apparcndy terminal products from such mclabolically useful inlcrmedialcs. One of thc imprcssivc i~spccls of alkaloid biosynthcsis by the czclscd toot cultures of N. I~boc~m and N. &/a,,c~ is thc ca••ordinary talc stability of the process. In out experience, alkaloid psoduction rate is a cional (i.e. inherited) character ~nd is not subject to ready modification b~ th.c usual components of root culture environment. Of particular inlc,~csl m this con- n~chon is the (allure of added precursors such as nicotine acid. clthct alone or with iysinc or.with'ornlthinc, tO increase significantly thc ylclds o! an•ha- sine or of nicotine. " ' The biosynthetic apparatus for nicotine and for •nab•sine arc con- sidcrcd to be sop_orated-into two distinct compartments'In the czclsed root, namcly the Trowing root tip and the matured ~ool axis.: However: the prob.- Icm ol~ explaining rate stability within compartments still remains. At p~escm, it seems well to adopt as • working hypolhcsis the prospect of • common ratc-llmiti~g step for both growth and nicotine production. O~&e~ ~r~m~or~ UnivcJsity of Missouri. Princeton Univcrsity, Columbia. Univcrsity, Rockefeller Foundation, U, S. Atomic Enc~'gy Commission, and The ~,mcrican Tobacco Company. "THE GIIII~ERELLIC ACID INiiIBITIOI~ OFf NICOTINE BIOSYN- Ttl F.qtS." l]y M. L. SOil. R. F. Dawson, and D. H.,Chris.tm_an, .De. patlm~nt of l~olany, Culumbia Univcrslty, New York, N.. ¥., •no urooznaven llonal Laboratory, Up/on, N. Y. Tobocco 5cien,;~, Vol. $, pages 95-98,, Sept. ~, 1961. ~ P~rpa~ o~ sh~J¥~ E. V. Parup~ (1959-1960))ms shown that mc re-. duccd nlcot|ne conical o! tobacco plants treated with gibbcrcllic acid is duc to a ~©du¢cd rate of synthesis and nol to an accelerated destruction of nicotine in the plant body. The authors have shown that the biosynthesis of nicotine possesses not only substantial rate stability but also • ratc de- pendency on growth. !! would bc experimentally advantageous if gibbcrcilic acid wcrc ¢l~cctlve in altering these rate rclationshlps. P~oreJ~r~.~z Excised r~x~t cuhuscs'of Nicoli~n~ ~bbacum L. vat. Turkish wcr¢ treated with glbbc~clllc acid, and labeled nicotine precursors, nicotinic acid and orn~thinc, wcrc added to thc cultures. After harvesting, both the dried root liSSuc and thc cu.ccnt,mtcd spent culture ~olutiun wcrc extracted, and the nicotine so obt-',incd was assa~cd for radiocativity by standard procedures. .r~a~/~n.~s~ Addition of gibbcrcllic acid to the culture medium 29 day.s bc|orc hal-vest produced -', marked reduction of nicotine output, the mum clicct of about 50 pcrccnt bcing obtained ~t a concentration of i ppm iclbbcrcllic acid. Similar effects wcrc obtained .y adding the equivaicn! of ~ ppm ~t cuch of several five-day intcrvals dusiu~ the Culture passage. The prcscncc of $1bbctcillc acid was not associated with an accelerated rate destruction of added labeled nicotine. When labckd nicotinic acid or laheled ornithinc was supplied to the cultures with and without ~gibbcrcilic acid. the results wcrc qualitivcly the same: nicotine yield was again reduced up to 50 pcrccnl by gibbcrcllic acid, but the reduction in yield occurred largely at the CI
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expense of endogenous precursors. "I'hes¢ results show that the inhibitory action of gibhercllic acid on nicotine biosynthesis v.cry likely occurs at thrcc different points in the metabolic scqurncc. O~er I~raazlor: U.S. Atomic Ener~ Commission. "DETERMINATION OF ARSENIC IN FLUE-CURED TOBACCO ' AND IN SOILS." By H. G. ~mall Jr. and C. B. McCants. Dcpaflment of SoiLs~ North Carolina Agr|cu1|ura] ,~xperiment Station, Raleigh. Soil Octobor 1961. (T.I.R.C. grantee: M.~Canls) .. . Procedures a~¢ described for t~© s~mimicro analysis tot a~scnic tn Auc.~urcd tob,,cco ~d in soils. ~ l~lant ma|crinl is dil~ested with a mixture of nitric, sulfuric nnd pcrchIoric acids and the soil w~th sulfuric and chioHe acids. Arsenic is dlstilicd directly from the digestion Ilask, absorbed in an iodine solution and determined colorimc~ieally by the moylbdcnum- bluc method. The data show that good rccovevj of arsenic and' reproducibility of rcsuJis were ot)taincd. The acid digestion method for plant matcrlal gave • results cJoscly comparable to those obtained by oxidation in an oxygen I~mb. The evidence from soils indicatc~ that the dlgcslion and distillation p~'ocedurc em~)loycd removed substnndnlly all of the arsenic. " • ~Fh.¢ ~vidcnc© p~cscntcd su~csts quite strongly that with wel-digcstion proccd,',re~, re.suits can I~ obtained that are equally as reliable as those from tho bom.t~'combu~tion method. . "MAMMALIAN DEGKADA'I'ION OF (-)-NICOTINE TO 3.PYRIDYt.. ACetiC ACID AND OTHPK COMPOUNDS, by Herbert Mcgcnnis Jr.. Edward R. Bowman, and lennox U. TurnbulJ, L~partmcnt of Pharmac- ology, Medical College of Virginia, Richmond. i'roce¢dine;. $ocie;y J,r ['~. perimen;o! Biology nod tdrdic~ne, VOl. 107, pages 145-148, May 1961. (T.I.R.C. pantce: Mcgcnnis) P,,rpose oJ Jtu~/Tr Research by the author~ and others has led to the identification of a wider complexity in the mctabollsm of nicotine than was estimated only three years before. J| was decided Io inve:stJgatc further the metabolism of randomly iaheled (-)-nicotinc-Ct'j in order to ascertain the sequence of metabolic rcactinns. Procedure; RandomJyo[al~led (-)-nicotlne-~j4 was administered intra- venously to two mongrel d~s over an K-hour period at a dosag© of 4.2:5 m$./kg. Urine was collected from the bladder by an indwelling calhcthcr d~ing infusion and a subsequent 19-hour period. Radioactive dctcrmina- lions wcrc made and chromatograms prcparcd. In a companion study (-)-cotinine was administered orally to a third dog. FJ~di~j~a~ |. The psttcrn of u~inary excretion of Cts in Ihc dog following in~'avcnous zdmin~radon of (-) n~:otlne-Ct6 was examined chromato- g~aphicuJl), by i~nprovcd p~occdurca. 2. The fractionatcA urine showed C activity corresponding ch~omalo~'aphicaliy to the known mctabolitcs: cotininc, gamma-(3-p, yrid~,l)-gamma-mcthylaminobutyric acid. d¢~meth)~J- cotininc-hydroxycotininc, and gamma- (3-pyridyi) -bcta-oxo-N-mcth.ylbutyr. antide. 3. Among many unldcntified radioactive compom:nts, the urine con- rained matcr"~d coFrcgpon~g chromat0~apbically to 3-pyrid~lucctic acid. 4. Following. oral administration 0f (.)..cotinine, 3-pyrldylacetic acid was isolated from urine and cha~aclcrizod by analysis, melting point, mined melt.- ing point and as its plc?,'c acid salt. 5. A precursor oir 3.pyridylacedc acid is on formal grounds gamma-(3-pyridyl-bcta-oxybotyric acid, derivable from the known mctaholite gamma-(3-pyr~),l),bcta-oso-N-mcthyl- butyramidc. Ofher I~ra~[orr The.American Tobacco Company. "DEMETHYL~TION IN THE METArtOLISM OF (-)-NICOTINE IN VJVO." Dy Herbert McKeanis0 Jt.o Einosuke 3,Vada, Edward. R. Bowman- and Lennox U. Turnbull, Dcpaslment of Pharmacology, Medical College of Virginia, Richmond. ,V~lur¢, pages 910-91 I. June ,3, 1961~ Purpose oJ JlJ.ly: Di~rcpancics existed among prcvio.us ~udi~ ~of..thc physiological disposil~n of nicodnc randomly lahel©d wiuz carting-t4. oral workers found 'no radioactive'carbon dioxide in expired air of mice and dc)gs after intravcnnos, admlnLstration of the labolcd nicotine, contrary previous work by the Virginia scientists which indicated thai mctabolLsm of nicotine involves degradation to single-carbon mctabolitcs. To. resolve the apparent contradiction, labclled nicotine containing a high level o1' activity in the methyl group was.employed. Prm'e~lu~e~ Male albino rats rccclved intrapezitoneally a s~,nthesiz~d n;cotinc-methyl.Cts. and eaplrcd carbon dioxide was collected .m sodium hydroxidc traps and then prccip;tated as barium carbonate. J"/n,I;nge~ Ou~ing the first 6-hour period after adminLstradon of the nico- line, the respiratory carbon dioxide from 3 rats Contained an average of 5.7 percent ol the administered radk)aclivity, with individual values 7.:5, 4.0 and 5.6 perccnl. Further climinatlon in a subsequent IK-hour I)CS~ad gave cumulative values of 12.1(. 6.2 and 8.4 percent of the administered do.st, in addition, a small but significant amount of carbon-1~4 acdvity was pre~cnt as urea in the individual 24-hour urines, as determined front carbon dloaidc evolved hy urcase. Since the radioactivity of randomly lahelcd eicotinc-Ct'j is eacretcd Io the extent of 94 perccnl in the orinc~ of rats. the addJlion of carbon-14 determined by carbon dioxide in these siud~s j]ives a total clim- ination approa~:hing ILK) percent. 'This provides cgnvincmg evidence that. after sinl~[c doses. ~,io~age of nicolinc or its metab01ilcs occurs Io only an extremely llmiled cxlenl. TI~ results point to the jmpO~lancc of single- carbon compounds in Ihe metabolism of nlcotinc ~n the rat. ('J~her &rnalorz The American TohaccoCompany. "NORCOTININE (DESMETIIYLCOTININE) AS A URINARY ME'rABOLITE OF NORNICOTINE." By Eino.~ukc Wada. Edward R. Bowman. Lcnnos B. Turnhull, and Hcrbcrl McKcnois. Jr.. Dcparlmenl of Pharmacology. Medical ('ollcgc ol Virginia, Richmond. J, urnul ol Mrdi¢inol und Pk~murturi¢cd Chtn~isery, VOl. 4. pages 21-30. July 1961. Following int~av©nc~us administration of (-)-nornJcozine, the dog cr¢lrs in Jhe urine a variety of Kocnig-positivc compounds. A chloroform extract ~ the alkalinized urine contained norcotlninc, nornicotin¢, and other components. The aqueous pha~ rcmalning front the chlorcd'~zcm tract contained gamma-(3.pyridil).gamma.aminobuty~ic acid. which was iactamizcd to (-)-norcodninc (2-(3-pyridil)-p),~rolidonc-$). Rcductio~
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oplically active norc~inine wilh lithium Mumlnum hydride resulted in the formalio, of a mixlUrC of optically aclivc and oplicully inactive nomieollne. "TILE ABSORPTION OF NICOTINE FROM TIlE URINARY BLAD- DER OF THE ~." By J~ph F. Bo~ilcca. ~panmcn~ c~gy, Medi~l C~ge ol Virginia. Ri~mond. drrhi~e," Inl~rnuli~l¢J d~ P~mar~yn~mi~, VoL 133. pages 444-4~1. ~1. 1961. (T.I.K.C. gr~n~e: Hcr~rl McKcnais Jr., McdicM College of Virginia) scv¢~l auihots as lo ~ tclalivc exaction ~ ab~plion o~ mcolinc, rc~ncd in laboralo~ sidles wilh dop and ca~s, which r~q.ircs fi~. Since b~ddcr rcab~tion of n~linc might have a ~aring on Ihc IoxicologJcal c~ccts ~ airline and ot~r subsla~cs it was decided to Pr~etlure.: Aduh ~n~cl ~ of ~lh xx. wcrc ancslhclizcd and ~ro~ b~ pro.me. [~pitztion. c~ct~zrdiograms, and urine w~c recorded. ~c bladder was drained and cleaned by zbrough which m]uz~ wcrc i~dl~d or ouzfl~ during ~r(usion ~currcd. Ah~r app~owiatc ~avcaouz zest do~s Io dctcmfioc z~ rc~ivcncss of ~ animals, z 20 m~ml ~lution o~ nicotine in an appropriate bugcr w~ ~r[~d zh:~zh Ihc blair al z ~zlc of ].5 ml/minotc. The pli ol ~hc ~using flu~ hum d~c b~d~¢ did ~ chan~c mo~c Zhan 0.2 pl I unit dur~g lhc cx~rimenlal ~:i~. Findi~g~: ~e ab~plion of n~ofinc from the bladd¢, ol Ihc dogs was ~m~slral~ Thc:¢ was no ~gni6canl di~crcncc ~wccn Ihc ~xcs. phys~logi~i changes lakcn as an indication o[ nicotine absorplinn were chaa;cs in bio~ ~c.ur¢, :cspirali~. and urinary omfluw. Wilhin pll ~nge invcsliga~d Ibc :al¢ of ab~rpiion afeared io ~ ~ndcnl u~a ~c pH ~ Ihe nicolinc ~ulion. Ol~r grnnlors: U.S. ~blic Heakh ~rvicc ~d ~c American Tobacco '~HE DA~ERIAL OXIDATIOH OF Hi~TIHD. IV. ~E ISOLA- TION AND IDE~IFICA~OH OF 2.~DIHYDROXY-N-M~llYL- MYOSMINE." and "V. IDENTIFICATJOH OF 2.6-DIHYDROXY- PSEU~XYHICOTIHE ~ ~E TIilAD OXIDATIV~ PAODU~." Dy S. H. R~rdson ~ Syd~y C. Riilen~rg, ~parlmcnl u~ Daclcriolo~y Univcrsizy nf ~ul~rn Calitomla. ~ Angc~s. Journal o/Bioluxir.i ('h~] istry. VoI. 236. ~ges 959.9~ a~ 964-967. March 1961. (T.I.R.C. ~anl~: Rizlca~rg). Put~w ~l studXx Prcvi~s studies in this ~r~ I~vc ~{ablishcd 6- hyd~oxyn~oli~ and ~hydroxyp~ud~xynJcotlne as Ib¢ first and ~cond oz,/live pr~ucts of n~ti~ mcla~li~ by a ~il bactcrium. Thc~ sludics were un~rlakcn to clarify ~ ~ub~qu¢nt mela~lic Iranzformations nlcot~c ~ to idcntify the ~d oxidative pr~ucl. ~tgtd~t~iz ~ ox~zion o~ nicminc. 6-hyd~oxynicufinc and ~hydruxy- ~.d,~xyn~ofine by zppropr~zc e~zymc ~racdons was ztud~d man~ m¢u~ally a~ s~cirophmo~zr~ally. ~ pt~ucl ~urn~d b~ Ih~ Ihrce, Iwo, or one s~cp o~idzfion, res~cfivcly, u~ these subslraics was s~nlh~zizcd enz~mal~ali~ and i~al~ i~ c~aJin¢ ~urm. Fimlisqx.: The isolated compound was idenli6ed as 2,6-dihy~oxy-N- ntclhyhnyusnzipe on chc b~bo~ i~ chc~cM prattles and i~ c~mcnlal analysis. ~c c~J~und was n~ fu~ct ~ta~l~d and ap~s to ~ a side pr~uct on I~ inai~ pathway of nicotine degradation by the bac~rium ~p~cd. The t~uc ~hird oxidalivc pr~ucl was ~li~ed as 2.~d~y~oxy- pscud~x~nicolinc which, in t~ ~c~ncc ~ the [ur~hcr nzc~a~l~d; olhc~isc it b convc~ed noa-oxi~zzvely and n~ cnzymzticzlly to the meZa~llcally inactive mi~, t~ command Wcviously ~lalcd. "PAPER CHROMAT~RAPHIC D~ERMIHATiOH OF RUTIH IN TOBACCO." Dy C. H. Yang, W. ~ncy, W. Dunlap, E, L. Mmpby. Y. Nakagawa, N. ~uily, R. Watana~ and S. W~r, Chcmbtry ~pzrlmcnl. Uaivu~ity of Oklahoma, Norman. a~ Medal Re.arch. Arg~ N~ional ~ralory, Arg~ne, ill Tobacco ~itnre. VoL 4, pages 238-242. ~c. 2~, 1960. (T.I.A.C. granite: Pr~edur~ which u~ Ihe aluminum cMmi~ or ~dc acidulate acid reagents, but do ~t ~parazc the rutln from other ~aol ~lyc~idcs from chlorogcn~ acid and rclat~ ~p~s ~ other ~bk intcrrcxing subsZanccs, may not ~ accmate for quantitative anaJys~ of rut~ in many tobacco .topics. ~rce ¢hwmatographic mclh~s ~velo~d for dclcrmina- tion of the rutln in tobacco ate ~ri~ in ~tail. Ex~Hmcnls involving additi~ of known quantities ~ ~tln to a tobacco extrac[ ~/o~c chr~zatm gravy usually 8ave 95 ~rccnl ~ ~tlcr rccovc~ of t~ addedturin after its pa~agc through the a~iylical pr~cdur~. Other grna~orx U.S. ~zom~ ~nc[gy Commission. Vi. Other Studies "SOME EVIDENCE FOR.A MECHANICAL RECEPTOR IN OLFAC- TORY FUNCTION." I]y Showa Ueki. Faculty of;Medicine. University of Kyushu, Japan, and ~dward F. Doafino. Department of Pharmacology, University of Michigan, Ann Arbor. Jqurnuf ol IV~uroplW~i, dol:y, V'ol. 24, pages 12-25, January 196 I. (T.I.R.C. grantee: Domino) Purl~s~" o/slsulyz In certain fish the olfaclo~ ~gans ate ~nsitivc to mechanical as wcU ~s chcm~al stimuli, whereas ~ mammals there is an .b~nce of cunclu~ve evidence for a mechanical rcccplor in olfactory func- tion. ~is study was undertaken in an attempt Io provide son~ cvidc~e for such a by.thesis. ~r~ed~r~z ElectiVes wc~c implanlcd su~[ically in anCsl~li~d do~ and mo.kcy~ in various ~o~ical and ~hi~nccphalic zlruciurcz including Ihc offaclory hulh, amy~dz~, and hip~ampus. One month later ga~s and ~mi[crous substances were applied Ihr~h a GI~s,, cannula in- ~cd into Ihc no~. and clcclrlcal "bursts" in the various olfacto~ szruc- lUrC~ wc~ ic~otdcd. Fimli~gJ~ Waves of 20 to 40 c./~c~ wcrc recorded synchronous with inspirat~n in ~ nmnkcy and wi~h inspiration and cxpi~aliun in do~s. phcno~na were prcdmnlnamly lpsilat~ral. E~cl~ical activity of qucncics could ~ clicilcd by blowin~ s~m air, va~iou~ ga~j a~ O
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inlo the ~ostriL |t appeared that a n~anical component was involved in the~ phenomena, ~e~or~ ;lud~ in acule ~gs given I~ai anesthesia and ~laced on ardheial r~piralion w(~ und~laEen. Evi~nce was ob;aincd thai m a~ul ~0 ~rc~nl of I~ do~ ~le~lrical disbar&ca w~re r~cordcd in Ihe &~aclor~ bulb ~o ~or-~ o;~g~n, niuo~en, a~ carbon dioxi~, ~nd w~rc ~ndcn~ u~ Ibe vcl~ky of g~ bow. The a~cas in the bulb where mechanical rc~n~s wc~c obtai~d wcrc ~clalivcly fcw com- ~ed I~ tho~ a~c~ r~nding to ~s. in all tbe animals studied c~clri~l r~s~nscs to aU ~ors i~ding t~acco smoke were cnhan~d ~th intrench& .flows of oz~gen when tbe ~w of the ~terial was kept constant. Thus Ih¢ c~cenlral~n of ~or ~r unit volume of ~s was ac. lually decreed at a ti~ w~n ~ olfacto~ bulb resents wcr¢ markedly chanced. .it is conclnd~ that prciim~a~ cvidcn~ has ~cn ~laincd for the cx~tcn~ of a metrical receptor in olfacto~ function, il is hy~thcsizcd I~t one of the rca~ns I~aceo smoke is ~ effective in stimulating olfactory bulb di~harge ~ ~t i~ smoke ~n~lcs a~c small c~ to mechan~ly as well as c~micalJy ~bard the olfact~ receptors. "E~E~S OF MECAMY~INE ON THE GO~I RECURRENT COLLATERAL-RENSHAW-CELL SYNAPSE IN THE SPINAL CORD." ~y"S. UcU. Univcr~ty of K~ushu, Japan. K. KoEc~u, ~paxlmc~Jt of ~t~, and ~ F. ~m~o. ~pa~mcnt of Pharmacoio~. Univc~sity of MiChigan, Ann Afar. Ex~r~en;al Neur~ox7, Y~. 3, ~gcs 141-148, Fcbrua~ 1961~ rur~se o~ study: ~ f~t that mccamyJaminc is a ~conda~y amine with "n~inic" bilking pro~ics su~st~ that h w~d act at r~cnl coJlatcral-~c~w~ciJ s~nap~ ~ the spinal cord. The cx~r;mcnt w~ deigned ~o t~ ~ Pr~edure; Tw~-onc adult cats of ~th ~xcs were anesthetized, and t~ spinal cord was cx~d ~r~caJJy and prepared for electrical stimula- tion. A gla~ micropi~ttc was intr~uced ~to t~ Rcnshaw-ccll ~J, and cl~lrical aclivity of the cells was recorded. AJJ drugs were ad- ministered in~avcnously. Findings: Anti~om~ stimu~t~, of the ventral r~ls p~uccd cxlta- cellular di~harges ~ the Rc~haw~elJs for variable ~i~s of time. Minimal ~ ~ s~nta~oos ~livily was rcco~dcd. T~ ~ri~ipal ~camylami~ was to decfe~ tbe terminal di~hargcs of I~ Renew ccJl to anlidr~ stimulation. No cJa~lc statistical a~lysis of the effects was un~flaken. N~ only could m~a~laminc alone reduce ~ acdv;ty of Rcnshaw ~lls t~t were fired ~ntidtomi~tJy, hu~ il w~ld al~ hick action of nicotine and ~tigmine. Nico6ne was very c~tive in slimulal- ing Rcns~w ~lls dirccdy. The c~cctivc~ss of mccamyl~minc to dcwcss t~ ~olgJ co~tcraI-Rcnshaw~eil s~nsp~ Js addldonaJ phurmacologlcal cvi~ncc that this is a "n~otJn~'-ty~ cholincr&~ synap~ in the cc~lral nerves system. Olher xrantort U.S. ~bEc Jlcahh "~HANGJNG ~ON~E~S OF THE ROLE OF TO~AC~ IN TJJJ~ MANAGEME~ OF DI5~S~" By Paul S. ~r~n. Ph.D.. Jla;vcy B. Haag, M.D., and ilcrberl Silvctte, Ph.D., Medical Co11¢&¢ of Virginia, Richmond. American Journal ol the Medical 5cienc¢~. VoL 240, pag~ 613- 63J5, November 1960. (T.I.R.C. grantee: Haag) For almost as long as people have been using tobacco, writers have bccn sixculating on its role in the genesis .of disuse. Except. for ,a . genuinely tobaccogcnic diseases (of which the most unequivocal is tonacco allerk"J), the etiological role of tobacco is just as obscure today as, say. • , century ago; but a survey of • coosidcrable sample of the clinical tobacco litcratu-rc ~f the past 50 years has revealed • signi/canl cban.~.c in'opini~'op. ' rcgardin~ the place of tobacco in the management oF r, crtain d~ca:cs. latter is ,ndepcndcnt of speculation or opinion regal:cling tobacco CtioloB.y. Thus. there is no perceptible agreement amon,~ clinicians conccrnin~ flu: role of tobacco in the etiology o| thromboungi,tls ob|iterans, but there unanimity thai tobacco exerts a harmful influence once the disease is ¢stab- ILd:ed. and should thcrclorc he strictly forbidden pallets wilh this condition. The present paper is concerned only with tobacco-use in the manage- mcnt of ccflain discuses: tobacco allergy, anna. and amblyopia; ¢ardlo- vascular disca~cs; chronic bronchitis, pulmonary emphyscma,'ano pulmonary tuberculosis; and peptic ulcer. It is emphasized that, with the perhaps sole exceptions of tobacco alicreles and nicotin© hypersensiliveness, the observed influence of tobacco or Io'~aceo-smokin~ on the course of any el;sense ford~ no valid i, formation concerning its etioio(:y. One may' yen|me to generalize thai. where once smo]cing was cat©goreully forbidclen' in many discu.u:s, il isnow permitted in moderation by competent authorilics. The main conclusions to bc drawn from this s,rvc~y are clear enough. In the case of specific tobacco~;e:Jic di~ca~cs properly dmgno~d, the of the disease, by definition, tobacco, may IX: forbidden without dOobls and should he prohibited wkhout equivocation, if one defines a non-tohaccogenic disease as one which occur~ indLstin;ui3habJy in both Iobacco users and non- users, regardless ol its respective incidcncc-ratcs, then it may be ¢on¢luck,'d that there i.: nnthing heifer than abstcnlion front tobacco, though somellmes there m,y b~ somc;hing worse: cmotioual disturbances of one sort or another, or the subslitution of an cvcn less desirable habit (for example. over-eating) for that of moderate tobacco-smoking. The fairly recent realiza- llon of' physicians thai the "psychic" j~ood c~eets of tobacco-smoking miFbt outweigh 81s "s~|||atic" harm. represents the "changing concept°" of the "SOME EFFF, CTS OF HICOTINF- AND SM@KING ON METABOLIC FUNCTIONS." By P. $. Lar.~on. Ph.D.. H. B. Hang. M.D.. and H. Silvctte. Ph.D.. Department of Pharmacology. Medical College of Virginiu. Rich- m¢)nd. Clinical ~h,,rm,,ruloxy ,,nd Th¢r¢p,~lics. Vol. 2. pages 1(0-109. January-February 1961. A survey of medical and scicnti~¢ literature on Ihe mctabo|ic clfccls of tobacco has drawn attention to the relative deficiency in this area of invcsligation, und the need to study the effects or nicotine u~ing concenlra- lions that incluck: those encountered in man. Studies sht)w that nicotine appears capable ol inerc-'.:;ing heal production, oxy~.cn consumption, meta- bolic talc. nod I)l~xJ :~ugar. The effect on serum eholeslcroi undlipoprotein levels is ,or ~cl clear. Gent:rally. Ihe Icvcis appear Io be hit~ber in smokcr, Ih~n in n~m-~,u)i~¢r.~, but Ih¢ reason I'or the dd[crence is obscure. It ~
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r, stlng to note ~bat Ihere arc ~'cw c]inical reports which implicate nicolinc or tobacco smoke r~iolugically m othcrwi~ in deficiency or metabolic disorders. So potcnl a drug as nicotine can bc made to hay,e, an influence on metabolism, whether in the intact organic, individual or~ans, tLssucs, ceils, or ccliular components -- when u~zJ in sull~¢~nt quantity. It may he cm- phas;ze.d that h is the concentration of nicotine obtaining in thc cells or Intra~..lluJar fluid of normal smoke~s which alone carries any validity in assessing the effects of tobacco smoking. . .'Expeflmental" concentrations of nicotine must bc matchnd to those "nmmally" occurrin~ in tissues nod body fluids of slnokers. Oflty such con- centrations can elbctdal¢ ~ pharmacologic aspects of tobacco smoUng: c_onccntration many times th~ express only the toxicolol~ic characteristics of nicotine, if toxic doses or ,:oncentrations of nicotine have no demon- strablc effect on mclabofic or other activities, this ncgallvu evidence is very probably valid with' respect to tobacco smoking; whereas the co,,a, vcrse is. equally probably, far from true. It is never a work of supcrero~'dion to repeat dud tobacco smoking, as it is pcrform~:d by the smbking m.llions, is pharmacologic, and only ver.~ rarely indcr.d a Ioxicudogic phcnouJcmm. "ACTIOH OF NICOTINE AND TODACCO-$MOKING ON Tile ADRENAL MEDULLA." Uy H. SJlvettc. Ph.D., P. $. I ~rson. Ph.D., and H. B. HaaS, M.D.~ Dcpartm©nt of Pharmacology, Medical College of Virginia, Richmond. ,4ruhi~j el Intets,al M~diclnc. Vol. 107, pages 9l 5- 931. June 196J. A review of the extensive fitcratur© on the systemic clrects of nicotine and ~moking shows that both may stimulate cpincphrine release from the adrenals, cithcr directly at reflexly. Endogenous cpincphrine and Icvartcrcnol exert a wide yariety of cfIccts in the body, but cpincpl;inc rclca~c from the adrenals remains on th~ whole an emergency "~ht or flight" mechanism The studies show that this effect of nicotine" or ~moking Tallects or clfe;:t~ .many body functions, rc|ativciy tdviel (e.g. blood sugar ri.~c) or rclativcly important (e.g. ~asocanstrietion). So far as smoking by man is concerned, these findings raise two ques. lions. Pirst: is the dose of nicotine dcrivcd from smoking suJ]icienl to activate the cpincphrinc-rclcasc mechanism, directly or indirectly? The answer appears to b¢a rathu hesitant aflrnJativc. Second: if so. is a repetitive stimulation of Ihe cpinephrine-rclca~ mechanism, and subsc~luently of epinephrine "shock organs" (particularly the catdiova~:ular syslcm), of any long-term consequence to the habitual smoker? The answer to this question is still unknownS' On the whole, very few clinicians have elected to advance this particular mr.ch~,nism to explain the clfccts of smoking on either the gencsis or course of cardiovascular dlscas¢ ~ or, in fact, of other diseases as well ~ in smokers. "IIEPATITIS--A FEATURE OF PERIODIC PERITONITIS." ny I-Iohart A. Rcimann. M.D., Hahacmann Medical College and Ilospital. Philadelphia. Journal o! IlJ~ Ameticw~ M~dical Aszm'imion. Voi. 178. pages 334-335° Oct. 21, 1961. Hepa!itls occurred in two patients during epismles of' periodic pcri- toniC, and overt and inapparcn! jaundice, hepatomegaly and splcnomeguly were obscrvcd 'in three others. It is suKcstcd that slmila~ involvement may occu~ in other victims of periodic ~ritonilis. Hcpatic involvement in odic ~ritonJlis rai~s.two matters for s~cu~lion: Has it a ~ing on lipid mcl~lism, to account (of I~ eliot of a d~t low in f~t ~at rc~ .the ~v~iiy and f;cqucs~y of ~ymptoms in ~m¢ vktim? A~, ~ cumulation of plasmacytcs a~ other cells in t~ liver, ~fo~. ~d c~w~ ~lay a ro~ in hy~rglobullncm~ I~t ~y ~ prc~nt in ~i~ to~t~ and t~ sesultant development of amyl~s~'! , "CANCER OF Tile LUNG 1930 TO 19~: A REVIEW." By R. H. Rigdon and Ilclen ~rcho~, ~paflmcnl of Pathology. Univc~ily of Tex~ Medial Brash. Galvcslon. T¢xm ~ep~t$ on Bioio.¢y and Medi¢in,, Vol. 19. pages 465-513. Fail 1961. (T.I.R;C. Oa, tcc: Rigdon) inlrt~,cing Ibis review of 4~5 ~ienfific ~rs on ~nc~r of the lung. the aut~rs say more has ~n w~itlcn ab~t this d~ in xienliflc ture and Ihe ~y p;css than an~ other n~pl~l~ di~a~. T~ question .. cancc~ of t~ lung actually on the intreat, and if so to what extent? ~cmains una~wc;cd~ it ~ not di~cult to undcrs~nd the ~nfusion when we rcmcm~r that the basic data ~ mo;talily incidence comes from ~alh tificatcs. It was 1933 Mfme we had nation-wi~ death r¢~rting in United S~atcs a~ 1939 ~fo~e bronchogenic ~in~a wu iistcd ~ such on our vital statistics. Rcgard~ ~ whether t~ incrca~ h ~ly'ap~r~t or real, in 1960 cancer of the lun~ ranked ~st as ~ ~u~ ~ dc~th from cancer among men. " . The ~o~ of smoking in lung cancer, although sugg~tcd ~f~e I~, continucd to ~ t~ burning qucsii~ ~twccn 1930 and 19~. ~ hy~ thcsls that s~k~g cauls lung ca~r is I~gcly baxd on ~udies tampa;rag the smoking habits of patien~ with mher d~s or.of ~althy ~oplc ~ studies in which the ca~s of ~ath arc compared in ~oups of ~p~ w~ sin,king habiU have prcvi~sly ~cn cstablis~d. Obvio~ly f;om • is review it is ~vJdcnl that t~ etk)logy and the pathogencsis of pulm~ry cancer m m~ is not known.
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19 • ~w)dd~s!p ~om~.~.pw~ )ql ~q 'IUIIOU.I=II) |0 S).q!~,!l)! II):' poolq ~Hq~ UO I~')]1) Sql pu~ u)ul In ,ql)) (d--3) ml :li:~t: u! ~n .p~J u~pu: Imm Ida3) ~sst.I ~U~ld m. NOl./.f~.l~M! QMV 3~LMWlD 'p:,l=ldmOO uooq o^eq s'l"~.oJd :tp joomos leq] po~ou oq plnoqs II "l, f61 olq m opera ona~ s~ut~ let.m o:)u!s p~tou ~o4~.^py s,~u~a0 jo s~uo~d!aa}I.
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ALBERT DAMON. M.D.. Px.D., R. F. DAW~N. hLD.. r~l~--~ 8olan~. C~umbia Univc~ly, Y~, H. Y. AHDKEW S. DIUH~R. PH.D.. (~c Whkkin) EDWARD ~, ~MINO. M.D.. P*ol~ ol P~,rm~olnt~. Univct~lly ol M~hJlan. ~nn JOIIN W. E~K~EIN. M.D.. lOW& C~ly. A sludy o1' Ih~ ~llcralion~ in Ihe human bronchial wall ~<cu~inl wilh 'wilh particular cmphas~, $u¢ Chang¢~ and u~ia~d ¢hanlc+ the blo~hial lu~n m Igvgh of ~slriC acid. Fp~n and uro~p+in LC--P) A Mudy o~ Ih¢ 1~¢¢1 SI~y o~ combed cA;el ol in,tied vital areola a~ cnv;ronmgnlal lacIors. cl~+nI carcinogenm and I~a+co mmoke. on Ih¢ tlaclg~ro~h~l I~g+ ~nd pal. m~ary ~rcnchyma o[ cx~r~nlml In;reals s~ o~ l;~s in m~n culture ~y (~m. ~ok;n¢. a~ alcohol c~- An inve-Jigal~on pyr~in¢ compounds in the tobacco plant Pxgchnlogical and ~hav~al ch~aclcr- I+I~ci ~ inhalcr+ ~.ff¢cl~ o| Iob~cco qmokc and eicnlinc on Ih¢ cent#~! oervo,,~ ¢,y~.lem Rc~pon..cs o( the peripheral vcin~ in man Io Ih¢ .inlravenou~ ado6ni~l~atmn o( n;col;n¢ ( P I F~ bl~ ~w r¢~ Io ~mok~nF m I~ we~nc¢ ol hy~lli~m~ and by. ~+lcm~ Examiml~ ot cilarcll¢ ~wr aml c/~r. ~ycycl~ hydr~a~ A ¢omp~lal~ o~ 4u~encc ~clra o( in~rcm in IIc slimy ~ a~ ~ll,lanls. und Ciill(llc woL¢ in ~clal~n Io lun; GRANTEE AND INb'TITUTION DAI~IA L. FARNSWORTH, M.D,, Iitnry g. Oliver Peole~z~w ol ilyxitm¢ a~ Di. , rtct+~ ol (Inivt~ II*nltk Service*, Ilarvard University. Cam~Mie. ' (~e Hcalh a~ McArth~) FRANK C. FERGUSOH. ogy. Al~ny Mcdlcal College. Albany. N.Y. 6.d £x~m~nfr. State ~ Mat~la~ Mgd~al ~h~. B~lli~C. ol C~¢¢r Rt~.r+'k. Mounl Zit~ I I~- lal .ml Mc~"I ('¢,1¢r. CaL (~¢¢~. gc Fish) ~REDERICK A. FKENCII, A.B., Re. JACK FREUND. M.D...t,.i+t,mt P¢olcJ+ ~+,r "1 I'lmr.~.',d.gy. Medical Collctcc o( V+r/inla. R~chmond. PRO JEll' TITLe m the dcl'cn,,,,' mccKa~m~ ~n dglonifi¢ll~Oll o| pOlJ'g~fclb lrootlllc h[droca;bons" lnd I1~ COml~.,I/liv¢ in- h~tinn Imwccn Ihc pol~cxchc hydro- carbons in coadcmalg with rc~ard to mucus un~r 'n~ml ¢olldlllOnS gollowi~l ¢tpolwc IO Pcrmnality and Imoklnl in ualcs: a fi|leC~year |ollo+w-up ~lUUy . ERecls ol tobacco smoke upon the |u~.+ lio~ of Ihe cardiova~ular syslcm m • animals and man (C) Palhololic--snalomic sludy O~ cellular chanles in human btm~hl (C) Carclnoicnic~ty. cocarcin~.cnlchy and anti-cMcitto$¢nlcity og dkt~ry (ac~ in rclat;~ ~ ~ry lu~ sibl¢ inlcrrelal~ip o[l~Co a~ diclary lactm~ C~m~al analop Co,clul~n o( mullilcchn~ul ~cdurcs ~r/o;med ~ Ihc ~ri~crzl of notmal i~ivMual~ in recum~m A ~y ~ t~ ¢ff~l~ o+ C~latcll+ mkinl vid~h wilh n~lc~mk ~limrans ul~+~nl m~l~al pr~mcu k~wn u~ ~hlc cagcbolcnic agcnls u~ s~h ~chadd~ O o c~ C] C
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RICHARD J. IIAYE|.. rro~e~or ol ~led~into Univu~ly ot ~d~orn~ Mcd~ ~h~ ~n Fraa- ¢~0. U~vc~y u~. ~n ~ru~o R~ds) PnOJE~T Prot~,~lyUc aclivhlcs of ~he while blood b~ cell acilvi¢~s of carci~gcas, nu- The effect ol"smoklns on certain |a~trlc ru~c~k~s (C) Pharma¢oloiic sludy of nicol/ne and I~tcd ~ltaJo~ (C| Preparation for publlceiion of a book on Ih¢ b~Oiolk: as~ccll O~ I~0 a~ ~mokc. (C~P) klcasmc~ll o( colona~y bi~ c~r~yd~ate ~la~llsm ~ n~len- sivc subj~ ~(me a~ afl~ anita. venom n~odnc a~ at~r ~kinl standard ciprcltcs (C--P) s~ud~ ~ Ihe cflccls o( s~k~nI and n~ollnc ~dminK(rali~ ~ sym~ihn. adrenal (U~li~ and (ally acid alia. Allem~s Io i~e Fulmofla~ neopla~m~ in cg~ri~nlal animals h~ e~ure ~ Ihc Irac~r~chial uy~tcm 1o ~¢co smoke Pg~nalily a~ ~kin8 in c~lege grad- ual~: u figigcn.ygaf follow.up slay A Comp~rallve study or carl? and DNA chanics in ihe Cpidcta~s two alrsi~ of m~¢ (C$7 Blacks and lions of wh~e cipretle s~kg con. crol~ oil) and Ihg ca~ino~ns mcthylcholanth~cnc and ),4.bcnxpy. GRANTEE AND INSTITUTION L.~WRENCE L.. IIESTER, Ja., M.D.. o] ObateldCt'and ~y~c~oty. Coliqe ~ ~th ~r~a, ~arl~ton. EBB~ CURTIS HO~, PgD., U~D., Peo~e~ and Chuir~. D~tment Jcge O( Vkgln~, ~h~, J~ and Ilead, De~tme~t of Pnlhol. slY. Lou~ ~ste Unlvc~ly ~ ~ ~cd~i~, Hew @deans. (dcc~a~d. ~c ~cG~I and ~lr~l) Re,arch Imliluic. Inc., ~am~c, ROBERT W. HULL. hi.D., Aublant Pmf¢~v ol ZoolOly. Notthwcslcrn Univcrl~y, Evaasloa, IU. JERRY IIART |A('OBSON, M.D.. I)J- • tcto~ st Elecltol~ysiolott¥. Hew Ymk Eye s~ Ear ]~f~ms~y. Hew York. MURRAY E. JARVIK. P$*.D., Auoc;ale rroles~o~ ol Pharm,woloay, Albert E~nslcin C~IcI¢ of Mcdic~n¢. Bronx, ANDREW A. KANDUTSCII. PH.D., StuO 5¢ien#i~t. Roscoe B. Jackson Me- modal Laboratory, Bar ||arbor. ANCEL KEYS, P~.D, P¢ole~=or o! Pkxr ~al~ o~ rhya~olk~ Ilyltene. lint- vcnily ~ Min~a ~h~ of Public HcaJlh. ~innca~. J~EPII B. KI~HER. M.D., P~ol~sor o~ Al~iat, Undyingly or c~a/o ~ ~ Mcd~ Ch~S~ IlL PROJECT TITLE ~he relationship ~t Ih4.nsg ~ lobe.go products to ~ ~lco~ of ~c~y ¢crcbcal autoaomlc cha~. produced by ~ ~obacco smoke, nicoilnc ~ co~in~ne, u melabo~ile of ni£o6n8 Pathcdojlc--anatomk: Mudy ~T cclluJar chsnses in human bronchi (C) The inllu~nce of tobacco unokb~| ee acute myocardial i~alc~Jo~ (C) Studlga on c~rcioojcne~b and the b~. assay of ~r¢~gn~ s~nts (P) ~om~ralive st~ ~ eff~u or vM~ t~c~ ~e ~i~ ~ sk~ d ~ Phol~y~m~ ~livul~ ~ ~s~ hy~r~s: el) ~l~ ~ ~y ~iq~ u~ p~ (b) inv~itut~ of ~ ~hus~ ~r~ by ~ a ~m ~ .dual~I ~ eff~t of ~d r~l c~Jat~ with ~hcr ~c~q~ f~ ~ ~r~;~ (C) ~unJ ho~trJnspJlntst~ (~) Pilol study o! hsbiluat~n to nicotine by means of rhesus mo~kcys TI~ c/Tool o! tobacco smokln| upon bs~J 65 o LO ~r o o L F C F F
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CF.CILI~. LEUCHTENBFRGER' PN.D.. Memorial Labcwatcwkj. Brooks No~pi. lal. B~ooklinc. Icao**i~hc Tcchnibch¢ Iluch~hulc, Zmich. 5whz~nd) pk~l. Minnca~. Minn. Vermont. Burlin¢l~ 6~ Poss~bl~ effccu o( tobacco ulna .cerebral ci~cu~atk~n., ~. ~,,:,..' ...'" Palh~oilc~anato~c uludy of ccllula~ chants ~ human br~hi , .. ";,v..,.*': . '~.,~. Pa~ailo~ Slay of c~JJular .. • .. ...,. .,~,.~. Ind ¢¢1~1cd ¢om~nds ~¢ ~bl¢ ¢~¢¢1 o( ~)acco ~mokc and n~od~ ~ aKOrb~ acid Sl~;¢s in bro~hki~: m~rrclalcd invc~li. ~al~ ~ {u) Ihe e~e~ of i~in¢ on tract d human~ and (b} the cilarcflc s~kc and sulfur dioxide {air ~llulanll on Ihe ¢~inS o( baclcfia animals (m~¢, ~ ¢~¢lalrd hi~lolical. ¢ylololical and cyl~cal ~ludy O[ Ihe Iracheo- Mcasurc~nl O( the di~crcnlial bl~ ~w in I~ mammalb~ lunl I~.o~a chc~ ani~ and ~ ~lh~l ~liv¢ ~a~d m~r~c~c, . The o~1~ of nic~;~ by ~uylcn: mcchuni~ II~Cli and /.;iikNl"El'; A~D I~'TITUTION o~ Planetology. Slate Un~vCl~ly Iowa. C~1c1¢ o( Mcd~;~. Iowa City. D~VID [ MANN. it. P,.O.. Pro/e~ oI Pkarm~olo~y Tcmp~ Un;vo~ly ~ ~ P~rmcy. P~la- dc~h~ Pc CHRI~OPHER M. MARTIN. M.D.. Aszi~tuat Pro/e~ el Med~i~ and Jc~y City. ~. J. CIIARI.U C. McARTIIUR. 'FinD.. P~yc~o4~t ~ tat Unie~slty Ile~th ~Mgc..M~ (~ Heath ~nd Far~- ciatr Prolt~ ol ~otls, ~h~ ~ cultm¢, N~ CMollna ~lg llENRY C. M~IM. J~.. M.D., slant ~1¢ Univcl~ty ~h~ ol Mcdi- VOKI)E A. McIVEK. M.D.. lose ol ~ulh CMollna. ~ulh Careliea. ChMI¢~I~ IIERDERT McKENNIS. IR.. Ph.D. I~.~ ,I t~,t,~ol~y. M~al Col- lie ~ V~llela. Richmond (~¢ L~r- Vi~OR A. McKUSICK. M.D.. ¢i,~le rro!r~ur ol E~,lo.i~docy Mcd~ine. Ballimo~c. Md. InstD, le. Univcr~ly of Michilan. Ann A~r. HUGII MONTGOMERY. M.D.. Cardiovascular cffgcls og nicotine rm,~bl~ in,actions oC vi,u~s and tub. Soc~-I aid p~noi~l cklcrminanls smoking bchevi~'(C--P) The ~oclal mcdlatloa of smok~ havio¢ (C) A~:nic contcn! o| xoih and nbsm'lalon by the tobacco plant (C--P) Th~ ¢ffCClS og ¢nvkonmcnlal (ncto¢~ on development o| alheeoscletmis as go. vgalcd by nulOp~y O( acg~drnl victims Envigo~mclal faclocx and pulmonary dip eu.~. I. Asbcsios dun4 n~mokcr, (C~P) ' Enzymt~ I~snsf~mlion~ of ~ic~i~ and ¢clalcd com~ad~ comblncd ~¢a¢1~, physi~ol~, clinical and ¢p~cm~ogic study Og a~rscr'* 25¢ I~havioral effects ot ~mok~| under xlrc~ It") 67
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GIUKI'U~ AND IPI~iTUTiON ~ P~oI~ ol P~olo~, Uni- vc~t~ o~ ~ca~, ~ulhw~rn Ncd~ul GEORGE ~ r~l~. Rmwcli Park ~cm~inl insti- l•It. auff:lo. DONALD M. PAC~ Nebraska, Lincoln. EDWARD W. PELIKAN, M.D.. c~s, Prolt+lo~ ol P~va~c~o#y and £z~,~im¢~l TA.n~u~lc~. Boston Univc~ly ~ of Ncd~, ~¢rul~vt DittcU~. ~vcr ~cd~ll RC- C. ~. ~ER~T, P~., D~r~l~ ol B~icul Rt~t~h. P~nu F~a- I~ for Hcd~al Kc~uch. CM. Cdkgc ~ ~lh Cuba, Charleston. I'i¢OJ£CT TITLE Invcsl~|ulio~l o| IIic role o( Ih~ nuclcolus in Ihc normal and Ih¢ mali|nanl c¢11 An invlsl|lalion ol Ih¢ phy,~olo|ica| c|- feels OI ~r~l inha~l~n o( I~co ~kc by la~alory animuls and slay ot Ihe bi~os~ul r~ la~al~ ani~ls Io con~nuous gcbl~on o~ d~l-lobacco ~uCl ~u~c~ (~) A sludy o~ Ihe c~ccls ol smoking on pul. monary (uncli~ The production o| gcnclically conlrollcd animals and lumor! |o~ ui¢ in cxFcri- menial rcs+arch on Iobac¢o in rclatin~ Io hcallh (C) Sludics o/ Ih~ mammary tumor.promol. in| qualltics of • vlru~-iikc principlc. uadc.r varyini hormonal and a|in| conditionc Fellowship for Irainin| in llssu¢ culture kchnklUCS (C) Sludy o( ll~ e//lets o/ Iobscco smoke constilucnl~ on various sir•ins c~ au~ cclb cultlvattd in vluo |P) A sludy o! lUu~iurc.•clivlty rc~alic~hlps neon| dru/s which •~'c¢1 n~oGnc. sensitive physiolo|ic•l mcch•nism~ I P) Pos~bi¢ cffccl ot Iobacco dcrivalivcs on arterial and myocardial li~u¢ cultures Fcllow~hip~ /or ~udyinI Ihc cuhurc o~ human luni li~ and Ihc effects of knuwn a~ ~blc ~rcinogcnic a~nls u~ such I~ oh•nice ~ hum~ bro~hi Appl~ai~ o( a nov bloa~y Icchniq~ in ezamlnallon ol c;qar¢lia smoke con- ~u~clnosc~is in I~ la~ralory animal: 6~ GI~IqT~£ AND I/~sTrruTION WALTER P.EDIS~H, M.D,0 Nc:w York, Univ©r~ty Research ~c~vlc¢. Goldwalcr Hlmor~al Ilospilul, Welfare hlnnd, Ncw yock, N. Y. (x~ ~ulz~rl~r) HOaART A. REIMANN. M.D., Pro~¢s. nor ol Me~'cla¢. llahncmann Mcchcal C~leBe ~nd Hos~t•l. Ph/l~l~hiao V|~TOR RICIIARD$o M.D.. o! Sw&er~ ~nd Ea~culiv¢ llcad, D~. ~mtml oJ 3u~l~. Slan/~d Univcr. CuI. (~, BENSON B. RO~, M.D., A~oc~t Pro. ItS. Unevenly Mcd~, ~n BENJAMIN A. RUBIN. Px.D, ~1 Prolt~ el P*tvtnlivt Mid'int. Dayl~ Unlv¢~ily Cdlqe of Med~i~. II~sl~. Tcx,. (now ul Wyclh ~alot~, Phi~dcl- ~ia, ~LLIAM O. RU~RI.L M.D., and Tumm inslhuie, ~niv~ly Texas M~d Ccnlcr..lio~l~. P~ER P. SALISBURY, Imlta~ivt Tt¢~Imtnl ~tn(tr. Sainl J~ph H~pilil, Bmbank. ~ul. PAUl. D. SAL~AN. P,.D~ ~ralt~ OI ~i~¢m~lry. Uaivc~ily ~LVIN R. ~iIMI~T. PII.D., ol Co~.;inl, Tu(~ Univc~ly, Mcd- Pslholol~--anllomic Iludy o| or, JlUlll cl~nlc+ in kum~ bronchi (C) 69 o u~ o ,C) (D
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I£ HOI.LV130SS¥ 3W11"II'1~ grlSb'll • ~Jl .L33 fOth~ NO~MI GMY
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JOHN P. WYATT. M.D.. P~o]~s~ae al PatJolog~. St. [.~u~s Univgr, i.ily ~:hooJ 72 qualitative a~d qu,~thsfiv¢ study individual ~lyp~ ~tcnt ~ in the ~ gg~vi~; ~ the v~ular pzt~. ~t~y ~ ~king ~bi~ ~r ~m~ (C~ An ;-vg~i~don o( biocbcmicxl fgtm o I- I

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