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 SCIENTIF7C ADVISORY BOARD
to The Council for Toh .cco Reaearch-U .S .A ., Inc .
' as o( June 30, 1971
SIIEI.IX)N C . SOMMERS. M .D ., Chairnren
Research Director. The Council for Tobacco Research-l/ S A . . Inc . (].ARENCB COOK LITIi.E, Se .D., LL.D ., Litt .I) .
Director of Laborarorkt, Leno : Hill Hospital
Clinical ProJetio+ of Pathology 18881971
I
Columbia University C.ellye of PhYsicians and Surgeons
New York, New York
HOWARD B . ANDERVOMT, 3c.D. Dr . Clarence Cook Littk, iMernatloeally known geneticist and
Scitnri/ic Editor (rndrrd), The Journal of the National Cancer Institute cancer researcher, died December 22 . 1971 . Ne had been Scientific
Bethesda, Maryland Director of The Council for Tobacco Research-U .S .A . . Inc. and
RICHARD M . BINO, M.D. its predecessor since shwtly after the latter i ertablishrnent in 1951 .
Dirrcror of CrllofoPr .wf lntrarnrrf Medic(ne He also served for many years as Chairman of the Scientific Ad-
Huatin6to. Menaial Hospital, Pas.drna, California
visory Board, an elective position for which only Board memAen
Pro/esfor of Medkinit vote. Former president of both the Univey of Maine (1922-
University of So .than California School of Medicine
Los AnBeks, CaNfor.i. 1925 ) and the University of Michipn (1926-1929 ), "Pete" or
McKEEN CATTELL, Pr .D ., M .D . "Prexy ; " as he was know. /o cvtkaNes asrd sludents, was a tower-
Pro/essor £ierrlav of Ph .m.coloty in` figure as a man and as a scientist . Wann, dynamk. an tnppn6
Cornell University Medical Colkae, New York, New York personality with a sharp wit, Dr . (.ittk was one of the first scientists
ROBERT 1 . HUEBNEER, M .D . to discover evidence of a viral agent isk pncer, an observation that
Chk/, Viral Carcinoteaesis Branch led eventually to the keneralieed virtis dseory of cancer . He also
Nalbeal Cancer Institute did pioneering work in imamuroto`r and was one of the early re-
Bethesda . Maryland searchers into the genetic eBeds of radiatbn . Dr. Littk founded
LEON O . IACOBSON, M .D . the world-famed Jackson Labotatory In Bar Harbor . Maine, ia
D4rr of tAt Dlr/aiow of B~ .f Scicncri 1929 . He served as ita director until 1956 and as director emeritus
Reewr srM Pro/tsior of eioiolicaf Scicncta
until his death . He formerly was Manapoj Director (1929-19lS)
llwi.enlty ol Chk.go, Iriaois
CLARENCE COOK LITTLQ Sc .D . . LL .D . . LtTT .D . of the American Asuociatfon for the ('.oatrvf of Cancer, which is
Scirnri)k Direclor, The Council for Toh .cco Rnearch-U .S .A ., Inc . now the American Cancer Society, and . .as a Fellow of the Na-
Director £n.MUftt, Roseoe B . Jackson Memorial Laboratory tional Academy of Scknces and a member of numervw other
Bar Harbor, Maine scientific societies . lie awhored many books and articles and his
CLAYTON O . LOOS1.1, hr .D., M .D. 1939 book, "CiviGsat3ost Apiest Canet :r," is still considered a
H.urlnjt Pro%sar oJ A!t/k1ne and Pathology classic for the layman . For 17 years Dr . Littk gave The Council
University of Sa .dient CaNtoniia 3chool d Medicine
inspired scientifk leadership and 6uid .nce. His contributions were
Los AnBeks, Cafiforaia
many and important. He will be deeply missed .
KENNETH MERRILL LYNCH . M .D., Sc .D . . LL .D.
Chancellor .n/ Pro/es,sw En .e.irus of Pathology
Medical College d Sowth Carolina, Charleston . South Carolina
.
WILLIAM F . RIENHOFF. 1 .., M .D .
Pro/rssor £nwrlrur of S+rgry
lohns Ik .Qkins University SCMcA of Medkine, Baltimo .e . Maryland

ROBP_RT C. HOCKETT . Pw . D .
AcNnt Scknli/ic Director
1 . MORRISON BRADY, M D . IONN H . KREISHER, PN .D .
Ai.roci.re Scirmn* Dirtrwr Ataacialt Scientific Dirrrtor
VINCENT F . LISANTI . D .M .D .
Scienll/k Af.rociare

. . . .
Introduction
!tlrc Cancer Program
ACardiovascular Research
JChronic Respiratory Diseases
iNeurophysiokofry . Psychophysiology and Pharmacology
Other Studics . .
Abstracts of Reports .
JPsyehophyswb6Kal Studies
✓ Carcinogenesis Swdics .
jCardiovaseular System .
/Respiratexy System .
tissue and Organ Culture .
Studies at the Cellular Level
✓ Pharmscoio6y and Psychophannacoio6y
J Metabolic Studies . . . . . . .
f7hemistry and Biochemistry .
. . . . .
EpidemiolM
J the potential importance of rnasy contributions by other investigators that
Active Projects . .
Completed Proiectu
m
~
Introduction
Previous Annual Reports have stated the general research policies of
The Council for Tobacco Research-U .S .A ., Inc . as conceived by the
COWTEN" Scientific Advisory Board. These policies, which continue to guide the
progam, emphasize study of the etiology of those d'aeases that are reputed
. . . . . . . . . . . . . . 5 to be related statistically in their incidence to cigarette smoking .
I Such diseases, especially cancer, cardiovascular ailments and chronic
respiratory afflictions, are not only leading causes of aorbibity and death
. . . . . . . . . . . . . . . 6
time the conquest of major infectious diseases but are universally reco`-
nized to be of multifactorial origin and to be strongly Influenced by con-
. . . . . . . . . . . . . . II genital predispositions . The rofe of tobacco use in their etiolo6y, if such
eaists, can therefore be defined or tneasured only within the context of a
. . . . . . . . . . . . 14 growing comprehension of the total etiologicd picture, invofs•in6 knowledge
of the complex interactions bttwees endogeaous and exogenous factors .
As new concepts develop with respeet to etiologieal mechanisms that
. . . . . 16
may be involved in the genesis of ehese eoratitwional diseaaes, these con-
cepts In turn suggest new biological test systtar for determining whether
. . . . . . . . . . . . . . . is chronic espoaure to cigarette smoke or sane inpedient thereof can con-
; trib rte to the operation of these mechaRdsan . In this way it is to be hoped
. . . . . 20 that a series of progressively more meaningful test systems will evolve as
. . . . . . . . . .
etiological understanding advances, to supersede the crude and inadequate
. . . . . . . . . . . 20 methoda of the past .
. . . . . . . . . . . . 23 All investiptors in the 1k1d we well swam that sckntifk progress
. . . . 34 takes place "in slow motion ." The description of proprss in a singk year
. . . . . . . .
is skin to attempting to depict the progrets of a baseball pine by describ-
. . . . . . . . . . . . . 42 ing one inning . Moreovrer, since the propm of studies in one sintle pro-
. . . . . . . . . . . 55 parn such as that of The Corrcil is inlatelMed in a rery complex maa~oer
. 56 with the progrea of manr other sw0iea t6rooghwtrt the scient ;fic world, the
. . . . . . . . .
report of any one program cm hnrdly hope to present anything resembling
. . . . . . . 59 aa Integrated picture of the status of knowledge in any particular &Id or
. . . . . . . 69 area of medical science.
Recognizing these limitatioes, we have attempted only to mention in
. . . . . . . . . . 71
this report a lew selected findings that have emerged in published form
. . . . . . . . . . 76 in the year ended June 1971 . These adectiom do not in any way minimize
. . . . . . . . . . . 79 do not receive particular merMio+t here. Sieoe all these contributions have
. . . .
entered the "public domain" of acknce, they will be aaimilated into the
body of total knowledge and oornprehension that occurs through the
. . . . . . . . . . . . 119
. . . . process of "dillatkx" and uubdine by the great eootraternity of investi-
ptors In the many disciplines Invofved .
Rr)mlaT C . IIOfR[TT
Acting Scientific Director
5

rThe Cancer Program
I or "safe." The model is only one new tool that provides comparative et-
viruset and Cancer
Viral aspects of anoer, inel .ding the human disease, are heing in-
lensively studied in many labora/ories throughout the world . Reports of
advances in this active Ik1d seem to appear almost weekly as scientists
strive to pin down esaet evidewce that hurnan eaneers, or at least some of
them, are caused by viral factors . Perhaps o( greatest prominence in this
field is the general virsl genorne concept . This postulates that c C-type
RNA viral genome eaists In atl snammdian cells but remains "switched
oft" until, for some ruson or reasons still largely unknown, it becomes
activated or "derepresacd" and triggen the development of cancer in forms
determined by genetic programming o( the strain or speeies .
Deoelopwaent o/ . Test Syaterw
A Council-sponsared study has been aimed at development (d super-
sensitive, virus-primed tissuettidture test systems for measuring the relative
potentials of various ehemicaM, in eollaboralion with the virus, to produce
"malipnnt transformation" of cells . For e:ample, rat embryo cells infeded
with Rauycber leukemia virus have bee. treated with various doses of
7/12-DimeMylbe.:(a)-.ndrtcese (DMBA) . MorDhobqC traant«ma-
tions Indicative of nooplasia waa noen . On the other h.nd, there was no
transformation in uninlected rat embryo cells similarly treated or in infected
cells not treated with tlr DMBA . When transplanted inlo newborn rats, the
lranaforn.ed cells produced subcutaneous sarcomas, but no tunon resulted
from like treatment with the idected or DM9A-treated, untraraformed
cells .
The work showed that in this rm+del, at kast, bo/h chernkal and virw
were necessary for cell tr .ndorrwalinn . According to the inroesriptor, the
Rndings wyest tha the C-type RNA virat llencwne o( the Rau .chcr ku-
kemia vitns proridcd specific oec'o`ene information for the malignant
transformalion .
6 7
It must be recognized that this model does not duplicate real life
situations . Rather it exaggerates certain factors and eliminates others (or the
sake of supersensitivity . The effects of chemicals on cell transformation are
greatly enhanced by priming with virus, whik the protective effects of the in-
tact animal's immunity system are elitninated . Nence the model can be es-
pecled to show positive effects by chemical agents which, on the basis of earlier
in vivo lest srstems, have been considered totally Inactive n"carciraeetu ."
Such indications from the new wpenensitive systeea therefore do not
simply or automatically imply that such wbsttnces are either "dangerous"
perirnental values on a single spk . Frorn nrur such evaluations a relative
••activitr scale" or act a[ saks auar dtvelop th .ti will permit more direct
and mwm nearly quantitative eowtp .risons of very feebly active compounds
and mixtures with those of high activity . Awy M/empt to estrapolate the
findinp from such a model to real life situalions, especially the human,
will require even greater eare and discretion 1h .n heretofore .
A hopeful potential for IAe model Iks in the ultimate possibility of
I including human tissue cultures in the system for comparison and contrast
with those (rom other species, under deM+ed, controlled and closely an .l-
agow conditions. A smre distant gbsl is development of a method for
assessing the relative degrees of cancer sulceptibility In human patients .
Another virus-related study of The Cot,ncil, completed during the
year, sought to determine whether a rdationship could exist between the
occurence of cancers in hwnans and the presence of cancer virus in house-
hold animals such as cats and dop . The work concluded that no such
relationship exists . The scientist who carried out the study reported that
while C-type viruses in an active state have been found in the domestic cat,
there is no evidence that they spread to dop or to man or even from cat to
cat . It appean, under natura/ eonditiorr, that feline C-type viruses are
inherited as indigenous lalent genes which may activate in the fetus or later
In life . The investigator cwtioned that swaptibilNy of certain human cells
to in vitro infection with Ihese C-type viruses does not imply infection in
the living organism .
The same scientist, reporting on another facet of the study, disclosed
indications that feline sarcotna virtis can transform human osteosarcoma
cells. This example of cell transformation by a non-host virus seems of
considerabk dRnifkance in virtn-eanoer research .
Findings gained by Ihis investiptor In the Council sup/wnled projn t
wene applied to later rewrch, funded by the National ('ancer Institute .
In which human cancer cells were Injecled Into the (elu .es of pregnant cats .
$ome of the cat fetuses developed tumors of human cells in which were
found particles similar to the ktto. .n C-tppe cancer virus particks of several
animal species . Present irmeunolo6jcyl evidence suggests that these may be
the long sought human cancer virw particks . If this finding is confirmed,
it should greatly facilitate testing in man the many implications of the vital
genome concept oi cancer etiology that appear to present a rather well-
intetrated picture in several animals . It might also make possibk the addi-
tion of virus-primed human odl cultures to the in vitro test system that has
been described .
odker Nirns-f..wc+er SqJ1ee
LytwQhosarcorna in nbbita, a tsire hs .a in that particular animal,
has been the subject of a .odter Cotrcil-sponaored project . A researcher
studied one arain of rabbits atrortd whicft a number had developed lympho-
sarce>.nas . Ik ao .lysed dte ped<pets of the affected animals and found
that Inheritance indiasted se a .wsontal rcaasive liewe oo.[errins suscepti-
bility to lytnpboaaroorna. The /adirtp, the invesliptor troted, were con-
txptuaNy compatible both with genetic susoepibility to malianant lymphorna
and with vertical tra.smirion of a vitvs .
The ueoptastic Involvement o/ various osans in the rabbits resanbkd
In many ways visceral lyniplwsatcontatasia of ats which has been proved
to be caused by feline k .kemia viru. . According to the investiptor, his
6ndinp on lymplrosarvwtta and its hereditary b .sis provide a new and
Important modd for studies of the p .thollesew of neoQtasia .
Still other studies being supported by The Council in the virus area
incfude : onoogeny aad dte .ndviral at .Yion of interferon, effects of respir .-
bry and orroolenie .irwa is orpa cultures of hutnan respiratory tract
tiasue . and asechaai.os of suppressioa of cellular Immunity by carcinogenic
hYdrearsos .
Sn.oke B:to .ore Dedcea
In Its search for more realiatie bioassay systems . The Council has for
many years supported studies involvieg dprstte smoke inhalatioN by
animals . A nujor aspect of this undertaking is, of eourse, the drsia .n
and production ol a"sntoke espaswe devios" that perntiu esposwe el
esperMa+Nal aniwraM to ssaokta inh.latbn b a manner and under cnWVdi-
Wwn that reaewrble A.w+a.,wakind M ebaty as possible . heviow Annual
Repo.ts of Tl.e Couacil have oa+tlYsd sevetal strict aiteria for the function
of such devices and these have subsequently been extended .
I
The Council has developed a machine which has been undergoing
tests in actual projects . While it has already deteottstrated its value in
several researches, a number of aeall but Important improvements are
being made to refine and define its operational characteristics.
In using such a device, perhaps the most difl'icuh problem is to measure
how much of the particulate phase of the smoke actually reaches the Iw+t
surfaces of animals that uornrpr breathe through their noses . Such
teeasurentents are being carried out with tagged smokes .
The machine now being ttae-taled by oe .eral Council grantees has
provision for inaertian of a Caobridge 61ter that removes particulate
tttateri .l and thus permits comparison of the effects of whole antoke inhala-
tioe with those of inhdint the pa .vapur phase alone.
NawJJLy and Stewdrdia.tl.w o/ Awltw .le
t It is irttportant to bear in mind that ha.dlirtg aninuls and confining
thea in a satoke esposwe device L very stresdul /o them . Hence "machine
oontrds" that are subjected b the same handling aod oonAnensent in a
functioning device, but withottt actwl smoke espoarte, tnust be induded
ia experiments as well as wtltandkd "cage aottttds ." Compnriaom of thtae
two sets of controls ca . be expected to disclose some ol the bio{ogical
effects o[ these particular stta .ea . 'fbese, at ka .t, am thee be taken ieto
acs~ount is the interpretatiom of stasoke Inhalation e :painsents in which
handlieg and oonfinetnent stresses cannot be separated directly from smoke
effects.
Sipi/kant biological e%cb d streas, originally observed in such
"ranchiee controls." have now b~eooae a ssject o( investigation in their
oaw tight as past of The Cat.cil'ra prooras .
I. connection with smoke Itthalatbw a weM as other kinds of studies,
'IUe Council has sought iaptotKwent i . dte standardization of asimais .
A .itw.h ssnd in most Cowtcil-wpported teswrch are delivered by ce .areaa
section and are suhstaaWy free troa pathoIt eea . Af.o, their virus profiles
are detennined as fully as ponibk Y wer s the wtw of the C-type RNA
viral genorne espreasion . Many eanoer researcht:rs tr .e Mbred arains of
miee becwse of the peat variety of Mraiar with known congenital tunar
susoeptibilities . I/.n.evrr, beewss dsere soesedtnta ue advantages in wing
hamalers, which have larWr lunp awd greater blood vdume, studies have
been starled with this species . Some inbred hamsters strains are now
available.
9
B>•po.are o/ Cdttnres to Sawoke
In one smoke study, three types of primary cultures from Snell mice-
kidney tissue, embryorwc hrn6 organ and IonA esplants-and one establ•shcd
cell line from Swiss mice were used to ass .y the biob6ical eRects, in vitro,
of the gas phase fran charco.l-Altetrd fresh cigarette amoke . Repeated
exposure to puffs of the smoke did arot prodree my sipri/kant changes in
the Snell mouse culhrres . The expoae/ 3wir fmrrse celb showed art en-
hanoemead of powth, tnibtk i.de:, and afiwtlar atrpiun . No morplaloeical
oeA transforwution was observed h ry of the exposed cultures . Such in
vitro studies are mainly tr.drl r oids to the irs/etpretatios of whok ardmal
studies . Bei.t by neoessitr "urphy .iologicd," they cannot be e :trapoLted
easily or directly to aorwrt We ao .diljos.
The researcher who perfotwed this study u.der a Council grant had
previously reported that Saidl aice, with viral Be+wrae expressed, exposed
chrddcapy to I .halation of e4Aer vAok awroke or its tas-vspor phase
(devoid of the p .nk.(Mes or "tan" ) deve{opod lung adenomas and
.dceocarciaowu. of the wne kYd tkrt they develop spontaneously . None
of the aniwub deveioped qrawrow eell IanA trruon. Mice of another
strain, lacting viral genome espreasion, ahowed a dramatkaMy lower
incidence of adenoma and adenocardnoma under the sune cond'Nions .
In a study of the incidenae ud appearance of lung tumors and
pneumonitis In mice, a Council-supported scientiat immunized mice with
an Influenza virus and then espo .ed them and eontroi mice to sub-lethal
and highly lethal nebulized clouds of fresh virus . The controls succumbed
quickly to the lethal clo .d of virus and had extensive and persisting
pulmonary changes toibwinA exposure to s .b-kihd clouds. The immun-
ised mice Denme only oildly IA a.d survived the lethal clouds, though
large arnowsts of virus were found In their lunp, which soon returned to
narnial . The researcher noted tlut Mununitation, while not preventing
infectlon, was beneficW b the auirnals etpoaed b aJrborne influenza virus .
It is kno .vn that many nwrse Mrt+iar develop adenonas in the bron-
chbb-aivoolar regions teprdkts of what b, or is oot, done to them .
Adenonrt do not seen+ to arise in the large broec .fii or In the tracheas of
these aninrals . Is thete a differcnoe In swoeptibility of these tksues to
eheaD3ca" a"sl Or is it that these (ncitift arents, when uaed esperi-
n.entallt, do no/ reach these difterewt tbra in eriuaf amcwntsT
In an e&xt to karn some anawen, 'tlro Council has supportal work
In which fraAnnnrs of liwa frorrr Irap, large br .rnchl and trachcas, re-
spectively, of BAt .B/c/Cb/Se mice were irnprepated with methyl :ho-
lanthrcne (MC) alone or mixed with tak powder in concentrations of 1 :10
10
and 1 :100. The fragments were then transplanted into the subcutaneous
lat pads of syngeneic hosts.
Results indicated that the sensitivity of bronchiolo-alvoolar epithelia
to MC was higher than that of tracheo .broncitial epithelia . Nowever, the
latter were not wholly resistant to the MC since there was almou eoestant
tumor growth after impregnation with the carcinolien . Thus, there does
appear to be some difference in tissue nrsoeptibdity .
A similar experiment with swbcutaneow pfftinA of traeheal, laryngeal,
btonchial and lung tisaues, followed by a single ietnpetitoneal Mjection ot
I urethane, produced adersonuu oaly ia the tr .hed lung tissue, showinA a
tissue specific effect of this p .rticdar agent and suggesting that the agent
was transported by systeanic torta to the locus of action .
Other Cwwter Strrliea
In other work related b eaneer, The Council b continuing support
of eRocts to develop "positive" w+odels for the production of aquanwua
cell hn+` cancer in animals . Guide lines are few in this area, but it some
simpk, easily reproducible method could be de•ised, it would be very
helpful in many research areas . It lung cancer ot the type reported preva-
knt in man could be produced repetilively, at perhaps the 20 percent level,
in an easiy handled aninul, it would then et possible to undertake Nudia
to see whether many factors - age, sex, hormones, irritants, dkt, streas,
infection, and others - might influence the level and rate of incidence of
the tumor.
Also being continued is a project in which a concentrated stream of
fresh cigarette smoke is being blown directlr on the skins of mice of a
strain previously used in a skin-p .inting test with tobacco-smoke con-
densate.
Among other ongoing projects being supported are : hetero-trarur
plantation studies with human lung aneer, the pathogenesis of urethane-
indueed lung adenomas in miee, and ho .t factors in lung cancer and other
hrnA ailments .
Cardiovascular Research
Iin .yn.w Ro/ated to Ath .ro .cf.ro .la
A study involving an enzyme has turned up Andinas that may be
significant in regard to atherosckrosis . The Council-supported project used
II
segments o/ human iliac arteries incubated with human serum . Samples
were heated to inactivate the enzyme kcithin-choksternl-acyl-traraterase
(t-CAT ) . It was found that when LCAT enzyme was present in the
incubation medium, virtually only free cholesterol left the arterial wall .
Ilrnrever, when LCAT enzyme was ab.ent, only cholesterol ester kft the
wall .
The results suggest that a decrease in serum free choksterol, caused
by a serum cholesterol esterifyimil eaarne, possibly LCAT, might be
important in promoting the rentord of free cholesterol from the arterial
wall . According to the investigators who performed the work, the results
are consistent with Mdinp that there is a tendency for LCAT acavity in
the serum to be higher in penoas with hypty+rhoksterolemia greater than
30(/ m8/t00 mt, which may reAett a snechanism for protecting'the arterial
wall from excessive free ehohslerol .
The scientists said their Vdinp oay be particularly important
because they have found that choksterd eaterilication Is sianukamly
impaired in persons with acute myoeardW infarction and chronic coronary
artery disease when compared with age-matched controls. Tt+ua, they said,
a deficiency of cholesterol esterifyift enayme, possibly LCAT, may be
important in the etiology or rate of development of ∎tberosckroais .
Cor .w .ry Mlcr.cires+J .ta .w
Co.liataws his wott on total aad twtritiaul coronary dow . another
grantee has reported a aew tecln*ue for determining the velocity of red
ceb in the capillaries . He has described capillary blood Row as that por-
tion of the total coraury f)ow involved is the nutritional function of heart
mwck, while total coronary dow represents all the blood enterin8 the
heart circulation .
. To measure the velocity of capillary ted e+e%, the in'vestiptor devel-
oped a method showing the (raase-lo-lraaae pro8rer o( individual red cetls
in moving pictures of the txpillariet . Thts lechnique aYo permits measure-
ment of the diameler of upillarien r it cMrtlpes from frame to frame .
Data frowt one part of the projeet i .dicated that rwrepiaephrine re-
sulted in opening of capillaria, that nitrv8lyeerise slowcd the Row in the
capiilaries, and that tneth.cl.oline trwhed M the oompkle arrest and even
retrograde Ao.r . WhBe irMerpretation of these /ndinp will depend on con-
tinrin8 atudy, the reacsreher beilkves the work wUl provide new infoNmation
ahout the cor++nary awkronladon .
Another aspect of the study wts a further elaboration of previously
reported findings on the measurement of total and nutritional coronary
12
flow by means ef a coincidence counting system usin6 rubidium-84 . Workin8
with this system, the grantee found that norepineprinc caused a dispropor-
tionately greater increase in total as compared with eRective f1ow, and the
same result also occurred with nicotine . Isflproterenol, on the other hand,
led to a proportionate increase in both nutritional and eRcctive coronary
Aows .
In another Council-supported study, mongrel do8a were exposed to
ci8arette smoke inhalation and also to injection of various pharmacologic
agents . A reduction in aortic blood pressure during smokin6 by the anes-
thetized animals was seen . This was attributed in part to the eReds of
nicotine on the central nervous system and in part to vasodilation caused
by the action of released catecholamines on certain receptors in the peri-
pheral vascular system .
Kinina and /w/LwsnarWry Re .ctiow•
Another investiptor Aaa been studying kinins, polypeptWa that are
involved in inflarnmatory reactions . There is evidence of vascular permea-
bitity occurring independently of known snediation systema, and the kinin-
fonnint system is btin4 i .vatipted as a puasible humoral mechanism in
the induction of vascrrlar injury .
Physical propcrtia of the components of the kinin-forming system In
rabbits are being studied . The eharacteristia of human components are
comparabk . It is hoped that this work will indicate the substance or sub-
stances that may affect inflammatory reactions in the IunB, particularly in
hypersensitivity states .
Fraaainslkan. Ne+rt Stsrdy
The Council has rnade atrant related to the Framingham Heart
Study, effective July 1, 1971 . Thb atudr was to have been ended for lack
of federal fundin8, but its lont-time direetor and several associates sought
and obtained outside support to keep it Roing . The Council's grant is for
an investigation of smoking dasses, risk factors and cardiovascular disease
in the population being followed by the project .
Other studies being supported 'wrclude : nicotine and various aspects
of cardiovascular functinn, carboayhernn<Ir>Mn and cardio-respirarory
functinn, .mi+kinR and air pollution In human myocardial natahrrli .m, in-
fluence of srmrktng ∎nd nicotine on lower limb clrtulation, sensitivity of
vascular tissue to niootine, and the effect of smoking on regional cerebral
bbod flow in smokers and nonsmokers . -
13
 Chronic Respiratory Diseases
llydine Merwbrswe Dimoae
A significant finding In regard to hyaline membrane disease ()I %ID)
has come from a Council-supported project that encompassed the an :.lysis
of 387 autopsies on newborn and atlltbor>t Mfants . It was found that the
adrenal Sfands were 19 percent lig/Ner ia idaata with 11MD than in those
free of the diseaae . Tlwse without drc diaease had a greater number of
adrenal cortical cells . Alao, a poaitire oortelation was found between the
presence of Miection arising before biAb and the absence of HMD .
In oonnection with swtactwN, which appears to play an Important
role in this disease, it is YNerest4K that a .e.cephalic neonates who had
little or no adrenal fetal cortical aonea aad haJ(-aized adult zrones, were
found to have only 45 percent the r .ass of osaiophilie pranuld in pul-
monary type 11 alveolar cells found la atos-anenoephalic control inlants .
These Rr.urks reportedly are the analomie representation of surfactant .
The investipton who conducted the study noted that the eortioosb_roid
mechanism "oAers the attractive possibility of relatively simple prophylaxis
against hYaline membrane disease in certain high risk aestat"ans ." But, they
caution . "This temptation to treat should be strongly resisted until the
mcchanisnx In question have been explored in the good experimcntal
models of hyaline membrane disease now available . The need for such,
caution is also supported by the observation that the doses of cortico-
steroids and ACTFI used to increase wrfactant tevels in the lungs of fetal
lambs have induccd toxic changes in other organs ."
Appr+i.ehl.w Coa/ Miw .ra
A quantitative swrpiroto& study was tandertaken of lung and hean
strvctwe in 322 Appalschi .n minen who were cl .ssibed by a6e, duration
of mining espoaure, rank of coal mined and nuroking habits . Right vcntric-
tdar hypcrtrophr as evidesoe of oor pulmonak was oananon after age 50 .
The volume of macdar dust lesions, Including associated silica crystab,
fibrosis and focal emphpsen+a, increased with aBe but these dust lesions were
not deemed to be aokly responsibk for dysprea since miners with dyspnea
aSur had a generalized form d ewiphYsema . Smoking was asu+ciated with a
rm~kst incrcaae in bronchitla asd emphysema in bituminous mincrs but
sfK>wed littk or no rclatbn to the extent of such lung conditions in anthra-
cite worken. and no.wnoUos mi.en alao developed these disorders .
11
Above-ground air pollution may play a role since the wives of some bi-
tuminous miners seem to be nearly as much affected as their husbands by
cough, phleyn, wheezing and breathkafness . The association of pncu-
moconiosis with coal rank was found to be fortuitous .
Microcircwlation oJ tlke Hans.n Lun6
During the year a Council grantee published a report describing the
blood and lymphatic microdrer .hation of the humaa lung that provides a
ckar, conciae summation of ma}or findings ie this particular field . The
investiptor, long involved in 1rerg rtaeareh, gave the results of correlated
macroscopic and micro .oopic studies of the hmp of humans, beagle dop
and mongrel dogs . The report wau primarily concerned with an6io-archi-
tectural relationships between the bnonchial aad pulmonary vascular sys-
tems, and the author aoteQ that dre relationships arL distinct In each . The
bronchial arteries are drvelly connecled Io each other, establishing a
"parallel" vascular supply . The bronchid veins nLo form the peribronchial
ven3w plexus . However, the pulmonary cireMlation, the pulnanary arteries
and veins form acrminal, intrafobufar branches . The bronchial and
pulmonary arteries also communicate in the bronchioka through a common
capillary network .
The grantee reported he has beep unable to observe broncho-pul-
monary arterioarterial or arteriovenous anaptoawaes In entirely normal
adult lunp of beagles, but said they seem to be normally present in the
lung of the human fetus and Infant . lie said they probably vanish in child-
hood but reappear in the adWt lung with the onset of even minimal pul-
monary Inflammatory reaetiona or processes .
The scientist also published another report ie which he described aUs
with the ultrastructural characlerWia of etvroaecrelory cells in the lung
lobules of prematurely born infants . He had previously suggested the
esistence of these cells on the basis of light and fluorescence microscopy
and noted that analogous cella had been reported by others . He said the
possibility eaists that these cells may be Involved in the regulation of
lobular growth and In modulation of normal perinatal cardiopulmonary
adaptation, and that they may play a rok in respiratory distress syndranne,
Prlwsen .ry Alowol.r M.rropb.pa
What b the origin of the pulmonary alveolar macrophaaes7 There has
been considerable controversy as to the cellular precursors of tlxse cells,
which comprise a major defense mechanism of the lung . A Cauncil•sup-
15
 ported study has elicited evidence to indicate that at least some of the
macrophaga originate from bone marrow . The study used genetically
related mice and substrains to investigate the possibility that macroph•Ses
originate in marrow stem cells .
Success of the experiment rested on the fact that the genetically re-
lated mice carry a rwnspecifit :, readily identi6abk pre-albumin esterase
marker . Lethal x-irradiatiow and injectiom of bone marrow from the mice
kd to llndinp conbrwring that M ktast some macrophases originate in bone
marrow . This particular work wa• p•rt of a project that is moving into the
biocheaniury of maaophaps.
Another Ca.rcil paMEe povided a de :acriptive eeport of the appear-
anoe . .der the dectron r .icro.oope d ttlveol .r macrophyes obWned by
endobroachi•1 lavW trour a.rotets and ao.sasokers.
Fie said thal in p.eral t..crophapa from smokers contained larger
and more helerolle.eo.•lf tMr.chtcd indr .ioas than those (rowt nos-
smoken . llowevet, ttiae was cousidetabk variatio . {n the aumber, size,
and beeerolesicitr of Inclusios within k+,dividud macrophsses from
smoken, suggesting that varbw st•rea af pAallocyb•ia ..ere represented
Is lavale samples. Further, the researcher s•id, some substanox that are
phagocytissd but not digestod probably accumulated in the larlper hetero-
geneous Inclusiar o( snroken.
Other studies of hteg n .cropaaga have shown that a peater number
are recovered by lavW from smoken than from nomnwkers, and that the
macrophages from ormoken show unimpiued phahocytiiina capacity in
vitro . ,
Neurophysiology,
Psychophysiology,
and Pharmacology
5 ..+' nicaiw . .wJ M.ws.ry C.wa.tll.ibt.
For several ytars The Council has been supporting reaeanh into thc
eflccts and action of wlooUw• ow sae .rory oaw>tidatioe . One researcher has
found thd rats put Urouflit • tr*Mins retime (maee solving and kver
pressing) karn at a meawr•bk rate . No.rever, it the animals are given an
16
electric shock' aficr a trainin6 session, they tend to "unlearn" cverythins
they had previously acquired . Apparently the shock caused an amnesiac
condition and prevented consolidation of the learning process.
When the animals were treated with nicotine prior to a training
session, it was found that the subsequent electric shock did not affect
memory consolidation ; the animals largely retained what they had Iearned,
apparently because the nicotine blocked any eRed of the shock . The time
of nicotine treatment was important in this experimental procedure, the
cRect being maximal some lime after administration . Cotinine, a nicotine
metabolite, also was effective Immediately, which suggests that the latter
substance may be the active agent . Other parts of the project included
testing the role of the serotonin ptecursor . S-hydroxytryptophan ; aEe diAer-
ences of the animals ; diAerentiat housing ; reduced brain amine levefs ; and
amine changes at the cellular kvel .
In work in a related area, a Council-supported researcher found that
chronic treatment with nicotine induoed an Increased turnover rate and
utilization of noradrenaline In the brains of rats . Pretreatment with nicotine
did not affect the action of sedative, antidepressant and central stimulant
drugs in the animals' brains . In short, the chronic administration of nicotine
appeared to stimulate 7he brains of the rats, making the animals function
more effectively.
Sex Horn .onea and BanpAry.ews.
A potentially sipnifkant report during the year cante from a Council
grante who has be n working on the xperimental induction of emphyaemy in rats
. lie has sought to determine whether such induced disease would
kad to pulmonary hypertension and oor pulmoaak as in man . 11 was
found that daily injections of proaesterone (the femak sex hormone) and
mcdroxyproEesterone (in a dose 1/SOth that of pro"erone) prevented
experimental induction of ernphysetna in the rats by • method that other-
wise was successful .
Another srantee, treating rats daily with nicotine injections, found an
ekvation in urinary excretion of eateehoiamines that peaked after three
days . After seven days of continuous tneatment, there was a marked falloff
in the urinary kvels, and by 14 days the eatocholamine excretion was
essentially normal . 'T'Ais suggests a phyrbk><ical aocommodation or adjust-
ment over a perird of time to chronic administration of nicutine .
The sckntist espkned three possible mochanisms that miaht be reapon-
sibk for the return to normal of the elevated urinary catechvlamines . lie
concluded that tolerance to the nicotine-Induced elevtions of urinary
I7
catecholamines resulted from increased metabolic enzyme activity that in
turn led to faster metabolism o( the catecholamines released from the
adrenal nxdulla and adrenergic nerve terminals .
Other Studies
Lon` .Terws Stady ./ vatar+.w .
TUe Council ham beea p .rticipeti" Is a bn"rm study that en-
compasses periodic e:aa+inatio~ of e+ore dua 2.000 male veterans. Pur-
pose of the project, which is supported saaiwly by the Veterans Administra-
tion, is to inveati`ale a broad range of changes that oocur in initially
healthy persons as they age . One ultimate purpose of the iovestiptioe is
to learn what factors aa .y be predictive o/ longevity or convenely, of early
decease .
In this study the irrvesti`ators became aware of "secularity effects" as
widely encountered, complicating factors in studies of human populations
that attend over relatively long ptriods of time . Whik in well-designed
animal experiments environments can be kept quite constant except fix the
indeptndent variable to be atudied, changing cultural and technological
aspects of human life Introduce time-dependent dterationa that are often
not taken into acco+at .
In a book published In 1971, the two Investigators conducting the
project noted that whew they learned substantial numbers of centenarians
were heavy saroken, they gave serious thought to the possibility that saak-
in& was seeular, namely . "that the earlier death of thoae that smoted more
and those that smoked cigarettes was due to the fact that they were born
later aad lived at a time when there was more smoking, rather than because
smoking was 4fe-shotlenins ."
Tlreir /indiep, they aaid, euMst that the correlation seen between
smoking and age-at-death may at least partially be e :plained by the secular
increase ie smoking . They further noted tlut in a study such as theirs, "in
which a1 the indi .id..V dk e .seetiaRy .t a sinde point le time, one can-
not precisely ma .ws the elleet of smokiV on lonilevity ,inre the prob-
ability of agirea Indl .idwl beiwg a cigarette smoker or m>mmrkcr Is te-
lated to the birth year ." Secularity eAeets, the authors suggest, may influ-
ence the results of many longitudinal human population studies .
la
Bioe6emical Effects o/ Streau
In a continuing study supported by Tlrc Council of certain biochemical
effects of chronic smoke inhalation by guinea piss, a researcher was able
to detect effects of stress and smoke inhalation on lung mitochondrial
phosphorylation . The nostrils of the animals were occluded with warm,
molten paraffin or a quick-settina . liquid silicone rubber to insure mouth
breathing . Sham-exposed animals were wbjected to nose pluggin6, con-
finement and machine noise without smoke .
The stresses of forced .ronth breathin6, handling, confinement and
noise resulted in kases in osidati .e phospfwrylatioe efRciency in the guinea
pig mitochondria. However, such loss of efticiency was considerably re-
duced by cigarette smoke inhalation . Nicotine is not the active ageot in
this effect .
Twiw Strdle.
I With financial aid from The Cou .cii, a. inteinational symposium on
twin studies was held in San luan, Puerto Rico, December 1-1, 1969 . A
report on the aymposium, titled "Twie registries in the study of chronic
disease with particular reference to cardiovascular and pulmonary disease,"
was published in Acts Medica Scandin.vica, Supplementum 321, 1971 .
The report discussed research into smoking that inwlved twin regis-
tries in Sweden and the United States . It said the clinical twin studies "do
indicate a presence of genr :tic (actor In coronary heart disease and in
variables which have beea found related to it . For inpance, blood pressure,
serum choksterol, and trioycerides terd to be correlated between the
members of pairs, and in addition post-exercise ST-depressions of the
ECG were the same in the twin pairs re6ardlen of smoking ."
The report further said : "A statistically siprifleantly higher mortality
among srrmoken was shown In dizy"ie aade pairs, born in 1901-1925, but
not in monozygotic nule pain, or In females of either tygosity . No in-
creased mortality was apparent among smoken in the older age-groups
(1889-1900) ."
Also in 1971, a second supplement to the 1961 anonosraph, "Tobacco
- Experimental and Qinieal Studks," was published . TThis was an update
of the colkctiorr, abitractinlL and analysis of the world literature on tob .cao
and includes published reporu on both esperirnentai and clinical studkr
'roa ('rwncil has wlvof ta1 this project throughout .
19
 Abstracts of Reports
Following are abstracts, approved by the authnrs, of reports on new
cspcrimental research acknowlcdsina support from The Council that have
aprcared in scientific journals since publication of the 1969-70 Rcport .
l he name of the recipient is in italics .
The abstracts are grouped under these headinas : I . Psychophysiodogi-
cal Studies, II . Carcino`enais Sttd'ies, 111 . Cardiovascular Systera . IV .
Rcspiratory System . V . Tiswe and Organ Culture . VI . Studies at the
Cellular Level, V 11 . Pharmacology and Psychopharmacob6y, V I1I . Me-
tabolic Swdies, IX . Chemistry mad Biochemiatry, and X . Epidemiokr6y .
1 . P,yclaophy .tolosicd Studies
PSYCIiOI.(X ;ICAL ASPECTS OF CIQARETTE SMOKING
IN MEN : A CLINICAL EVALUATION
Certain psychological factors inffuetsce snwkin6 behavior patterns ;
i their assessment of parental disapproval . Thus the meaning ascribed to
psychological factors, the t+ame or others, are also involved in the discon-
tinuance of the habit . In this atudy, heavy cigarette smoking in men is
theorized to be associated with an oral-impuFsive personality constellation .
Clinical interviews with 130 subjecu, repr2sentin` ran-, tormer, mild, and
heavy unokers, supported previous questionnaire fusdinpthat the last
named group is characterized by features of : dcfiance, impulsiveness,
danger-seckin`, neurotic lability, and oral preoccupation . In this sampk,
heavy smokers' relationships with their fathen were more disturbed t~n
were the othergroups paternal relatioruhip . . Intensive /ollow-up interviews
with a smaM aeeketbn o/ subjects indicated factors associated with startin6
and stoppin6 smoking and an alternate personality pattern in heavy smokers
n prevsously seee as false negatives on the questionnaires . This subsample
handkd underlying oral conflict with traits d obsessiveness, guardedness,
arRd cautiousness . Former anaken seem able to discontinue the habit when
rv pers.+nallr meaning/ul, positive events occur and/or when their health is
actually threatened Both life events and lactors of personal resourcefulness
are relevant in understanding why some men can give up the habit and
others cannot .
lacobs, M . A ., Knapp . P. ll ., Roanthal . S . and 1(askcll, D.
Psychosa+ark Medicine 3 2( S) : 469-4 S S, 1970 .
From the Division of Psychiatry . Boston University School of Medicine .
BoatrNt .
Sl)Mf VARIABLfS CONTRIBIIIINU lO 'hIlli ONSlif ()1 ('1(tA-
RkF"11? SMOKINO AM(/N(1 11/N1OR I11(311 S<'11(N)1 . S'11IU1•N1S
By analyzing student responses to a detailed qucstiomnaire, thii study
m
Ln systematically explored a subject's perception of the conditions ∎nd forces
r
m
B
20
Q`
N
LJ
CQ
present when he smoked for the first time . The sample consisted of a total
of 2,729 junior high school students . Acco.ding to their answers, re-
spoodents were ranked as nonsmokers, esperMsenlal smokers, or regular
smokers. Results showed that smoking by junior high school students was
partly a function of smoking incidence by their prevailing models since
one of the best predictors for children smoking is still whether or not
their parents smoke . Regular smoking adolescents appcared to have the
highest proportion of parents and friends who smoked regularly . The
social nature of smoking became quite obvious when the data were
anal~zed . Boys were generally either encouraged to smoke or aclually
snsoked with other boys while tirla maintained the aanse relationship with
other tirh . Neither parents nor siblings appeared to assume any direct role
In the instiption of smoking . The age at which the Arst smokinS experience
occurred varied somewhat for boys and Rirls By ape 12 most boys who
were going to try to smoke had already done so while nrost~ rb had at
least tried to smoke by the age o( 14 . Cirts refraMed (rwn snwkin` because
of the possibility of parental di .approva1 while boys were afraid of its
potential effect on ahetr athktie akilh Changlea in students' smoking status
oce.rred ie spite of their bnowlt:dge. about
potential harmful eflects and
ansoking by the culture and its place In the adolescent subculture was of
teaainwm unportance to the sttrdents .
Palwser, A . S.
Sorld Science and Medjcine 4 :359-366, 1970 .
From the Department o( Psychoiop . University of Tokdo, Toktdo, O .
VISUAL DEPRIVATION AND PAROTID RESPONSE TO
CIGARETTE SMOKING
Smoking while blindfolded siptificaAtly and consistently reduces sa-
livary flow rates compared to flow rates associated with normal smoking .
In this experiment, cigarette snakin significantly increased parotid salivary
aecretion in eight smokers and ei~tt nonsmokers . Obstructing vision by
wearing opaque goggles consistently reduced the adivary response to smok-
ing in all 16 subjects . Unstimulated resting ktveh were lower when vision
was blocked, suggesting a more general phenomenon than merely removal
of the sight of the stimulus-object . Seaking cigarettes through a Cambridge
filter assembly, which trapped the particulate matter and rendered the
exhaled smoke invisible, ha-rj no effect on salivary secretion . This indicates
that the salivary stimulation derives from irritating materials in the Ras
phase of the snxrke .
PonRborn, R . M. and Sharon, 1 . M .
PhyiMfoRy and N .hov/u. 6( S) :339•361, 1971 .
From the Department of Food Science and Technology, Ilnivcnity of
California, 1)avis, and the University of the Pacific School of Dentistry,
San Francisco .
21
t'
SOME CHARACTERISTICS RELATED TO THE CAREER
STATUS OF WOMEN PHYSICIANS
Between the years 1948 and 1955 . E1 women graduated (rom The
Johns Hopkins Medical School, often with grade records surpassing those
of their male classmates . Of these at women, 69 were in active prac ice in
1967 . Over one-4uarter had attained sped .hy certification and 21 R held
pro(essional appointments ; thest two crMeria were taken as a crude wasure
d career success . Two factors related to career status were marital status
and family size . Being nurried, especially at an earlr ase, was associated
with a less successlul career, r wr increaain6lamily size . Although nearly
78% of these graduates had snarried, the tnost successful won .en, the "pro-
tessors" poup, were most likd7 to be sinsk . They were also more likely
to be regular cigarette seakers nd to have kower scores on "habits of
nervous knsioe" than their ooikapes . 1• these two respects they were
similar to their male medicat sA wd colleagues . Daughters of managers and
proprieton had the best p .dea and most Promincnt careers ; daugh ;en of
physicians were most likely t~o be In praetsoe . It is suggested that Ivrt of
the reason women medkal Qadrates do arol realize their full potential in
later careers lia iw the views and practicd ol society .
Westling-Wikstraod, H ., Monk, M. A . and Thon .er, C. B .
The lohRS IlopAnu Medkd lournrl 127(S) :273-266, 1970 .
From the Department of Environmental Medicine and Community Health,
State University of New York . New York (Sty, snd the Department of
Mcdicine, The )ohs Ilopkiws University School of Medicine, Baltimore .
PERSONALITY CIIARACTERIST7CS OF MEDICAL STUDENTS
AS REFLECTED BY Ti1B STRONG VOCATIONAL INTEREST
TEST WITH SPECIAL REFERENCE TO SMOKING HABITS
Tbe Strong Voeationd INerest Blank (SVIB), a psychological meas-
uremeat tool, was administered to Johns Hopkins medical itudents in seven
consecutive classes gradwting in the period 195E-1964 . A total o( 393
white m.k students with known saaokint habits st a mean aSe d 23 .2 years
oompkled the SVIB . Using the SVIB asid trtwking measuranents, discrim-
inant L .etien analysis for two eriterioa Ov .p was carried out by means
of a rnrhi .ariale Results showed that smoken and nonsmokers
had significantly Rereat personality duncteristics as measured by the
SVIB ; this overall diAetenoe was highly uVmIkant . When single SVIB
variabks were oompared, light tipretle saankers shared sorne of the main
occupational intereats d the heavy snroken, but had distinctive differences
as wcll Pipe snNrkers were si6nih>rty diAerent from nonsmokers in rcR,ard
to another set ol single ocup .tbnal variables . 1• 1964 the smoking habits
of the test group were rechecked and it waa found that k .s than a third
of Ihc original group of heavy cigarette smoken had slopped snakin .'TAe
group of physicians who had stopped smoking more closely resemMe~ non-
22
smokers in their vocational interests while in medical school than did those
who were continuing to smoke .
Thontar, C . B ., Far6o, R . and Ea.kin, K .
The lohna /fopkins Medical lonrnaf 127(6) •323-335, 1970 .
From the Department of Medicine. The lohrn Hopkins University School
of Medicine . Baltimore, and The Genesee Computing Center, Inc .,
Rochester, N . Y .
CHARACTERISTICS OF MALE MEDICAL STUDENTS
RELATED TO TIIEIR SUBSEQUENT CAREERS
This study of 724 194t-19St nuk proodsata from lohm Hopkins
Medical School shows that nc.dnnic standin and aBe at graduation were
closely associated with professional careers. The t~pe of practice. Me
attainment of specialty Sosads, srtd to sane eslent the academic position
of those on medicd schod faculties were atl relaled, sometimes in a oorn-
pka way, to class standing and a~e . Other Lcyors such as /ather's occupa-
tion, ethnic backsround, type otT college atladed, and some selected
psychological and physical measures were eot sigdbcantly related to later
careen . Marital status during medical achool seenrpd to have sonre rela-
timuhip to later achievement regardless o( academic standing and age . In
this study medical school grades were definitely related to later achievement
for graduates. It is not clear whether or how trsdes reflm later ability but
they do seem so influence careers . That trades do influence opportunities
for graduate training and eaneers suggests that these grades should be based
on courses and training adequate to the variety of activities which physi-
cians are now eapected to perform .
Monk, M . A . and Thowras. C . e.
The lohnr Hop4ins Medical Josrwd 127( S) :254-272, 1970 .
From the Department d Envirosmenta1 Medieine and Community Health,
State University of New York, New York City, and the Department d
Medicine . The lohns Hopkins University School of Medicine . B.Mimore .
lt . CRrei,.oRenesta Studies
TUMORI POLMONARI DA IDRAZINA SOLFATO A DOSI
RIDOTTE IN TOPI BALB/c/Cb/Sc OONADE( :TOMITZATI
Administration of hydrazine sulfate Mcrtased the percentage al
pulmonary tur .Mws in pnadeelorwiaed, 1ntaN vkgin, and breeding /emak
mice. Tumrxa were Induced by hydrasine sul/ale In the same frequency
in Vnadectanirtd mice and i . Mtact virgins . Endoge n ovarian stimulation
associated with hydrarSne sulfate induccd In breeders pulmonary tumnn
more malignant than those seen in intact virgins . Without hydrazine tul-
23
(atc, the incidence of pulmonary tumors in aonadectomitcd LIAI_D/c/
Cb/Se mice was as low as it was in the corrtrols .
R/an(IfitNf, C .
Lov. Anar . Pat. Perugia 30( 2) : I I 3-119, 1970 .
Orher .rppsrt : Anna Fuller Fund .
From the Division of Cancer Resurch, University of Perugia . Italy .
TUMORI POLMONARI ED EPATICI DA IDRAZINA SOLFATO
A DOSI RIDOTTE IN TOPI BALB/c/Cb/Se
In these inveatiptions, the incidcrsx of spontaneous pulrionary
tumors was low (24% in malea, 4% in females) while that of liver tumors
was zero . Itydrasjne suNak adminiaterod in reduced doxs increased the
f requency o( pulnioeary tueron aa /oMo .rs : 0.56 mg (total mg 84), 65 %
in males and 76% in fewmks ; 0.28 rrq (lotal mg 42) . 62% and 99% ;
0.14 mg (totalrrq 21) 54% and 32% ; 1 .13 mg (total mg 32) . IIS36 and
75% . and induced liver tumors : 0 .56 aiy, 7% in maks and 8% in fr maks ;
0.211 mg. 8% in maks. When the average Induction time of pulrnonary
tumon was bneer, liver turnora were also observed . MorpholoFicrlly the
pulmonary tumors were adenowus and/or carcinomas ; the liver tumors
were highly vaxulsrited hePatocarcinomas . The possibilitr of irducin6
r /monary and liver tureors in mice with per-kilo doses of Aydra :ine sul-
e, equivalent to those per-kilo derived from the administration of
isoniatid in man, is important for its applicability to the use of isoniazid
In human pathology .
Bionci/iori, C .
Lar, Anar . Pat . Pe.utia 30( 2) :t9-99, 1970 .
Other ..pp.rtr Anna Fuller Fund.
From the Division of Cancer Research, University of Perugia . Italy .
OVARIAN INFLUENCE ON PULMONARY CARCINOGENESIS
BY HYDRAZINE SULFATE IN BALB/e/Cb/Se MICE
Aheration of the hormonal stak af mitx Influenced the incidence of
pulmonary tumort irdrecd hydrari .e sulfate (ItS) . Daily adminisera-
tion of IIS to BALB/c/Cb/Se feerak anioe in various hormonal atates
varied the Incidence awd the average wmber of pulmonary tumors per
tumor-bearing mouse as follows : in intaQ vrrp na, 90 .09f% and,• in breeders,
1(N)9L and 14 ; in iaed mice . 60 .0~G and 5 . I/istoloaically, in
intact virgins, 3 .) were carcinomas and 96 .6% were adenomas ; in
brceders, 47 .2% were eareMros>,ar and 32 .7% were adennnsss ; In ~ona-
dcctomirrd mice . 4% were cardwomaa and 96?t% were aderw .nnas Many
pulmonary carcinomas Induced I . broeders infHtratcd the thorack wall and
thc mediastinal orpns and metadasited to the adrensl Rlands ∎nd myo-
cardium The increaud biolotic and morphologic mali~ ancy of pulmonary
luawrs aeea.s so denWnslrate that a ptater ovarian lwrmoae production,
24
as occurred in brecdcrs, accentuated the already existent susceptibility to
pulmonary tumor induction in BALB/c mice . Whether this is associated
with an inhibitiun of the immunologic factors remains to be detcrmined .
slQnCllsOlr . C.
Journal of the Norional Cancer Insrirure 45(S) :963-970, 1970 .
Other support : Anna Fuller Fund .
From the Division of Cancer Reaearch, University of Perugia, Italy .
CANCEROGENESI DA IDRAZINA SOLFATO IN TRAPIANTI
ISOGENICI TRACIIEO-BRONCOPOLMONARI IN TOPI
BALB/cA_"b/Sc
Carcinogenic activity of hyorazine sulfate on the trachea, bronchus,
and lung fragments of nesiborn BALB/e/Cb/Se mice, transplanted to the
same strain, was studied In this eaperiarent . The luns fragments by them-
selves showed 35% adenotnas and 13% eardnomas . When the lung frag-
ments were transplanted, aydratine sulfate induced tumors, which showed
greater mali6nancy, in a shorter time in the newborn lung fragments than
it did in the lungs of the ad .N how . It wo.W aeern that this was caused
by the marked suxepttbiiity of newborn rrw .ae tissue to the carcinogen .
Explanation of the hndin6s with regard to the divergent frequencies at
which the trachea, broneai, and lung parenchyma developed tumors re-
quires further research .
Bionci/iorl, C .
L.r . Anar, Pat . Perrrsfe 30( 3) :137-146, 1970 .
From the Diviaion of Cancer Research, University of Peru6ia, Italy .
TRANSFORMATION AND PRODUCTIVE INFECTION OF 1(UMAN
OSTEOSARCOMA CELLS BY A FELINE SARCOMA VIRUS
The studies reported here indicate that feline sarcoma virw ( FSV )
can transform human osteaurcoma cells ; two lines ( MT-PSV and MT-
FSV, subline 2) of transfotwrod cells now have been established . When
compared with the parent MT cell line, the FSV-/ransformed lines have, in
early passaae, an altered ~yinereaaed saturation density, in-
creased growth rate in 2% ~t wrr, and Increased plating efficiency in apt .
The transformed cell lines contain C-type virus p .rticks and feline C-type
virus antigens not detected in the MT line . Particles released from the
transformed lines have a hoat r .np (dog and human eetls ) similar to that
of the parent hSV . •Celh of at,bhne 2 M seventh passage indueed flbro-
sarcomas in prenatally inoculated kittem ; the lunror ceMs, adjacent muscle
cells, and suhrnasillsry Oand celle shed C-typeps rticks . In a .econd set of
esperirrrent ., the cells of the osteoaarerwna cell Une in passage 7 have been
transformed by each of two stocks of FSV (the stock used In the original
study and one derived from a line of FSV-transfonned beagle cells) . 7hcx
trans(ormed cells, as those in the first esperiment, contained feline C'•typc
25
virus antigens, shed particks with focui-formin6 activity on beagle ∎nd
human celts, and exhibited C-type virus morphology and a density of ap-
proa imately 1 .16 t/cc .
McAllister, R . M . . Filbert, 1. E .. Nioolson, M . 0. . Rongey . R . W . . Gardner.
M . B ., Giiden, R . V . and Iluebner. R . 1 .
Narure New Bidory 230(17 ) :279-2a2, 1971 .
Orbrr a.pr.rt : National Cancer Iastlhr/n .
From the Departments of Pediatrica tted Patholo6y . University of California
School of MedKtne, I.as Artgdcs.
REDUCED LYMPHATIC DRAiNAOE FROM HAMSTER CIIEEK
POUCH : A PROPOSED EXPLANATION OF ITS
IMMUNOLOGICALLY PRIVILEGED CHARACTER
To arwer the questjon of whether or .ot a direct route exists txtween
the hasnster's cheek poudr and itn regional lymph nodes, the klt cheek
pouches of ei Bo{den hanMen were e.erted and Injected with 0 .1 ml of
(enitin . Serial sacriAoes were perloroed at ItMer.als of 2, 4 . 6, and 24
hours poa injection and the Idt dseek porc`e ., left aed right w,snrcntat
lymph nodea, and liven were reaoved and bislodranicapy stained . Another
group of eight hanruen, serving as oonlrolr, reoeived 0 .1 ml of the ferritin
solution iatrawtanoovaal~ to the Idt part d their upper lips . 'ilrese .nimak
were sacribced and tlr;ir tissues proceaaed as in the eheek pouch 6roup .
Histochernkdy de .a .Mrabk ilvs was presetrt only in a ./ew loe of lhe
ipsilateral soda in the group sacr%ia+d at 24 hours post injection of krritin
in the cheek pouch . la eorrrparisos+, the same tt~oda already oontained a
greater amount and diatrititlon of stainable inoa at two hours after injec-
tion to thd lip . TlKae readls Indicate that while thern is a direct roule from
cheek to lymph node, drainage via this roule is reduced and delayed . Im-
munotoficaNy, this situation of a reduced and delayed drainage /rom the
hamster cheek pouch aAords foreign grafts In this site a decisive advantage
for prolorqed awvivaim f',ofdrnberg
. 0. M .
E.rprrknHa 26( R ) :907-90a, 1970.
From the Department of PathokM . University of Pittsburgh School of
Medicine, Pittsburgh .
Fi1STOGENETIC RELATIONSHIP BETWEEN CARCINOIDS AND
MUCIN-SECRETING CARCINOMAS OF COLON AS REVEALF.D
BY IiETEROTRANSPLANTATION
A human colonic weoplwr with rnorphoh .Ric characterisrks rrf 8
carcinoW was .ueeewf .Mt transPaNed to check pgwches of adult pdden
hamsten after a short soFourw tn odl-impermeabk chambers In rats . Al-
though no mucin•secreting eelb wene detected in the donor carcinoid, the
cheek pouch transptanu exclusively exhibited mucin-secreting tumor cells
26
of signet-rin6 type consistent with adenocarcinoma . Tbis transplantable
tumor, designated GW-77, has retained this appearance as well as expan-
sive growth characteristics in tenoaeneic hosts /or a period of four years .
The findings presented here represent strong biological evidence consonant
with views advocating a histogenctic relationship between colonic carcinoid
and adenocarcinoma .
GoWrnbe.a, D . M, and Fisher, E . R .
Bririth /ownof oJ Cancrr 24 ( 3) :610-614, 1970 .
Other support : U . S . Public Health Service .
From Ihe Dcput ment of Patboba . University of Pittsburgh School of
Medicine, and the Veteraau Administration Hospital, Pittsburgh .
REDUCED LYMPHATIC DRAINAGE FROM
HAMSTER CHEEK POUCH
A transparent isoiatioa chamber permitting continuous obaervation of
the haaester choek pouch was taed to study the reovement of injectcd India
ink from the cheek pourlt .nN to thn negiowal cervical ipaitateral or coetra-
t l.ncral lymph nodea. Tke irolatio, dtarrrber was oowtr>.eted speei/kally to
obviate the esperinratta" ertor of dye kakiaB out of the cheek pouch proper
to adjacent tiss.es . A brow .idEblack e~o{oratiou of only ahe ifieftteral sub-
mental lymph was first obsetved 20 Aours after i}eca ,yiw+ ; coloration
waa deMitely localized tvrs abo.io distinct llrttrphatit : channels in the
pouch could not be seea . T1tne Mdi.Rs lead support to the thesis that
there are lyraphatics ie the Iratqer eheek pouch Compared to the time
eeoessary lor e6res .ioa of dye from other areaa of the hamster head, it
appears that thcre is a delayed re Maisa~e from the cheek ponch,
by a factor of ten . In li of these obaervatiaa, it is suggested that the
so-called "immunolodc privikBed" character of the hamster cheek
pouch is related to a delayed atd reduced lymphatic drainage from this site .
r'~ofdenberg. D . M ., and Stei.bma, W.
Proceedn4s of the Sodery /or EtperJinewrol Bfoloty mrd Medicinr 13 S( 3) :
724-726, 1970 . •
From the Department of Pathobp. University of Pittsburgh School 4
Medicine, Pittsburgh .
RETENTION OF HUMAN PROPERTIES BY A XENOGRAFTED
HUMAN COIANIC TUMOR, OW-77, PROPAGATED IN
UNCONDITIONED IIAMSTERS
OW-77, a newly established tr .naplantabk neoplasm of human
eolonk oridn, Is capable of eapanaive growth in unoorwlHa .wred, adull
r>tden harn,ters, 'fAis unusual Ftowth•behavior of OW-77 raias a yucstt.m
as to the tumrx's apecies-idenlMy . In the present study, this question was
studied by immunoAuoresoent and biochemical means . Both the direct
fluorescent antibody test and its lactate dehydrogenase isoenzyme-mobility
27
pattern revealed the human specin-specific character of GW-77 . The re-
tention of its original species-identity is consistent with GW-77's relatively
less malisnant, only locally expansive, growth-behavior in various sitcs of
the hamster .
Go(denbtrs, l) . M. . Bhan, R . D . and Pavia, R . A .
Proceedings of the Socrrry for Experimental Beoloa y and Medicine 135 ( 3) :
657-659,1970 .
OrA .r .orr.rt : National Cancer institule .
From the Department of Pathoiop. U .ivenity of Pittsburgh School of
Medicine, Pittsburgh .
STATHMOKINETIC EFFECT OF COLCEMID ON A
PRESUMPTIVE HUMAN-HAMSTER HYBRID TUMOR . GW-478
The action of Cokemid on the ascilea variant of the (',W-478 tumor,
originally a human stem-cell lyntpitorna propapted in h.mstcr check
p,uches, was canpa red to its action on Fortner's hamster amelanntic
melanuma A . Mel . No . 3 . T*e two tuttwrrypa eahibited strikingly diRerent
stalhmokine/ic resporres to the alkakoid Cokdttid . The prrcent un-
treated .acita tumor cctls in metaphase was found to be 0.98t0 17 of and
0.95±0 .23 for GW-478A and A . Mel . No. 3, respectively . The aooRce
of melaphase arrest in the A . Mel. No. 3 ascites tumor cells oocurrctj at a
dose of 60 m`/ka Colcemid, while the apo8ee (or GW-478A was at 20
m6/k8 . These results, which were quite unespDcted, indicate that GW-47t
asciles tumor cells respond to Coiamid more as human than as hamster
cells . It appean, therefore, that although (iW-478, a highly malignant trans-
plantabk tumor in unconditioned hamslen, predominantly has hamster-like
propertia, It lacks the Srrian hamster's genetically controlled resistance
to this cokhkine derivative. This further supports the hybrid character
of this neoplasm and the use of this Inil as a`enNic marker in hybridiza-
lion esperiments with Syrian hamster and other xenoseneic cells .
GoJdenbtrs, D . M.
Ea prrinunta( and Molacrfar Pathology 14 ( I) :134-137, 197 t .
OrAer .rrr.rtr National Cancer Institute .
From the Department of Pathology, Temple University Health Sciences
Center, Philadelphia .
INIIIBITION OF MURINE SUBCUTANEOUS AND
INTRAVENOUS BENZO(RST)PENTAPHENE ('ARCIN(x7F.NfSIS
BY SWEET ORAN(3E 0113 AND d-LIMONENE
Orange oils and d liatoeene slow the rate of tumor fmmatiom (ioIknring
subcutaneous injectiow of benno(rs1)psntapbene (DBP) in C'S7B1 ./b Jsx
mice . These anlicardnoge tk prope of the terpenes were discoveted
during the course of studies daipred~to evaluate the possible cocarcino-
28
genicity of natural terpenes (citrus oils) and of pure d-limonene in sub-
cutaneous injcction sites and in the lunp of mice . In the studies reported
here, injections of oran~e oils with low and high terpene arntent, d-limo-
nene, and a mixture of d-limonene and 6% of its hydroperoxide were madc
into the same site of C378L/6 la : mice 24 hours afler subcutaneous in-
jections of 25 r6 DBP in tricaprylin . This procedure reduced the tumor
incidence to less than 50% after 30 weeks (compared with 90% in con-
lrols receiving the carcinogen alone or the carcinogen followed by tri-
caprylin) . The time of latency was markedly prolonged. In A/lan mice
with spontaneous adcno+nas and adenomas induced with subcutaneous
carcinosert, orange oils, as well as limorteee, reduced the incidence of lung
adatorrtas when given weekly for from 13 to 16 weeks . The acceleration
of lumor growth usually observed following the transfer of multiple pwled
carcinogen injection sites into new hosts was inhibited by orange oils .
Hom6wKr, F., Tre6er, A . and Bo6er, E.
Oncdop 25 :1-10, 1971 .
Ot6 .r s .prertr American Cancer Society and U . S. Public Ilealth Service .
Frorn the Bio-Research InsUtule, Cambridge, Mass .
EINFLUSS CHRONISCHER INHALATIONEN VON FRISCHIIEM
ZIGARETTENRAUCII UND DESSEN GASPHASE AUF DIE
ENTWICKLUNG VON LUNGENTUMOREN BEI SNELL'S MAUSEN
Chronic inhalation of 0rah ci6arette smoke and of the Eas phase alone
contribute to the carcinogenesis of glandular luns tumors in Snell mice .
In experiments reported here, one group of mice was expuaed chronically,
i .e ., over the longest possible time span, to total ci6arctle smoke, and
another group for an equal length of tMte to only the gas phase of the
smoke• ∎ third group of Snell mice served aa a control . Two 1ypes of
¢landular lung tumors, adenomas and adeeocarcinomas, were observed
in these animals . In the corttrds . the euk animals exhibited twice as many
sponIaneous lun` tumors as the femaks . After inhalation of cigarette smoke
the number of lung tumors was incteased• this increased (rcquency of
tumors was particularly noticeable after inhdation of the gas phase . The
effect was more marked in male than in female mice . It is interesting to
note that in the controls, moat of the tumors were observed only in mice
which were more than two years ok1, whereas in the majority of the ea-
ptrimental mice tumors were found al a much earlkr age . Brorkho8enk
carcirwma, such as that which frequently occurs In human cigarette smok-
ers, was never observed in the mice . Since adenomaa and adcnocarcinomas
were found in controls as well as in experimental mioe, i/ seems reasonable
to suggest Ihal inhalallon of d8arelle smoke by mice enhances nxxe or less
cellular abnormalities which are already present in the lung of the mice .
1.rrrAtrnA.rr.r, ( : and l .euchlenberter, R .
Ztlrtchr(/t fur Pnvrntlrnredizln 17 :437-462, 1970 .
From the Swiss Institute for Experimental Cancer Research, Lausanne .
29
EFFf:CTS OF CIIRONIC INHALATION OF WHOLE FRESI(
CIGARETTE SMOKE AND OF ITS GAS PHASE ON
PULMONARY TUMORIGENESIS IN SNELL'S MICE
Does chronic Inhalatinn of fresh whole cigarette amoke conrainin6
particulate matter have the same or a diAerent biolosical efled then that
of inhalation of the gas phase of fresh cigarette smoke7 To answer this
Question, 467 inbred Soells mice were eapaed to chronic inhalation of
puAs of whok fresh cigarette sa .oke or d its pS phase tlone for one year
or longer . The smoking saachiae wed Iot dw esperiment permitted e :-
posure of iedividud stiee to ishalatioes d pols of ciaarette smoke alter-
natin8 with air . Eapowro to bvtlr t.bk eiprette smote and ita 6as phase
alone resrked in an earfier ooetrteacz and a higher frequency of Rlusdular
pulmonary tunsors when eompared with thoae of controls . The enhanoe-
tneat of pulmonary trnsotiBenKais waa partiarlarlr strikin6 after exposure
b the ps pAase ak,twe and was more pronatnoed in males than In femaks .
Maks eapcwcd to the psphase disclosed swt only a siptificant shiff from
pulnwnary adeearw to adenocarcinomas, but the frequency of adcnocar-
cinomas was 23% . that Is. Ave times greater thu that of eontrds, which
was 4 .7% . No brvnchoBenie eatdnoma was observed in controls or in
mice exposed to whole fresh eiB.retk snsoke or its 6as phase .
L.arcl4tenbtrrer . C . and LeucfilenberBer, R.
In Nettesheim, P ., Hsnna, M . G ., )r ., and Deathera6e, J . W ., Jr . (eds . ) :
Morpholory of L:rptrinwnro/ Rripirorory CerrinorrnetL, Oak Ridge .
Tenn . : U . S . Atomic Energy C,omm'rsion, 1970, pp 329-346 .
From the Swiss Institute for Experimental Cancer Research, Lausanne .
EINFLUSS VON FRISCHEM ZIGARLrTTENRAUCH AUF DIE
ENTWICKLUNG VON LUNGENTUMOREN UND AUF
LUNGENKULTUREN BEI DER SNELL.MAUS
TAis report deals with tha dect of ehroek inhaWion of cip rette
smoke oo the devek,ipr.eat o/1..5 tts .wrs i. S.d's toniee. and the influence
of c4suette ssoke o. dvaolar Srowltai o.t (ram hmS expiant
cultwes of S .eY's nske . Rearlts of e=perissenb showed that chronic
iehalatioa of whok frds dpretle ta>toke, or of Mapa phue abne, occa-
sione~ the e.rlier oocwnesoe asd hi#et I of hang tunsora in Sndl's
mice . T#ie e.Asataent of prh.o ..rj ~r and adenoearcitwmu
was partic.larly striti .g dter eapwore to the Br phase alone and more
proeorwseed is nraks than Itt fewsln ; so bronclsoBenk areinotna was ob-
served . Lrng eapiaaA cuhrrea, . .Mdr wera exposed to whole charewl-
Mtered cigarette anwke trvrw .uhkA cybbaic factors were nearly all
eliminated, showed a selective damaBs b dw dvoolar macroph.ies . After
exposure of lung explant erlturp b the gas phase trwn charcoal Rllered
ciprette s.wttc, the tlveolst twactopAars showed a selective stimulation
of DNA synthesis . These results iadreate, on oaie Iwd, the importance of
particulate matter for the inhibitioa of cell asetaboliaw, and on the other
30
hand the importance of the gas phase for the stimulation of cell mctabolism
of alveolar macrophages .
L.euchrenberter. C . and Leuchtenberser, R .
Schweizerische Med izinisrhe Wocbrnxhri/t 101( 3S ) :1374-1351, 1971 .
Other support : Association Suisse des Fabricants de Ciprettes .
From the Swiss Institute for Experimental Carscer Research, Lausanne .
LYMPHOSARCOMA IN THE RABBIT :
GENETICS AND PATHOLOGY
L~rmphosarcomas are rare in rabbits . However, since 1962, 29 rabbits
of straws ~yH at The Jackson Laboratory have exhibited lymphosarcoma .
Becatae d this unusual .ggrega tion of tumors, the pedigrees of the affected
animals were analyzed . The inheritance indkated an autosomal recessive
gene conferring susceptibility to lymphosarcoma ; this gene was designated
Is . The data were compatible with both concepts of genetic susceptibility to
lymplsosarcoma and vertical Iraasmission d a virus. The neoplastic in-
volvement of lymphoreticular aed other orpns, especially kidneps, cor-
i responded to a pattern observed in lysnpho .arcoma of other domeslic
animals . SpeciRcally, it resembled in many ways visceral lymphosarcnmato-
sis of cats which has been proved unequivocally to be caused by feline
kukemia virus . Because ofi the vast anmrnt of morphofosic, phys'rolo6ic,
and biochemical data available on rabbits, the simplicity of rabbrt care
and braedina, and their tar¢ site, rabbits are of considerable value in
biomedical research . The finding of 1pmphosarcorna and its hereditary basis
provides a new and important nadel for studies a the pathogenesis of
ncoQlasia .
Fos, R . R ., Meier, H ., Crary, D . D ., Myers, D. D., Norbers, R . F. and
Laird, C. W . Journal of the Nations/ Cawrer l naritrte 45 ( 4) : 719-729,
1970.
Other a.rr.rtr U. S. Public Health Service and Hyoel, lnc ., Ilouston .
From The Jackson Laboratory. Bar Harbor, Me .
MALIGNANT TRANSFORMATION INDUCED BY 7,12-
DIMETHYLBENZ(s)ANTHRACENE IN RAT EMBRYO CELLS
INFECTED WITH RAUSCHER LEUKEMIA VIRUS
Morpholo6jcal alterations of cells and an abnormal growth pattern
were noted 42-45 days after treatment of Rwacher kukemia virus (RI .V)
infected rat embryo (RE) cells with various levels of 7,12•dimethyltrcn :-
(a)anthr .ocne (t)MBA) for seven days . Uninfected eclls treated with
I)MBA and RLV intected RI'E cells untreated with I)MBA failcd to shnw
any evidence of transformation . When stained with (3iemsa, the foci iof
transformed cells consisted of randomly oriented eriss-crossinR spindle-
shaped cells having much more rapid replication rstes than the untreated
and untranslormed RE cells . The transformed cells were more resistant
31
to the tosicity of DMBA than were the untreated RE cells and rnily the
transformed cells were capable of producing local subcutaneous sa ~comas
when transplanted into newborn rats . When re-established in tissue culture,
cells derived from the tumors, like the tumor tissue itself, contained group-
specific compkment-fiRint antigens characteristic of the murine leukemia-
sarcoma virus compk>< and the C-type RNA particks . These resuits, which
showed that both chemical and virus were required for rransf(xriatinn,
suggest that the C-type RNA vital genowrc of RI .V provided epccitic
oncogene information for the maliptaM transformation .
Rhim, 1 . S . . Vass, W ., Cho, H. Y. and Huebner . R . 1 . (Microhioloair•al
Alsuciarrs . I nc. )
Inrrrnarional /ournaf of Cancer 7 :65-74, 1971 .
OrA.r .rpprf : National Cancer Institute .
From the Departmcnt of Virw Research . Microbiofo6ical Associater, Inc.,
and Viral Carcinogenesis Branch, National Cancer Institute, Bethesda, Md .
POLMONITE INTERSTIZIALE CRONICA IN CORSO DI
SARCOMA MURINO DA METILC()LANTRENE
Histobgical eaaminatbn of the lunp of 147 mice with mcthylcho-
lanthrene-induced sarcomas or transplants of the same tumcxs revealed
24.5% chronic interstitial pneumonia . Mice used for Ihis study were of the
C3H .B/Cb/Se, RIII/Dm/Se, CBA/Cb/Se, and FI(C311,B/Cb/Se X
Rfll/Dm/Se) strains . The pneumonia seen in these mice diRered from
brwrchopievmonia, which is frequently seen in old mice, by reason o( the
a~e o/ anaet, the absence of alveolar esrdale, and the intense proliferation
d raeptal celh.
Mah:e11, N . (Stvr.l. L .)
Lw . An.r. P.r. Ptrulia 30(1) : I S-2 S . 1970 .
From the Division of Cancer Research, University of Perugia, Italy .
I TUMORI DEI . POLMONE, DEL RETICOLO E DP.I .LA MAM-
MELLA NEI TOPI BALB/e/Cb/Se DISCENDENTI DA GENITORI
TRATTATI CON URETANO NEL PERIODO NEONATALE
Two groups of BALB/c mice were treated as newborns with one and
five milligrams of urethane respeetively, and then mated . Offspring of these
treated mice were folkrned in a study of the incidence of spontaneous
tumors . Descendants showed an increase of lung and reticular tunxxs, in
mak and female, virgin and mated mice . A d'ncussion of the mechanism
through which urethane, inoculated into newbrxn mice, enhances slwrn-
taneous tunvnrisencsis in the neat generation is rcpurted .
Rib .cchi, R . (Srvr .f, l. )
tev . Anal. Par . Pr .wr1a 30(1) :27-39, 1970 .
From the Divisir.n of Cancer Research . University of Pcrugia• Italy .
32
DETECTION OF A LUNG TUMOR AGENT IN BALIi/c/(b/Se
IRRADIATED MICE
In this investigation lung tissue from newborn mice was grafted into
adult syngeneic recipients areviousl~ panirradiated in an attempt to meet
the most suitable caperimental conditions for the delection of endogenous
lung lumor agents . Of the 29 recipients irradiated befcxe grafting, 21 had
recoverable lung grafts and 6ve of them, or 23 .e%, showed alveolar
adcnomas in their lung grafts . The number of luna grafts recovered from
irradiated recipienta was 44 . No tumors were observed in the 43 grafts of
newborn lungs recovered fran 23 non-irradiated control recipients . A
strong association was observed between leukemia in irradiated recipients
and adenomas in the lung grafts . Although four of the irradiated recipients
died spontaneously of thymic kukemia and the recovery of lung grafts was
m+t possible, four other mice were lerkemic when kilkd and three of these
had recoverable lung grafts showing alveolar adenomas . These results
suggcs t that whole body irradiation activates a lung lumor agent in
BALB/c mice .
Squartini . F . and Bolis, G . B . (Sevrr(, L .)
L.v. Anal. Pat . Perugla 30( 3) :123-12e, 1970 .
From the Division of Cancer Research . University of Perugia . Italy .
DIVERSA SUSCFTTIBILITA DEGLI EPITELI ALVEOI .ARE E
TRACIIEOBRONCIIIAL .E DEL TOPO BALB/c/Cb/Se ALLA
TUMORIGENESI DA URETANO NEI TRAPIANTI ISOGENICI
Data rekvant to the susceptibility of alveolar and Iracheobronchial
mouse epithelium to urethane tumoriBene .ia are reported. Grafts of trachea
together with the lower section of lary na, of main bronehi, and of peripheral
lung tissue of newborn BALB/c mice were subcutaneously implanted in
2-month-old isogenic mice . Five days after eratling, one group o/ mice was
treated intraperitoneally with a single injection of urethane at the drne of
I mg/g of body weight . Another group of untreated mice was used as die
control . Six months later . 86 .4% of femaks and 96 .19G of males developed
lung tumors of alveolar origin in the grafted lunes . No hyperplastic .
preneoplastic, and/or neoplastic kskm caused by the carcinogen was
observed in the eracheal, laryngeal, and bronchial grafts . No Iumors were
observed In the contn>ts .
Ribacchi . R . (Stvrrl, ! . .)
Lav. Anal . Pat . Prruaia 30(3) :147-1ti0, 1970 .
From the Division of Cancer Research . University of Perugia . Italy .
33
 111. Cardiovascular System
TlIF EVALUATION AND TREATMENT OF
CARDIOGENIC SHOCK
T6is thorough review paper discusses the clinical asscssment and
therapy of cardio,enic shock and presents new information which could
modify an overall approach to the roe of vasopressor agents in shoch . For
diagnostic purposes% shock is coaveMioraallr classified into h~povokmic
(hemorrha`ic), septk, and catdio~e>tk types . In each of these shock
classiRcatiorx, early diagnosis and Instit .tios of treatment are the 1 ey to
improved survival . An eiSht-point, annotated scheduk for the assessment
of the shock state is presented here . In cardio`enic shock, the rnl of
therapy is the restoraliom of myocardial function to the point where il can
adequately provide the contr .ctile force necessary for the perlusion •3f the
systemic circulation . The t.se, as well as choice, of vasoactive asents for
maintenance of satisfactory arterial pressure in cardio6enic .:hock is L very
arntrovenial subject right now . Vasoactive aeents discussed in detai, here
include 1•noreF+inephrine, ianproterenol, chlorpromarine, meterainirKol,
mctham hmrne, and dop.mine ; steroids and antibiotks also arc con-
sidered briefly .
Mueller, 11 . S ., Ayrrs, S . M ., Gre`ory, 1 . 1 ., Giannclli, S . . )r ., and (',race,
W. ).
Mrdicol Times 9E(7) 1)7-152, 1970.
OtA.r auppertr (1 . S . Public Health Service .
From the Dcpartments of Medicine and Sur~+ery, St . Vincent's Fiospitnl and
New York University School of Medicine, New York C'ity .
TtiE LUNG IN SHOCIC : ALVEOLAR-CAPILLARY GAS
EXCHANGE IN TIIE S11OCK SYNDROME
In an attempt to delineate the effects of circulatory collapse on
puthwnary ventilation, this p .per reviews certain physiologic considerations
rekvant to abnormal alveolar ps exchange in the patient with shock .
Alveolar pa eschattBe in eight p .tients whh shock revealed marked reduc-
tion in arterial oxygen lensioa (PaOr) and increaae in the alveolar-artcrial
oxygen diAerence while the were breathingtoom air . Failure to adequately
inereaae PaOt whik breatb 100% oxygen indicated significant increases
in veeoarterias shwMin4 . demonstrated persistent periusion of non-
ventilated hrn~ units . A• Mrcrease In Ihe alveolar-artenal carbon dioxide
difference indka/ed increaaed alveolar dead speee, suqnting that some
alveolar units were rrnderperfuaed . Con/inuous pressure breathing Improved
Pa(h in sis of seven patienls but lewded to increasc venrws pressure and
reduce aortic pressure . Tlrcse observations suggest that alteratioxn in lung
function are part d the generalized metabolic dccoxnpensation seen in
shuck . Decreased pulnxwary nutrition after decreased bkxxI flow, increased
34
left atrial pressurc, and pulmonary venoconstriction arc all imphcatcd .
Progressive pulmonary changes may preclude revcrsihility of the shock
state .
Ayrrs, S. M ., Mueller, I( ., Giannelli, S., Jr ., Fleming. P. and Grace . W . l .
The Americon luurnol o/ Cardiolosy 26( 6) : Ses-594, 1970 .
Other support : U . S. Public Health Service and New York Ileart
Association .
From the Departments of Medicine and Surgery, St . Vincent's Hospital and
Medical Center of New York and New York University School of Medicine,
New York City.
MYOCARDIAL AND SYSTEMIC RESPONSES TO
CARBOXYHEMOGLOBIN
This paper reviews certain theoretical aspects of systemic and myo-
cardial oxygen eschange and summarizes a aeeries of experimental sludies
of the physiftical effects of telativety small amounts of carbosyhenw-
glrbin (CVI1B) . Measuren+enta ot alveotar-eapillary gas eachanse, sys-
temic hemodrnamics, and myocardial metabofant were made in a series
of h .rman and caninc studies before and after the administration of amounts
of either 5% or 0 .196 carbon monoxide sullicient to raise COIIB satura-
lion to between 5 and 25'S, . Arterial and mixed venous oxygen tensions
were decreased by administration d either concentration and changes could
be identified with COHB satrrations below 5% . Cardiac output and
minute ventilation increased when CONB was elevated by breathing the
hi6het concentration . The coronary arteriovenous oxygen difference was
uniformly decreased and coronary blood flow inereased when COHB was
raised to between 5 and 10% saturation with either gas mixture in the
human studies. Certain patients with coronary artc'ry disease developed
dtered lactate ard pycuvate nsetabolism following elevation of COIIB
suggesting myocardial hypoaia. Siptificant myocardial changes were seen in
patients with elevation of COHB above 6% COHB . The caninepr epara-
lion, in eontrast, was notably more resistant to COHB and si6nificant al-
terations were not observed rntil COHB saturation exceeded 25% .
Ayrrt, S . M., Giannelli, S., Jr., and Muelkr, H .
AnnaLr oJ the New York Acsiew+y o/ Sclenctt 174(1) :26a-293, 1970 .
Other support : National Air Pollution Control Administration and Na-
tiorul Heart Institute . '
From the Departments of Medieine and SurBery, St . Vincent's Hospital and
Medical Ceoter, New York City .
IIP.MODYNAMI(-'S, CORONARY BLOOD F1AW, ANI)
MY(x:ARUTAI, MI?1'ABtN .ISM IN CORONARY SH(x'K ;
RISPONSE '10 I-NOREPINE?PHRINt? AND ISOPROTI:RFNt)1 .
This paper presents myocardial metabolism ∎nd systemic hemody-
35
namic data in 19 patients with severe coronary shock . Cardiac index (CI )
and stroke index were markedly reduced in all patients. Mean arterial pres-
sure fanred from 40 to 65 mm FI while systemic vascular resistance varied
widely . Coronary blood flow (CB~) was decreased in all but three patients .
While myocardial oxygen consumption (MV„) was normal or increased,
myocardial oxygen extraction was above 70% and coronary sinus oxygen
tension was below 22 mm Hg in nwst of the patients . The detection of the
abnormal oxygen p.ttern insp1 e ot aaatwplinS ot mixed coronary venous
blood indicates the severity of myocardW •~posia . In 15 patients myo-
cardial lactate production was deawtrMraled ; in the remaining three lactate
extraction was below 10% . 'flre reapaue to f-aorepinephrine was studied
in seven cases and the re .pore to ioprvldeaol In four. Considention of
both hemodyn.mic and lactate Irut data wtggests that f-norcpineptxine is
superior 1o isoprotnenol in shock . Early administration a : dilute
solutinn of /-arorepi .epAri.e, p~rd-
regulated by intn-arteri .l pressure
monitoring b prevent etttnaive is+eaeases ia ventricular work, mia \t well
preserve the intcpit7 o( twaidan :fod ~ of the myacardium and
prtvenl the deve/opseM of tirertattrry
Muelkr, H .. Ayres. S . M., Greyory,1 .1 ., OiatondN, S . . Ir., and Grace . W . 1 .
The lai.wd of Clidc.l Iw.ra*afow 49(10) :ISa5-1902, 1970.
Other . .p'.rt . National Heart Institute .
From the Dep.rtmenu of Medicine and Sur`ery, St . Vincent's Hoapital and
Medical Ce.kr, New York City .
ALTERATIONS IN 2-3 DIPHOSPHOGLYCERATE AND 0 .
HEMOGLOBIN AFFINITY IN PATIENTS UNDERGOING
OPEN-IIEART SURGERY
Siace it has btea ahhowa that affinity for oxygen is inversely
related to the level of red blood eeN~ (It~BC) 2-3 diphosphoglyceratc (2-3
DPG), both of thesep~rs~e te» w~ere s+eaat.red in 14 tients undersoina
heart-lu to deA .e the is~llrena d this ure on 0, deliverr
in patients rnder bypass goinS opeo-heart mrtery . RBC 2-3 DPO deereased with
Instilutioo a " and continued to decrease during bypaa . The day
following heart-frinS bypar RBC 2-3 DP(7 kveb returned to noreul, but were
lower tha.pecoptrative control values. In vkro st.dies demonstrated that a
portion of the RBC 2-3 DPG loe wu due to circulation of blood through
the oxygenator itself, but other taciors alaoappeu to be involved . ttemo-
globin dMtity for oirp iacrea .ed during Ireart-lung bypass in most
patients. Ilowever . It was forwd that the Mcreaaed affinity was less than
would be expected relatiw to the demonstrated RBC 2-3 DP(3 decrease,
and that .pgr .pestive deertus In RSC p!1 partially corrected the altcra-
tk+n In 0, affinity . The data suaest that other factors such as carbon mrM-
o .ide levels and rak of R9C destnrction by the n:ticuloendothelial system
are involved in the demonstrated alteration in hemoglobin ∎fTinity for 0 . .
36
$ordiuk, l . M . . McKenna, P . 1 ., Giannelli, S ., lr ., and A yres, S . M .
Supplement I to Cirrulnriun XLIII and XLIV :1-141-I-146, 1971 .
Otber support : U . S . Public Health Service .
From the Ikpartments of Pediatrics, Patholo6y, Surgery and Medicine . St .
Vincent's Hospital and Medical Center, and New York University School
of Medicine, New York City .
TOTAL AND NUTRITIONAL CORONARY FLOW
The first part of this methodology paper describes a new technique
for determining the velocity of red cells in the capillaries . Such measure-
ment isaccompIrshed by determining the fnree to frame progress of indi-
vidual red celk in movuy= pictwea of the capillaries . So far data have
demonstrated that norepincpMine leads to the opening of capillarks, that
nitrollycerine slows the fio.r in the capillaries, and thN methacholine re-
wit.in the complete artest and even retropade /low . The remainder of the
report is concerned with the meaarreme .t of total and nutritional coronary
flow by means of coincidence eotNMiag with a positron emitter, rubidium-e4 .
r
Nutritional as well as lotai eoronary Aow eaw be determined by means of
the clearance or the Fick principle, respectively. Resalts of this technique
demonstrate a dichotomy of the coronary eitsWatias and illustrate that the
action of drup on the coronary circulation can vary with respect to nutri-
tional and lotal flow . Norepinephrine causes a disproportionately greater
increaae in total as campared with effective flow, and the same is true for
nicotine . Isflproterenol, on the other hand, causes a proportion .k Increase
in both the nutritional and effective coronary flows .
Tillich . G ., Mendoza. LL and eMt. R . 1 .
Circulation Rt'srarch XXVIII and XXIX (suppl 1) :1-14a-1-IS3, 1971 .
OtAer arrr+rt : U . S . Public Health Service and Hartford Foundation.
Frn.m the Huntington MemaW Hospital, rasadena, Cal ., and the Uni-
versity of Southern Ca6tornia School of Medicine, Los An6eles .
THE EFFECT OF INTRAVENOUS ETHYL ALCOHOL ON THE
CORONARY CIRCULATION AND MYOCARDIAL
CONTRACTILITY OF TIIE HUMAN AND CANINE HEART
In this attempt to examine closely an area of sane eaperimental con-
troveny, the effects of Intnvenowlr administered ethyl akohol on coronary
blood flow, contractility, and hernodynamka were investigated in 10 pa-
tients and in 23 anesthetized dop . Resrlb obtained In man witb a dose
of alcohol comparable to that contained In two to three ounces of whiskey
ahowed a consistent hut not sigsrificant irKreaae in effective coronary fhrw
accompanied by a fall In coronary vascular resistance whkh was also not
significant. There was no siSnificant change in cardiac index, heart rate, or
peripheral vascular resistance . Likewise, the studies conducted with dogs
showed that when small amounts of alcohol were Infused the eflective
, 37
coronary Row rate diminished slightly but not siprificantly, without signifi-
cant changes in coronary vascular resistance . llowever, when the dcnage
levels were increased, a significant increase in effective coronary 8uw was
noted along with a significant fall in coronary vascular resistancc . At a
mean akohol blood level of 195 m6/100 cc of btood, there was a marked
diminution in the velocity of left vcntricular contraction ; the reasons for
this diminished myocardial contractility arc not ckar .
Mendo¢a, L C., llellberg, K ., Rickart, A . . Tiltich, G . and Bing . R . l.
lownnl o/ Cfinic.f PMrnmco(fty I1(3) :165-176, 1971 .
OtAer a.Pr.rtr U . S . Public Heahh Set.ioe .
From the Huntington MemorW Hoapital, Pasadena, Cal ., and the Uni-
versity of Southern California School of Medieine, Lo. Angeles .
EFFECT OF NITROOLYCERIN ON TOrTAL AND REGIONAI .
CORONARY BLOOD FLOW IN THE NORMAL AND ISCIIF.MIC
CANINE MYOCARDIUM
In esperiments reported herc, fractional estradion of Rb-86 was used
to estimate the regional distribution of coronary flow in adult mongrel dogs.
With this nsethod, the effecl ot nitroglycerin on total coronary flow and its
regional distributinn was determined in normal conditions and in myo-
cardial ischemis . In normal hearts, capillary flow was 9 .5% higher in the
inner than in the outer myocardial half . When partial occlusion of coronary
arteries was folMwed by infusion of noridrenaline, subendocardial fiow
was less than capillary flow in wbepkardial layers . In thesr coeditiorn the
administration of nitroglycerin resulted in a redistribution of capillary fi,nv
towards normal .
Mathes, P . and Rival, 1 . (eint, R . l .)
Carliovascufa . Reit+rcA S(1) :34-61, 1971 .
Other s .~'.rtr Michigan lleart Association, American Medical Aswxia-
tioa - Education and Research Foundation, and Detroit General I lospital
Research Corporation .
From the Wayne State Uaiversity School of Medicine, Detroit .
THE ESTIMATION OF BLOOD PLATELET SURVIVAL :
11 . TIIE MULTIPLE HIT METHOD
The controversy o.et the pattern of platelet destructinn has not yet
been resolved . Some contend that it is thne-roew`eneous and inAiacrim-
inale . llo..ever, a great nany studies have been published in which the
pattern of dexaybowh ia wnm ond in esperlrnenlal animals, eonforw» well
to a"1ir.ear" deca~ pathrn over a period of 10 days or so . This p∎per
develops (orr nrcrdcls for estinution of blood platelet survivsl . 7'hey are
presented not as completely reali .tle but as at least first order apQrosi-
mstions which should at once provide a systematic b .sis for estimation of
mean platelet survival and the standard ertor of the estimate . They will
39
at the sanx timt circumvent the subjective element in analyzing the data
with the attendant biases and also provide a unifying theory for the several
different models which various investigators have more or less esplicilly
used in the past . The modeb may perhaps be thought of as srrtorNhing
functions to iron out the high expertmental error inherent in the study of
platelet survival . Primarily, an attempt has been made here to construct the
model on the basis of present knowledge of the economy of the platekt and
the factors influencing its survival .
Murplrr, E. A . and Francis, M . E.
Tlrrornboais er Diorhrefi Heerorrhosky 2S( I) :S3-a0, 1971 .
Other wP'.rt r U . S. Public Heahh Service .
Frorn the Departments of Medicine and Biostatistics, The Johns Hopkins
Univenity School of Medicine, Baltimore .
ARRHYTHMIAS FOLLOWING INFUSIONS OF FATTY ACIDS
In esperiments reported here . lOml/kg of a I in 1 .000 w/v suspen-
sion were infuued into dop over a five-taiinu4 period . The acids infuscd
were rc, stearic, okx, liwoknic, and oornbinations of okic-palmitic
and -atearic . A total of 178 dop were used in these studies . A char-
ackristic sequence of ekclroeardiotraphie abnortnalitiea occurred after the
r infusion of tong-chained saturated fatty aeids (stearie, palmitic) . In
addition to an injury cyrreM, ekctrocardioraphie changes were sinus
bradycard'u . supraventricu7ar bradycardia, varying degrees of intraventric-
ular bbck, sinus standslitl, and complete standstill . Similar inlusioru of
nwrwunsaturaled (oieic) and polyunsaturated (linokic) acids and a slower
infusion of large quantities of lott6tlurin saturated fatty acids fiven for
hours day after day produced no untoward clinical or ekctrocardagr .phic
effects . The differences in effects between the saturated and unsatur .ed
t
fatty acids and the differences in effects of r.pid and slow infusion of
saturated fatty acids might be due to diAerenees in the rate of binding of
these acids to albumin .
SoloO, L . A .
Awrerin Hearr lournol d0(S) :671-674, 1970 .
Od .r s .rPr.rtr U . S . Public Health Service .
From the Division of Cardiology . Temple University Health Sciences
Center, Philadelphia .
SIMULATION OF "LEFT ATRIAL RHYTHM" BY RI(111T
ATRIAI . PACING
This case history report concerns a patknt with ( I) the crireria frn
the diatnoais of so calkd left atrld rhythm and (2) a sinular pattern
produced by a catheter pacemaker stimulatin` the wall of the mid right
atrium, low right atrium, and ooronary sinus . Reaults noted, although not
negating a left strial site for pacemaker activity, suEScst a nx .re likely site
39

in the nodal Of A-V ''unctional arca . The findings presented here serve as
f evidence for the need of increascd caution before assuming that a kft to
riRht pattern of atriai depolarization, as Interpreted in kads 1 . V„ and V,
of the scakr ekctrocardrogram, can pinpoint the anatomic origin of the
pacemaker .
Rutenberg. II . L. and Sob#, L . A .
The An+rrkan loarnol of Carrlobty 26(4) :427-431, 1970 .
Oth .r auPP.rr : U . S . Public Healdt Service.
From the Division of Cardiolov, Temple University Health Sciences Cen-
ter. Philadelphia .
INFLUENCE OF ANTICOAOULANTS AND AUTONOMIC
DRUGS ON PLASMA FREE FATTY ACIDS AND GLUCC)SE
The initid kvel of free fatty acW (FFA) In the do` may be a critical
factor in determining whether or not aMieoaplanta will eaent significant
lipoly1k activrtr . le ea Musw reported here, anesthetized which
had been fasted overni~ to ceived knows q .antities of heparin~sodium
polyanhydrornannuronk acid adfate (Maauronate) In dilute solutions . In
animds so fasted, initid pre-druS pfasma FFA levels were low and quite
coaparsbk and no significant changes in FFA or glucose occurred after
admrnistration of heparin or Manw+onate alone . In other groups similarly
f.aed and receiving heparin, the intravenous infusion of nicotine, epi-
ne nne, or iaoprokrenoi inducrd clearly signi/kant ekvations in plasma
F A along with increases in plasma glucose . Non-fasted doss, on the other
hand, showed high initial levels of plasma FFA that were further increased
with great variabilityt heparin a{one while glucose levels were relatively
unaffected. These rauka indiute that, under the eaperimental conditions
described, valid esperiarents can be performed in dogs in the presence of
heparin or Manuronate while studying the infiuence on plasma FFA of
certain other eornpo .ndt such as atalorsomie agents .
PaQaoostas, C. A ., Weiss, L M. and Sol4, L . A .
Archives Irarrrnarloewks 1r PAarwrecodynanrk rr de ThErapir Ie7(1) :
46-51, 1970.
OrA.r .rPP.rtr U . S . Public Health Service and National Heart Institute .
From the Departments of Pharmacology and Cardiology . Temple Univer-
sity Medical Center . Pht7adclphi. .
POSSIBLE MECHANISM OF PARf'.SS OI : FRI :E CI IOI .ES 1 F.R(N .
FROM THE ARTERIAL WALL
If an equilibrium esists between free cholesterol of the serum and of
the arterial tnsue, the rate of eskrYkatios of free choksterol might be an
Important factor In allowingmore cholesterol to leave the arterial wall . To
test those hypothesis, serments of human iliac artcries (treated and un-
40
i
treated) were incubated with human serum (treated and untreated) . In the
case of both arteries and seruns, treatnsewt consisted of heating the sampk
at 36' C for 31) minutes to inactivate the enzyme kcithin{hoksterol-acyl-
transferase (LCAT) . When LCAT enzyme was present in the incubation
medium, virtually only free cholesterol left the arterial wall, whereas when
LCAT enzyme was absent, only cholesterol eskr left the wall . Thnc re-
sults suggest that a decrease in serum free choksterol, caused by a serum
cholesterol esterifying enzysse, possibly LCAT, ntielst be important in
promoting the removal of fres cholesterol from the arterial wall . Since
cholesterol esterifscation has boat slawa recently to be ai6nificantly im-
psired in subjects with acute tn~ocardial Mfarctioe and chronic coronary
artery disease, it appears that a deficienqr of chokatesd esterifyinS en :yme,
posaibly LCAT, may be important in the etiology or rate of development
of atAerosckroais.
Rutenberg, H . L . and SoloQ, L. A .
Nature 230 :123-125, 1971 .
tDrA .r .upr.rtr U. S . Public Heahh Service .
i From the Department of Modicine, Temple University Health Sciences
Center, Philadclphia .
STUDIES ON FIGURE DRAWINGS : BIOLOGICAL
IMPLICATIONS OF STRUCTURAL AND GRAPHIC
CHARACTERISTICS
The Fi6urt-Drawin4 Teat has been used since 1951 in the Study of the
Precursors of Hyperknaron awd Cereavy Drease to see whether figures
drawn in young adulthood by tuibjects w develop hypertension or eor-
on.ry disease in middle life are signi8cantly different from those of subjects
who remain free from these disorden, and to Identify the nature of the
differences . Figure drawinp by 837 Johns Hopkins medical students in the
dasses of 1932-1964 are u.cNrded in the prssent analysis . The butk of the
drawings were by 725 white male students in the dasses of 1952-1963 ;
drawings by 50 white women studenta In theae dasaea were used for the
sex comparison . Drawings by 62 white nule swbjecta in the class of 1964
were added to the original makgroup fwcompa riaons invdvinSph ysio-
ko6ical and metabolic variables. T'he raults d this study indicate that the
structural and graphic characteristics of /lpre drawinp may indeed have
biological correlates, so that individuab of different makeup tend to draw
different kinds of figures . For etampk, men draw the male fipre fint
rncNe often than do women and thin people draw /llrrres with belta more
often than do fat people . In view of t airly estenaive literature on per-
sonality differences between smokers and nonamokers, it is puzzling that
their figure drawings showed so few differences . The final significance of the
study's findings remains to be ascertained in view of the hypothesis-seeking
nature of this investigation .
41
Thomas, C. B ., lones, L W . and Rost, D. C. oxidation is coupled to phosphorylation ; adenoaine diphosphate (ADP) :
Ptychialric Qua.Irrly Suppltmrnt 12( 2) :223-251, 1969 . oxyden ratios are approximately 2 for Aavin-linked and 3(or pyridine
nuckotidc-linked substrates . Cadmium ion, a common air pollutant and
Ot6rr .rrP.rtr National Heart Inttitute, National Institutes of Ilcallh and a reported component of cigarette amoke, advcrxly affects respiration of
International Busineas Machines Corporation . alveolar macropha6es . It completely inhibits macrophage mitochondrial
From the Department of Medicine, The Johns Hopkins University School oxygen uptake at S0 rmolar concentrations and wrcoupks oxidative phos-
of Medicine. Baltimore . phorylalion at 5 rmolar concentratiom . Cd+ + and several other divaknt
calions, like Cu r r, Ifs* + . $n+ f and ZnF+, also inhibit adenosine tri-
pho.phatase (ATPase) activity of alveolar rnaerophaBes . Since metal
1 V . Rdptrtltory System lumes~ and osides are common air poUutants, a study of this sort might
provide information on mechanisms at the biochemical level as to how
toxic inhalants initiate pulmonary pathology .
EFFECT OF CADMIUM ION ON RESPIRATION AND ATPase
ACTIVITY OF THE PULMONARY ALVEOLAR MACROPIIAGE : Mustafa, M. C., Cro.t.., C. E. and Tyler, W. S.
A MODEL FOR THE STUDY OF ENVIRONMENTAL Arclrivet of In/ra .af MrtdkJee 127(6) :105(1`10SS, 1971 .
INTFRFERENCE WITH PULMONARY CELL FUNCTION OtA .r .urp.rsr U . S . Public Health Service and California Tuberculosis
Pulmonary alveolar rnaeruphakes (PAM cells) were isolated from and Respiratory Disease Association .
sheep and resprratan studies were oonduded at two levels of otpnizatirm :
From the Departments of Biokasical Chemistry . Physinlo6Y, In-
intact PAM cells and isolated miloehoedria . Approximately SmM 2'dlr ternal Medicine, and Analorny . University of California School of Medicine
Inhibited endokemwa respiration in PAM cells and 0 .5 mM Cds+ inhibited i
aed Veterinary Medicine, Davis .
respiration in the isolated mitoehoodria . Tetrameth7l-p-phenyknediamine,
∎n artificial electron nrrier, restored the Cd2 F-inhibrted respiration in both TIIE ORIGIN OF PULMONARY ALVEOLAR MACROPI/AGFS :
cells and mitnchondria, indicalina that Cdi+ presumably bound certain STUDIES OF STEM CELLS USING THE Es-2 MARKER OF MICE
respiratory chain components . Cadmium ion also inhibited the Na I-K i,
Msz / ATPase system of PAM cells and cellular membranes . The results Although it is well known that pulmonary alveolar macrophages
of this investigation have quantitated in vitro the inhibitory eRects of Cd2 4a constiluent of botlh urb (PAMs) constitute a major Irn6 cellular defense mechanism . there is at
.w envitonments and cigarette smoke, on cellular this time a considerabk controversy concerning the cellular prKurwrs of
and subcetwiar biochewueal prvcsra of the PAM cell . Although separate the resident PAM population. la this attempt So iderMi(y the precursor,
studies are neceasary to eorrelate these observations with Cdia-induced genetically related IRF/Al(+) and RF/AI(-)1 wbatrains of mice were
pulmonarr diaeases . the mrodel prexnted here affords an opportunity for used to investi6ate the possibility of PAM origin from marrow alem cells .
studyina Jw vitro an isolated and hnportant lung cell system and assessin6 The RF/Al (+) mice carry a .oaaPocilk readily identi6abk prealbumin
the effects of environmenul agents potentially hazardous to pulmonary esterase marker. Es-2 . Reciprocal ehrmerism was produced by administer-
ing a lethal doae of i-irradiation to (I) RF/AI(7,-) mice and sub .e-
tissue . qrentlyinjectin6themwithRF AI(-~)boeeeurrow ;and(2) RF/AI(-{-)
Crotz . C . E., Ibrahim, A . B ., Ahmod, M . and Mustafa, M . G, mice and subsequentlr inject~ them with RF/Al(-) bone marrow .
Enr!!own.n.Lf Renareti 3(S-6) :512-320, 1970. Eight weeks after Irradiation pulmonary wacropl1 .Bes wete obtained b~r
Other ..pr.rtr Tuberculosis and Respkatory Disease Association of bronchial lavage. PAMs from RF/Al(-) a .inub transplanted wwh
RF/AI(+) bone marrow showed the prealbutnis e .terase marker . Es-2,
California . while PAMs from the RF/AI(+) anhnab tiven RF/AI(-) bone marrow
From the Department of Internal Medicine . University of California School had an but lost their Es-2 marker band, which coeArer the marrow origin
of Medicine, Davis . of PAMs.
Btunsletter, M-A .. Ilardie, 1 . A., 3ehifl,'R ., Lewia, J . P. and Cro», C. E.
INTERFERENCE OF CADMIUM ION WITH OXIDATIVE
METABOI.ISM OF ALVEOLAR MACROPIIAOFS Arcl11 vrr of 1n/errwf MrJk4a 127( 6) :1064-196d, 1971 .
Most of the entajy-requirl .~ poaeaao of pulmnnary alvep4r macro- OtA.r .arr.rtr U . S . Publit Ilealth Service and Atomic I :ner`y (-om-
phatcs are dependent upon aetobic anetaboliun . ln rllro studies show miniou.
that these cells con.nme 0.15 b 0.2 rmo(ar 0,/mg protein/aec . Mito- From the Department of Medicine . University of .'alifornia School of
chondria from alveolv macropA./os manifest a respiratory rate of 0.3 to Medicine, Davis, and the Department of Anatomy, Tufts University School
0 .6 rrnolar 0 ./mg prdcia/aec for Necinale as a substrate . Mitochondrial of Medicine . Boston .

42 43
PULMONARY ALVEOLAR MACROPHAGE : MEMBRANE
ASSOCIATEf) SODIUM ION . POTASSIUM ION, AND
MA( ;NF.SIUM ION ADENOSINE TRIPHOSPHATASI : SYSTEM
This paper presents one type of cellular ATPaie system . a system
which appears to be located primarily on the plasma membrane, to he
activated b~ Na+ and K+ and specifically inhibited by the cardiac gly-
cosidc, ouabain . Accordinaly, this e~ me a m is presumably a part of
a transport "pump" methanirn ot the nwnary alveolar macrophage
(PAM) cell membrane . The of this ATPase system were
investiaated ie subcellular fradbw a.d is i .tact cells derived from rabbits
and sheep. Equimoiar arnaanb of M`++ rd ATP were needed for masi-
mal activation by Na+ or K+ . While Na+ or K+ alone had a little cffect on
ATPaae, siariltaneous additioe d boU catioas produced a 50% stimulation
of basal acti.ity . The Na+-K+, ++ATPase activity was inhibited by
ouabain but was insenaidre b yeh and dinitropfienol . Fcrther
studies revealed that this ATPre rity waa located predorninant(y in the
plasma membrane and IlcserNOd 20rwols inorpnk phosphate pcr milli-
pam of protein per hottr at 30' C . Thia woe+nbrane-ssociated A1'Pase
may be Interrelated with oelhdar esbrp-requirins prnceaaes, which akr ∎
biochemical mesoucernent suitable for st.dy of the interad'an of air po(-
lutants with the ceN .rnwbrane of alveolar nacrophages .
Cron, C . E., Mustafa . M. O ., Peterson, P . and Hardie,l . A .
Archives o/ Inrtn .of MrNetne 127(6) :1069-1077, 1971 .
Ot6er aoPprtr California Tuberculosis and Respiratory Disease Asaocia-
tion.
From the Departments of Intetea) Medicine and Biological Chemistry,
University of Califarnia School of Medicine, Davis .
LOCALI7ATION OF NA+-K+,M ++
ADENOSINE TRIPNOSPHATASI~ ACt7VITY IN PULMONARY
ALVEOLAR MACROPHAGE SUBCELLULAR FRACTIONS
-Putmonary alveolar mac~~p potress an entyme system . Na+-K t,
M++ATPaae, that may be related to active cation transport and inward
I b fk+w mech .nisnts. For the pdent studies, pulmonary alveolar macro-
pha`es from shce~ were eolketed, frtactiauted, and analyzed for protein
and ATPaae activity in the variow cell fractions . One membrane fraction,
namely the middle layer from a density gradient contained most of the
macrophage cellular plasou mew+tinane and athi 'ted the higitest ATPase
activity compared to otAer membrane fractions . Ouabain inhibited a~
proaimately 30% of Na+-K+,Mg++AT*ase activity in both intact ce(Is
and membrane prep.ratioay . This inhibition by ouabain implies that this
ATPase subaerves active eatiota tranaport acroas the alveolar macropha¢e
pfasma membrane . 31ece Na+-K+,Mg + 4 ATPase was sensitive to ouabain
and p<hloromercuribennoate but inaensitive to o(igomycin, it seems that
this enzyme srstem may be rc~ted to enerp-dependcnt membranc-linked
proccua of alveolar n+acrophara .
44
Mustafa. M . G ., Cross . C. E. and Hardie, J . A .
Lilr Sciencrs 9(1) :947-954, 1970 .
OtAer support : Tuberculosis and Respiratory Disease Association of
California .
From the Departments of Biological Chemistry and Internal Medicine, lJni-
versey of California School of Medicine, Davis .
EFFECTS OF DIVALENT METAL IONS ON ALVEOLAR
MACROPHAGE MEMBRANE ADENOSINE TRIPIIOSPIIATASE
ACTIVITY
This study of the basic mechanisms of pa~fchan6e in the lung
shows that a number of divalent metd ions e=ert itthibitory eRects on the
adenoaine triphosphatne (fiTPase) activitr ofpr Imon .ry alveolar macro-
phage ( PAM ) cells . The oyeraNsurveysfwrred that theinhibi~ory eRects
of inetd ions were variable . Cd + , Co+ , Ctt Fe +, 11~ , Pb ,
Sn+ +, Sr+ +, and T,e # + in'tibiled the ATPue syatetn by 30% or higher
at 0 .3 to 2 .0 mM coeoentratians . Other ioaa srch as na++, Ca++, Mn++,
and Ni++ were kss inhibitory . Sinoe eradmium (which is both a common
t
air ~otlutant and a comporxnt of cigarette smoke) can induce both pu1-
nwnary emphysema and pttlmonary /fbrasis in snan, the eRects of Cd++
were studied in greater detail . The endogesors oarlt:n uptake of PAMs
was almostcanpk tely Inhibited in the presence of 5 mM Cd+ + . A 50 rM
concentration of Cd 4+ oompktely blocked the oxidation of succin.te and
a-0:odutarate, and a 5 rM eonoeatration of Cd++ abolished the P1ata
phorylation and respiratory control in PAM mitochondria . On the grounds
of these results, a relationship between divalent cation-induced injury of
PAM biochemical machinery and the dekkriau effeeb of certain divalent
cations on pulmonary tissue is waested .
Mustafa, M . G ., Cross, C. E., Mun., R . l . and Hardie, l . A .
Tlre lownd o/ Laboroto .y .nl C/!wk»f Melleinne 77(4) :363-571, 1971 .
OtAe . .rr'.rrr Tuberculosis and Respiratory Disease Association of
California and U . S. Public Health Servrce .
From the Departments of Biological Chemistry and Internal Medicine, Uni-
versi/y of California School of Mcdicine . Davis.
DETERMINATION OF ALVEOLAR SURFACE AREA AND
TENSION FROM IN SITU PRESSURE-VOLUME DATA
This investi6ation set out first to determine the total alveolar surface
area of the cat lung from the M sJtn pressure-volume (PV ) curves for both
deflation and infiation, and seoordly to determine the alveolar surface ten-
sion as a function of the alveolar surface area for the complete cyck /aMn
the same /n situ gas and liquid PV data . To accomplish these ends cats
were anesthetized and placed, with the ehestope ned, inside a whole-body
pkthysna6raph . In recording gas and liquid PV eurves, 100% oaysen and
)trnser-Locke solution were used . Gas and liquid flows were varied from
45
2 .9-6 .0 ml/sec and 0.5-5 .0 mI/sec respectively, with no change in either
the hysteresis or the shape of the PV curve . A constant, K, was determined
by comparing the gas and liquid inflation curves at maximal lung volumes
and using the equation K- 3PV4S/2r, where r was assurned to be 50
dyne/cm . The mean value for K in eight experiments was 1225 ± 100
SEM. At a functional residual eapanty of 90 ml the alveolar surface area
of the cat/ka body mass was 1 .03 t 0 .09 ms . Surface lension was caku-
.
lalcd during inllation and deflation . The results indicate that surface tension
approaches zero at low lung volrt .es or areaa and is always lower during
deflation than during intation at a divea roltarne or area .
Fisher. M . I . . Wilson, M. F . aad weber, K . C . (Student Fellowship Re-
cipient)
Relpirorlon PhysioJo=y 10(2) :159-171, 1970 .
Or4rr .arP.rtr West Virpnia Heart Aaweiation .
From the Department of Heakh. Educatiow and Welfare, U . S . Public
Health Service, Consumer Protection and Environmental Hedth Service,
f?nvwonmeMal Control Administration, Appalachian Laboralory for Oocu-
patioaal Respiratory Diseases, and Departn .ent of Physiology ard Bio-
physio, West Virginia University Medical Center, Morpntown .
INFLUENCE OF CIOARETTE SMOKE ON GUINEA PIGS :
EFFECT ON PULMONARY CELLS AND SERUM
ANTITRYPSIN LEVELS
A total of 50 male guiaca pip was exposed to the smoke from two
p.cks of ciprettes per da) for two weeks ; this espowre was then rcduced
to one pack per day for the rewsai .irtS eight weeks of the expow ro period .
A corresqOrrdmg group d 50 animals served as control . Measutements
were made of the cdlr recoverabk from the lung and of the serum anti-
trypsia kvels is both poups of guisea pip . Repeated exposure lo ci6a-
rttte amoke caused a siprilkaet iecreaae in the total number of cells
recoverable f renn thehop . Dil[eresMlal ceM eowtb showed also that animal+
e:Qo.od to dpreae anmke had au iaa~eaacd ta .mber dpdyanorphoeuckar
kakocytes ( PMNa) is the Mid obtained by lavare of their lunp . Thh
incRase was aooontpaaied by .o change (n serum andtrypsin kvds over
the te+-week eapoaure period. The findint that inhalation of cigarette
amoke rear.lta is a sipniIkant iwcrere in the aMUnber of PMNs recoverabk
from the lond may be of sipd/ka .oe in the pathogenesis of chronic pul-
nwnarr emphyserea in man.
Flint, C . L . . Maxwell, K . W . and Retmetd, A . D ., Jr . (Student Fellowship
Recipient )
Archi .eiof EnrMowminWNeufrA22(3) :366-369, 1971 .
(H/Irr .rPr .rtr Nationat InatWNes of 1lealth .
From the Microbiobfl Researeh Laboratory . Department of Medicine,
Veterans Adminntratioa Hoapilat, and Unrversity of Utah College of
MedKlne, Salt f.ake City .
46
TNE ULTRASTRUCTURE OF ALVEOLAR MACROPt/AGES
FROM IIUMAN CIGARETTE SMOKERS AND NONSMOKERS
Alveolar macrophages of cigarette smoken and nonsmokers, obtained
by endobronchial lava6e, were examined with the ekctron micr~
The macrophages are charscterixed by tmriace pr~~• p~r
nucki, an extensive Golpi apparaNu,, eYtop(asmie filaments, and varwus
inclusion . . These inclusions are menlbrane-bowlded and contain acid
pho .phatase. Thus they are probably lysosomes and their derivatives,
or6anelks which function in the digestion asd storage of phaeocytosed
su~ances . In general, alveolar macrophailes from smokers contain larger
and more heterogeneously stnrctwed inclusions than alveolar macrophages
from nonanwkers . There i., however, considerable variation in the number,
si:e, and hetervgenicity of incfuaions within individual macrophages /rom
srnoten, suggesting that various daees of phadocylosis are represented In
lavage samples . Furthermore, some substances which are phaaocytosed but
not digested probably aecuewlate in the larger heterogeneous inclusions of
smokers .
Pratt, S . A ., Smith, M . II ., Ladnrn, A . l . and Finley . T . N .
Laboratory InresriprJon 24(S) :331-33a, 1971 .
Other wrr.rt . National ItattitMa of Health .
From the Departnsents of Anatomy and Medicine, The University of New
Meaioo School of Medicine, Albuquerque .
THE JUXTA-ALVEOLAR LYMPHATICS IN THE HUMAN
ADULT LUNG : HISTOLOGIC STUDIES IN 15 CASES OF
DROWNING
A dear definitiom of alveolar ly~ados Is vital to the understanding
of pulmonary clearance of YNra-al Ooid atad particulate matter. In
order to study closely the lytaptratia of the adult human luna, eaten .ive
tiawe aeetion . were taken /rom_ the Iwp of 13 pfrwns who died from
drowning . These lungs exhibited eacelktnt demamation and o/ten d'datation
of the lymphatic capillaries . Two main ttels of lymphatics were distinguished
here : the superficial or pleural set and the deep or parenchymatou . (peri-
bronchovascular) lynph.de pkaw. Repudins the disputed oarorrena of
alveolar Irinphatia, a sharp distinction was made b this study between
the air-blood the inleralvedar t+tptr .m, and the alveolar wall . No
lymphatic capillaries were observed at the level of the alr--0lood barrier or
the Interalveolar septum, but eharacterbtic hrmphatic capillaries were
present between the alveolar walls aqd the (nterlobular, pkural, peri-
brrwrchial, or perivascular eaMecdve sheets . These wero de/{ned u"juata-
alveolar" lymphatic capillaries because of their close tofx)Sraphic and
pnrbabk functional relationship to the alveolar lumina without being a part
of the interalveolar aepta themselves. The occurence of these lymphatin
might help to explain the ckarance of intra-alveolar transudates . esudates,
or inhaled materials via the lung lymphatics that eventually drain the bkrod
stream .
47
Lauwtrynt . 1 . M.
Amerkon Review of Rrlpirawry Disease 102 : 877-885, 1970 .
From the Dep.rtment of Patholoty . University of Lcuven School of Medi-
cine . Leuven, Belgium.
ARGYROPHII., FLUORESCENT AND GRANULATED (PEPTIDE
AND AMINE PRODUCINGt) AFO CELLS IN IIUMAN INFANT
BRONCHIAL EPITHEUUM . LIGHT AND ELEC7RON
MICROSCOPIC STUDIES
Light optical. hisbchemkal and elodron micra .copical studies of 22
newborn human infanb have slww . Ihat Ihe epitheliws of the bronchi con-
tains an impressive nwnber d di .tinctly arprophil, fluorescent (after
freea-0ryinS and forwtalddtyde vapor treabneM) and uhlastructuraMy
Sranulated cells . Theae AFO atia oo.tain stwnerous round ekctron-
op.que dense-cored resicles. Ltnrawc.+asd trerro endings ate also present,
su6Sestin~ a"direct eo .tact" with the AFO cells . It is proposed that these
cells in the human lung are relNed to the powinS list of presunublr
peptide and amine soctetinS "artyrophil" or APUD, and other celia whkh
have been reported in different other tissues and organs . A chemaeceptor-
like lwrction also may be possible . In addition, il might be that tbe AFG
cells could interiere with various pulmonary areas, such as bronchial
smooth muscle tone, pulmonary vasomolion, the circulatory adaptrtion (or
failure) of the newborw at baih, and pulmonary oncokly (carcinoid and
oat ceU tumors) .
Leu+vrrywr, / . M ., Pcmkens, l . C . and Cokclaere, M .
L+Ic Srilencer 9, pt I(24) :1417-1429, 1970 .
Ork .r ..rr.rir Belgian National Fonds voor Wetenschappelijk Onder-
soek .
From the Esperimental Laboratory of Cardiopulmonary and Genital
PathoioSy, University d Leuven School d Medicine, Leuven, Beltium .
Li1LTRASTRUCTUItE DE LA,CLOISON INTERALVEOI-AIRE
DU POUMON APRES CRYODECAPAGE
The recently dealoQed hoeae-etch trocMdque was applied to an elec-
tron oktoaoopkal In .estiptiom of the btenlvedar septum and the air-
blood basier of hutp of adrh miot; guinea pigs, and rats . This hxhnique
in dillereel fratm tr.dltioe.l electron snicraoopy because it avoids some
cheatkal Ider .ctfo.s h the tirrea, exposes tiswe structures in relief, and
allows the ob .ertation of rneanbe.ne surfaces en face . Mos1 importantly .
this lechniq.e hera re .edod new data concerning the lamellar
inelusbws of the Ir* ahnt+olar 11 ., favoring furthermore the
Ypoprvtehk nature d the .s and their relati,n.hip with the
"alvcdar aartl-aldectade /atour ." The wrlaod of ~ lamellae o( these
Inclusions are studded with twW d 170 A, which are not ob-
served with traditional efeetron nsc ~. The distance between two
48
successive lamellae is remarkably constant . Their configuration strikingly
resembks the frcezeelch ultrastructure of synthetic lipoprotein micelles
(and of lipid incluskxts of yeaat cells), suggesting that the small plaques
could represent the protein fraction of the lamellar inclusions, while the
lamellae themselves could contain lipids .
[auwrrynr, l . and Gombeer-Destnecht . M .
lournd de Microscopie 10( 2) :139-145, 1971 .
From the Department of Patholo8y . Univetsity of Leuven School of Mcdi-
cine, Leuven, Belgium.
L'ULTRASTRUCTURE DE L'EPITHELIUM BRONCHIQUE ET
BRONCIIIOLAIRE DE LA SOURIS
The ultrastructure of the bronchial aed bronchiolar epithelium and
especially of the Clara cdla of adult mice has been investigated with the
light and the electron microscope (after fitation with osmium tetrotyde) .
The uhrastructure of the ciliated eelb conforms to the clas .kal data. Tbe
Clara cells are characleriaed by an extremely abundant smooth endoplumic
reticulum, the absence of cilia and the occurrence of numerous peculiar
mitochondria . Some calenux of the amooth entloplasmk reticulum flatten
out around the mitochondria . The Golgi zone seems to form sonte secretory
vacuoks. As discwsed, these ultrastrtictrral data suggest a secretory
function for the Clara ceNs, but do not allow an identification of the nature
of this presumed socrelion . Moreover, sonte aspects of the ultrastructure of
the Clara cells are variabk, three diAerent types bein distinguishable and
dcscribed, i.e., the "usual type," the "clear type," and the "adult type ." It
is postulated that these types probably represent different functional phases
of the presumed secretory eyck, i .e., a young form (the clear type),
an adult form (the usual type) and an involutionary phase (the dense
type) .
L.awe.yru, l . M ., Cokelaae, M . and Bouwauw, L
BuNetin de fAssocl.Non det An.ton.trtet 146 :54a-S60, 1971 .
From the Department d Pathok+gy. University of Leuven School of Medi-
cine, Leuven, Bel6ium .
THE BLOOD AND LYMPHATIC MICROCIRCULATION
I OF TIIE LUNG
This easay sy .thesinea the rewdla obtained while studying one of the
I most Intriguing .nd perplexing problems of the human lung, i .e ., its blood
and lymphatk microcirculatbn . One thing that ia essential and preliminary
to an undentandin of the mkrodreulatbn Is some knowledge of the
micro.rchitecture o~the lunt . This is presented in this paper for both the
adult and the premature lung . Results of correlated macroscopic and micro-
scopic studies of the lunsa of humans, beagle dogs, and mon8rcl dogs are
, 49
presented . Primarily, this study is concerned with the an6ioarchitectural
relationships between the bronchial and the pulmonary vascular s3•stcm% .
The relationships are distinct in each circulatory network . The bnmchial
arteries are directly connected to each other, establishing a"parallel" type
of vascular su r . The bronchial veins also form thepe ribronchial venous
pksus . In the pulmonary circulation, however, the pulmonary arteries and
veins form terminal intrakrbular branches . The bronchial and pulmonary
arteries also communicate in the brorrchiola by means of a common
capillary network . As extendvd7 dicnred, the authors were unable to
observe bronchopulmonary artenoarlerW or arleriovenous anastomoses in
entirely normal adult lungs of beaSles, but they seem to be normally present
in the luns of the human fetw and infarM. Psob .bly they disappear during
chifdfwod, 1o reappear easily I . the aduit lung in the presence o7 even
minimal pulmonary inArrnmatory ttadiona or processes . Of the lyrnPhatie
mkrodreutation . suny~ arr presented and prefupy considered
but few are answered ty.
LauweryRS, l . M.
(n Sommen, S . C. (ed.) : Pathology Annual 1971, New York : Applcton-
Century-Crofts, 1971, pp 365-415 .
t hibited incorporation of radiwctivity from eluooaaanine by 44-7246 and from
Oth.r .u'r.rt : U . S. Public Health Service and the Bel6ian National
Fonds voor Wetenschappelijk Onderr.ock .
From the Department o/ Patho(o`y . University of Leuven School of Medi-
cine . L.euven, Belgium .
AIRBORNE INFLUENZA PRe-A VIRUS INFECTIONS IN
ACTIVELY IMMUNIZED MICE
Circulating antibody in actively immunized animals can be effective in
preventing death, dinical iMness, and residual pathoiW . In this study of
the production of airborne pulrtsonary virm infections, young adult white
mice, immunized subculaneowly with formalized motue-lung suspensions
of influenza PRt ;-A virw (teat mioe), along with eorrespad rng unim-
munized (control) miee, were exposed to sublethal and highly kthal
ck+uds of freshly harvested homologous virw . The control mice developed
rapid and fatal pulmoeury infectiona following exposure to the lethal ctiwd
of virus and eatensive and persisting pu(monary changes following exposure
to sublethal viral clouds . The test mice became only mildly ill and survived
the lethal airborne infedions, althouo the virusgr ew to high titcr in the
lungs . Pneumaric involvenxnt was focal and confined to the bronchial air
passages and adjaeent alveoli . Resofution occurred and residual lung scar-
ring was no/ seen is recovered mice . Thus, while nnt preventing infection,
Immunization affected in a hi6Aly favorable and si6nihcant way the clinical
co,urse and lung pathdoltical Ilndinp of the mice espe»ed to airftxne in-
flucnza virus .
f .ooiti, C . G., flertweck, M . S . and flockwa(d, R . S.
Archrver o/ F.nvirnnmenrd Health 21(3) :333-346, 1970 .
50
OtA .r suProrrr U . S. Army Medical Research and Development Com-
mand, U . S . Public Health Service, Hughes Employees' Give Once Club,
and Hastings Foundation Fund.
From the Departments of Medicine and Pathology . University of Southern
California Schonl of Medicine, Los Angeks, and University of Chicago
School of Medicine, Chicago.
GLYCOPROTEIN SYNTHESIS BY THE TRACHEA
Because glywproteins make up a ma portion of the sdids of
tracheobronchial secretions, their synthesis ~y slices of rat trachea was
studied by using radioactively labeled Shsco .amine as the substrate . Upon
incubation the radioactivity was Incorporated into pootein, that ia, material
insoluble in cold ethanol, cold and hot trichloro .ectic acid, and not ex-
tracted by li d sofvents. Incorporation was dose-dependent, occurred at
an optimal pC of a, and was detreued in the presence of glucose . A small
amount of t)-afucn.amine-r sC was metabolized b r4COs . Compared to
L-kucine-r rC, the curve of Slrooaateinu i.oorporation rose ksa steeply
initially, and the ascending limb aaawned a sipnoW ahape . Puromycin in-
kucineby more than 95% . The tnicroaomal fraetion of tracheal homo`enate
had the highest specific activity of the rwbeellular fractions throughout a
four-hour incubation. The akohol-israolubk radioactive product was matly
resistant to hyaluronidase but wr made nolubk by Pronase . When tracheal
slices were incubated with D-gfuooatmine-6-3H and were examined by
radioautography, the greatest density of Sraint was found in the epithelium .
Yeager,lf ., )r., Mar .ro, O. nnd Mara.ro, D.
Ansrric.w Review of RtzPirrbry DLseiste 103( 2) :1 Ea-197, 1971 .
OtAer arPr .rtr Awseriat,'Ilwack Society .
From the Pulmonary Diviaion, Veterans Administration - Gcor6e Wash-
ington University Medical Center, Washinpon, D .C .
PULMONARY ARTERY LIGATION : EFFECT ON IN VITRO
PROTEIN SYNTHESIS ,
Left pulmonary artery ligation was performed in adult mon6rtl dop
of both sexes . The dop were killed at variow intervals following ligation ;
lung slices from both the lipted and non-lipted aides were prepared and
incubated and cell-free proteM synthesis was studied . Results showed that
one week following pulm .nary artery liptiun In vino protcin synthesis
wr highe r in nonhemorrh.gic tissue from the tipted side than it was in
tiruc from the non-lip ted aide . 71re physiological si6nifk•ance of this in-
creaae In protein ∎ynthesia atad the meehanit+m or stimulus by which it is
brought about arc not clear . -
Massero, D ., Weiss, If . and White, O. '
Archivet of Internal Medicine 127 ( S) : d61-S62, 1971 .
51
Other support : American TboraCtic Society .
From the Pulmonary Divyion, Veterans Administration-l::rnr6e Wash-
ington University Medical Center. Wahington, D .C.
DIFFERENTIATING TYPE I AND TYPE 11 ALVEOLAR CELLS
IN RAT LUNG BY OsO4-Nal STAINING
A histochemical method oQering a usable differential stain for the type
II alveolar epithelial cell is presented htx+e . The 6xin6-stainin6 mixture used
in this investigation consisted of oaep .rt of 2% aqueous OsO, and three
parts of 3% Nal In distilled water. Fresh nt lunp were cut into 2 mm
slicea and immersed in this solution /or 24 hours at room tempe ra ure .
Controls were 6 :ed in buAercd OsO, alone . Selective stainin~ d type 11
alveolar cells was shown by the OsO ; Nal miature but was absent in the
controls . No additional staining d the sections was required, and the sekc-
livity was readily observable in either p .raffln or Arakdite sections by light
microscopy and in Araldite aections by ekctrvn microscopy .
McNory, W . F ., Jr . and FJ-Bertnaai, A-W .
Srein Trcl4noioty 4 S( S) : 215-219, 1970 .
Ot/ier .ur,r.rir Boston University School d Medicine .
From Boston University School d Medicine, Boston .
CHRONIC COR PULMONAI .E : ITS PATHOGENESIS IN
APPALACHIAN SITUMINtJUS COAL WORKERS
This strdy, prde .er a qwntkalive,po .tarortem analysis of cardiac and
pulmonary vaac.lar strrchate In 178 Appalachian adt coal workers . A
total of St% d these oider bihrnirwru miners with coal worker's pneu-
moconiosis had anatomic evidences of moderate or severe chronic cot
pulmoruk at death . The degree d cot pulmonak correlated best with
theperceM d Irnrt comprised d abnorwal .ir space which is a measurc of
emph~rsema ; the observed enphysenta was of both eentrilobydar and more
Benerdited types . There was no appatent correlation between degree of
cor puimonak and the volume of dwl mae.ks, or the content of bire-
frineeM silin crystals and odlalleer In the dwt oacuks . Abo, in 10 younger
miners medial muscle n .ss of small p.hiwnacy arteries inside dust macu/es
was 2 .3 tinres those o .tafde the rwactila . Tlrra was due mainly to hyper-
trophy of individual muscle f<bers. 'Tltia vascular abnormality helps esplain
the mild pulmonary arterial hypertension and cot pulmonak o( many
younger miners .
Narye, R . L . and Laqucur, W . A.
Archlves of Parholoty 90 :4t7-493, 1970 .
OtA.r .upP .rtr U . S . Public Neahh Service .
From the Department of PNho{oRy, Pennsylvania State University College
of Medicine. Itershcy .
52
EFFECTS OF SMOKING ON LUNG STRUCTURE OF
APPALACIIIAN COAL WORKERS
Long-term cigarette smokie+g a11en twrne structural features of pneu-
moconiosis in soft coal workers but has little effect on the disease process
in anthracite miners . lbis apQraisd is based on a quantitative, morpeoM~ic
study of the poumortem ttieart and hrng structure of 144 Appalachian
unteraround coal workers . Of these miners, 32 had a lifetime history of
nonsrnokm6 . 24 smoked a pipe or cisan, and es anroked cigarettes in
various amounts . Results showed that there wat no infiuence of smoking
on the primary coal duat macuk and i4 direct cornpliptions, but the
bituminous-coal miners who rrwked had a 17% to 33% greater degree
d cor prrlmonak, 9% to 25% rnor ernphyserru, and 56% to 68% more
brdrchrolar aoblet cells as evidence of chronic bronchiolitis than non-
smoking biluminous-eoal rniners. No significant effect of smoking on lung
and heart structure was found is aMhracrk miners .
Narye, R . L., Mahon, l . K . and Dellinger, W . S.
Archives of Envlronn.rnr.f Ileaflh 22 :190-193, 1971 .
OrA.r .urrorrr U . S. Public Health Service .
i From the Department of Pattwlogy, Pennsylvania State University College
of Medicine. Ilcrshey .
RANK OF COAL AND COAL WORKERS PNEUMOCONIOSIS
This study presents evidence that the emch-n :ported association be-
tween coal rank and preumoconiosis is probably fortuitous . Regional
differences in the prevalence aed severity ot coal workerspne umoconiosis
often have been attributed to the rank of oo.l mined ; the higher the rank
of the coal, the greater the prewknoe of 1he pulmonary disease . Ilerc a
quantitative, morphologic at was undertaken of Iung and heart structure
of 312 Appalachian miners w wete daaified by rank of coal mined . A
total of 390 oorresponding ooetrds was studied also . Amon6 the miners
chronic rnr pulnaeak was ooanton in dl groups . Pulmonary fibrosis in-
ereased with the number of p .rcnchymal silin erystah and with bronchiolar
goblet cell hyperptasia, an evidence of ehronk bronchitis . The actual volume
d coal dust retained in the hrnp, eadrding Its silica content, seemed to
have only a small effect on the developrnent of cot pulmonak and symp-
toms of pulmonary insufRcieoey ; the prevalence and severity of pneu-
rnocnn&nrs are more likely related to chrdtk bronchitis and e .posure to
silica than to rank of coal miamd .
N .rye, R . L ., Mahnn, 1. K . and Dellineer, W. S.
Amtrinn Review of Rrspb.tory Mxair 103( 3) :310-35 S, 197 1 .
Other supports U . S . Public Health Service .
From the Department of Pathology, Pennsylvania Stste Univertity College
of Medicine . Nershey .
53
ADRENAL GLAND STRUCTURE AND THE DEVELOPMENT
0F IIYALINE MEMBRANE DISEASE
There is a demonstrable relationship between adrenal gland structure
and the development of hyaline membrane disease in newborn infants .
Analysis of 397 consecutive autopsies on human neonates showed that
adrenal glands were 19% lighter in infants with hyaline membrane disease
than in those without the disorder owin~ to a Srealer number of adrenal
cortical cells in the latter infants . A~ positive oondation was found between
the presence of infection arising beiae blrth and the absence of hyatine
membrane disease, the infected in6rNa having lareer adrerpl glands . Since
surfactant appears to play an ia" rok is tiyaline membrane diseax,
it is of interest that anenoephalre neoaMa who had little or no adrenal
fetal cortical zones and hal(-sinrd addt no .ea had 45% the nuss of
wrniophilk tr.m.ks in p.lrnarrp 11 alveoiar cells as did non-anenco-
phalic control infants . The t iceQarwka are reportedly the anatomic
representation of surfactawt .
Narrr, R . L ., Ilarrke,ll . T ., Ir ., and Sla.e, W . A .
rel/arks 17(1)630-657, 1971 .
Other ..p'.rtr U . S . Pubik Heahh Service and Heahh Research Council
of the City of New York .
From the Department of Pathology . Pennsylvania State University Colkse
of Medicine. Ilenhey. and Dep.rtment of Pathology, Columbia University
College of Physicians and Surgeons . New York City .
ACQUIRED ATTENUATION OF CHEMORECEPTOR FUNCTION
IN CHRONICALLY HYPOXIC MAN AT HIGH ALTITUDE
Chtonk exposure to h)sia during adulthood produces alteraticxn
In a person's control of breat~ Meawrrements of the resting ventilatory
respawse to hy :ia in ei~At persons native to high ahitude, 10 long-term
no.-naUve N aititude residea~ts, ard 10 low altitt .de oontrob show that
hiah altitude .ing resuhs in a ditdrdted rentilalorY reapome to hypoxia .
The degree of attetwation is nelaed to the kagth of time spent at high
akitude . Similarfy, hrpercapeie vewtilalory drive is reduced In non-native
high dtit.de tesidesb r it ia to a peater depw in high ahitude natives
In wntrast with theae li .dinp at teM, induction of hyposia during exercise
prodroes In both groups of MsW. .den an inerease In ventilation eom-
parable to that in the ooaMrds . T%M that there is a marked dis-
crep.ncy between hypo :k responae =11xerdse and hypoxic drive at
rest, whkh is presumably mediated by peripheral chcmoreceptors . The
observation here that hypoxic rewtiWotrr drive ia alwion completely absent
while hypercapnk drive is oNy prtWly red .c'ed paralkls closely the
~encrally accep~ed view dut th . peripheral orn are resdonsibk
Lr virtually all of the resting bypmtlt drive and ro+ y half of the hyper-
capnk drive in man . Thia w~aesla tAat the aiteratiar in ventilatory control
at high aNitudes are due b IaRun ot peripheral chemoreceptor function .
3+
t,51E+u ~tj55
Wiil, ! . V ., Byrne-Ouinn, E . . Sodal, 1 . E .. Filky, G . F. and Grover . R . F .
The Journal of Clinical lnvettitation S0(1) :1 a6-19S, 1971 .
Other .u'prt : U . S . Army . Department of Health . Education, and Wel-
fare, U. S . Public Ilcalth Service, and American Thoracic Society .
From the department of Medicine . University of Colorado Medical Center,
Denver.
V . Ti.aue and Organ Culture
DIFFERENTIAL CYTOLOGICAL AND CYTOCHEMICAL
RESPONSES OF VARIOUS CULTURES FROM MOUSE TISSUES
TO REPEATED EXPOSURES TO PUFFS FROM THE GAS
PIIASE OF CHARCOAL-FILTERED FRESH CIGARETTE SMOKE
A total of three types of prieury cyhtues, namdr kidney tiuue,
em lun~ or`an, and lung esplants traw Saiell mioe, and one eatab-
1' oeN line, 3T' cells from Swim mke, were used to naay the biobgicd
ef(eds or the gas phase from charcoal-IUtered fresh dprette amoke . Re-
peated exposure to puffs of the 6rs phase of charcoal-filtered fresh cip rette
smoke did not evoke a significant alteration of growth in primary kidney
tissue and embryonic lun6 oraan cultures frorn Snell's mioe . There was also
no effect on Snell primary lung explants, and on their ootgrowin6 macro-
PhaRes and epithelioid cells . There was, however, an eRect on 3T3 cells,
m that exposed 3T3 cultures showed an enhaacement of 6rowth, of mitotic
indea, and of cellular atypism, ineludinS variations in DNA content . In
none of the exposed cultures was a morphological cell transformation ob-
served .
Ln.chrrnbrrter. C. and LeuchtenberRer, R .
E.rperimtnral Crll Research 62(1) :161-172, 1970.
Other nrp'.rtr Association Suisse des Fabricants de Cigarettes .
From the Department of Cytochemistry. Swiu Institute for Experimental
Cancer Research, Lausanne .
TISSUE CULTURES ,
In this first of a series of monographs on athetoackroais, the fieid of
tissue culture is examined from its inoeption throrh its differentiations to
its future possibilities . There are seven tKctions a~this book as follows :
I . Back6round ; 11 . Vascular organ crltwes ; Ill . Now-vascular tissue cul-
turea ; IV . Vaacu4r tissue cvllurea• V . Cell aqregatitun• VI . M vivo vas-
cular tissue cultures ; and VII . Review . Section IV, the longest division of
the book, eonsiders such aspects of this discipline as hiuory, methndnbp .
quantitative aspects of cell cultures, rnised cell populations, single cell pr,p-
ulations, lipoid transport by cells, metabolisni, eytoph .rmaeology, cytoto.i-
cok~r, cytogenetics, and atheroaenesis and fw vitro cultures . Summarizing
original findings and surveying the work reported in the literaturc, this
55
. ∎
informative, succinct book inoorporates all the features of an easily read
tissue culture textbook .
PollaA, O. ! .
Tis:ur Culrrrr: Monotrvplir on ArMoaderoait . Basel : S . Karscr, and
Baltimore : Williams & Wilkins Co ., 1969, vol . 1, pp 1-143 .
Oeh.r ..~r.rtz Delaware Ileart Aasociatioa, Dover Medical Research
Center, Lilly Research Laboratoria, asd U . S. Public Ilealth Service .
From the Dover Medical Researt :h (kaler, 10e., Dover, Del.
V1 . Strsdlta at the Ce12tdarLerd
STREPTOVARICINS INHIBIT RNA DEPENDENT DNA
POLYMERASE PRESENT IN AN ONCOGENIC RNA VIRUS
The prep1ovaride taowpks Y Y e∎ y pd eat inhibitor d the
reaction by whidr DNA is tnn aarWed froas the RNA teatplate reaidest in
purilkd tnurMe kuke .da Hrioaa . Steep/or .ricin C and rilamrcin S%' are
also quite active, whik shepadydipim and rif in are relatively poor
inhibitors . la esperinenb reported here, the Moloney strain of mnrine
leukemia virvs was pow>t In JLS-V9 cells and purified using a double
sucrose gradient centrifup tion. Eloctron micro.oopr of the puribed Irac-
tions revoakd 203 X 10r r particks/aa1 . ; the protein ooncentration was
0 .S-0 .7S mg/wd. The resrlts of iabibitios strdies showed that tlx strt ."o-
varicin compies, a mixture of seven teacrolidea (plus undetermined .vm-
ponents), ia a poteat inhibitor of the MLV polymerase readion . More
uM. 75% inAibition is obtained with t :once.trations as fo+w as 40 rP/ml .
Compkk inhibition is not obtained, b•rever, evest with concentrations of
400 p=/d . Strcplovarkia C, ap~re aacrdide . was also quite active but
less so (on a wei~ltt basis) tMaa tha aoatplen . Ri(amIcin SV gave an inhibi-
tion similar ia a+agnit.de b that of streplovarkia (` .
Broclwun, W. W ., Carter, N' . A ., U, Li-11 ., Retaner, F . and Nichol, F. R .
N.rre 230( 3291) : 249-250, 1971 .
OtAsr .rr'.rri U . S . Public Health Service and American Cancer Society .
From the Departmcnes of Medicine and Microbiob6y . The Johns Flof .kins
University School of Medicine. B.ltiaaore.
COMPARATIVE PRO[KICTTON OF INTERFERON BY FIUMAN
FE:TAL, NFANATAL, AND MATERNAL CELLS
This report compares interleron (IF) productkm In nine primary
human fetal cell lines with thek (na maternal cell lieea . Ran-
domly sekclcd neonatal tirre, obu between the first and third days
of eRtrauterine life, was studied aLo. IF ion was measured after
exposure to two inducers, virus (Newt :ast disease virus) and synthetic .
56
double-stranded ribopolynuckotide (poly r1 :rC) . Results su"est that fetal
cells display, in tissue culture, increased responsiveness to both inductrs .
Fetal cells rekased 300-fold more IF than maternal cells on exposure to
poly r1 :rC. This enhanced capacity for IF production was consistent in
cultures developed from fetal skin obtained between the 10th and 20th
acstational week . The response was relatively stable, persisting in cells
cultured for 18 generations (about 14 weeks) . On infection with New-
astk disease virus, fetal cells prmduced, on the avera6e, 4 to 6 .5 times
more IF than maternal or neonatal cells . The virus was adsorbed with
equal efficiency by each type of cell . Inaeased production is appa rently
independent of the rates of overall protein synthesis, since (dal and
maternal cells have very similar rates of total protein synthesis .
Carrn, W . A ., Ilande, K . R ., Esskn, B ., Proehownik, E . and Kaback,
M. M.
In/ecrionanJlnunrwiry 3(S) :671-677, 1971 .
OrAar ..'r.rt : U . S . Public Health Strvice, American Cancer Society,
Maryland Division, and National Inatitates d Health .
From the Dep.rtmenas of /rCedicine. Microbioiop and Pediatrics . The Johns
r Hopkins University School of Medicine, Baltimore .
STRUCTURAL REQUIREMENTS OF RIBOPOLYMERS FOR
INDUCTION OF HUMAN INTERFERON : EVIDENCE FOR
INTERFERON SUBUNITS
The binding of sH labeled poly I :C-DEAE-de>atran complexes to
cells has been measured . Low teaperattrra were used to separate the
binding reaction from later steps involved in oeM uptake . About 0 .5% of
uncomplexed poly IC is bouad at 2• after one buur ; 20 times trwre of the
wncromokrwlar aggrepte is bound whea DEAF .dextran is present . Thua,
this enhancer potentiatp hwmrw interferon (IF) release by delivering rnore
of the active poly IC complex to the triggerlnl ; site . The IF proteins induced
by both virus and synthetk tibopolrmen hare been purified and their
apparent subunit structure detected . As an Mitial step in the charaderi :a-
tiou of IF's, the IF's have been extensivdyQar i(led by means of the new
technique of electrotociain6 in polyacrylamide gels . In gel chromatography
of unpurified IF's, mouse IF behaved as a single mokcular species with a
MW of 3E,000 . Human IF eluted predominantly in a position correa
ins to a MW of 24 .000 . Isotkctric focusin of mouse and human 1 was
performed on the IF's obtained from chromatography . Data gel from
these studies strongly suggest that IF exists as a dimer of two similar,
perhaps identical, wbunits . Tfrc .ronometie unit of human IF has ∎ MW
of 12 .000. The different isoelectrk: points for the dimer and rnorrrMner
wgyesl that certain surface eharpes rnust rearrange during oli6omer furma-
tion, but without Inlluencina activity, since there don not seem to t+e a
ercasurabk cooperative effect between the subunits in the dimcr form . The
mechanism of the convenion is currently under study .
57
 Carter, W . A . and Pitha, P . M .
In Becrs, R . F. . lr ., and Braun, W . (eds .) : BioG,girol Effects o/ P.,ly-
nrKlrotiArr, New York : Sprineer-Verla6, 1971, pp R9-105 .
(HArr .nPprr : U . S . Public Health Service and American Cancer Society,
Maryland Division .
From the Departments of Medicine and Microbiolo6y . The Johns Ifopkins
University School of Medicine, Balti .ore.
MEMBRANE-ASSOCIATED DNA IN THE CYTOPLASM OF
DIPLOID HUMAN LYMPHOCYTES
To determine whethn awwndtochondrial, cytoplasmic DNA exists in
human lymphocytes and b iwveslip/e its atabcehular Mcaliration, cellular
DNA was uniformly labeled with (2-r4C)thymidine, and cells were lysed
with the nowionic detergent NP-40. This detergent lyses the plasma mem-
brane, but not the nuclear nuwrbnne, as shown by phase-contrast micro-
scopy ; nuclei can be quantitatively rerooved from lysates by low-spced
eentrifuption . The lysate obtained after removal of nuclei was separated
I VI1 . Pl.orntoeolosy and Ptyekopl .ormocolosy
into several fractions. Virtually aY cyloplaswric DNA was found in a frac-
tion sedinrcntinf at 1),000 X & and of this kss than 10% was supercoikd .
This cytoplasmic DNA, a speeies that is apparently as.uxiated with the
plasma membrane of d'pioid human lymphocytes that arc continuously
growin6, ia described . Thu DNA differs from nuclear or mitochondrial
DNA by virtue of its location M the eell, time of synthesis in the cell cyck,
and various physical properties. At prexnt, the role of this DNA is un-
known .
Lernn, R . A ., Meinke, W. and Goldstein, D. A .
Procttdints ol tlle National An/enyy of Sciences 69 ( 6) :12 I 2-12 I 6, 1971 .
OrAer wP'.rsr National InnhWes of Heahh, National Cancer Institute
and American Ca .oer Society .
From the Departnsentt of EsptrMtental Pathology and Microbiology,
Sciipps Clinic and Research Forndation, La Jolla, C .I .
. z OXYGEN TOXICITY IN THE NEWBORN GUINEA PIG LUNG :
~ THE INCORPORATION OF TRfT1ATED URIDINE INTO
MONORIBOSOMES
Wepropo .e that oaygen InteAetes 1• the ecology of cellular popula-
tions of the hrng and have designed a varkty o/approaches to this thesis .
In this eaperinsent, ne. .bo.n pinea pigs were poiaorrcd in 100% o .yfpen
for four daya When moaoribosomcaprepared from their lung han~enstes
were esamined, uslaS a sed T-widine label !n vivu and sucrose aadient
ultracentrifugation technue the results suggested that ribosorne synthesis
per surviving cell was probably inaeased . It is the fourth day also which
.•
marks the dcvekK+ment of bronchiolar muotxal necrosis, the beEinnin6 of
5E
bronchiolar metaplasia, the appearance of anomalous ribc .somal protein,
and a severe depression in DNA synthesis. Thus, the emer6cnce of a new
cell population is tied to certain nalecular changes apparently induced by
a toxic environment, and is followed by restructurina of the lung in a
permanently disturtcd pattern, which inckdes emphysema .
The observaticxn raise fundamental ~uestions about the nature of
regeneration in the lung kobuk, particularly the role of cell populations, and
suggest a need for improved experimeatal models based on molecular
techniques. An incidental and surprssin6 discovery was the sharp absolute
reduction in ribrnunsc synthesis of controls and esperiments by the fourth
day of life .
Bieber, M . M ., CoMn, M . G ., DurbridBe, T . C., and Roson, R . C .
Biologio Neonatrnum 17( I-2 ) :25-42, 1971 .
Orh .r support : California Tuberculosis and Health Association.
From the Department of Palhok+Ry, Stanford University Medical ('enter,
Palo Alto, Cal .
ANTIASTHMATIC ACTION OF SYMPATHOMIMETICS : A
REVIEW OF THE LITERATURE ON THEIR
BRONCHOPULMONARY EFFECTS
In this review p.per, aynspathomimetic bronchodilators are grouped
into specific cateaories based upon the e :tent of their activity on adrenergic
receptors . In the brorschopWmonary aystetn, there are two types of adrener-
gic receptors : the alpha receptors and the bNe receptors . These receptors
can be activated either directlr or ind'wsctly by the release of catechda-
miae.s . The end result d stiewlatio ., either direN or indirect, of both alp/w
and 6Ne receptors is a reductiou is aitway teaistanoe, which is the basis of
the antiaNhmatic effect . Oe the poundn of their stirnulatory actions, the
syrnpdhomimetic brvsdrodilalors ean be divided iMo four classes : diroct
stinwlanta of doha and bd. ta~epton, k~tdirect stimulants of alp/w and
beta teceptors, dired stimulaats aflectM~ predominantly alldia receptors .
and direct stimulants aRecUng natqlr bere receptors . Among the
16 aympathomimetk bronchOdifstm which ate useful in the treatment of
bronchial asthma are : (I) Dired dpls-bet. stimrlant : epinephrine ; (2)
Indirect alpha-beta stimulants : ephedrine, phenrlpropanofamine ; (3) Direct
alpha stimulant : phenykphrine• (4) Direct beta srimulants : 11 drup in-
cludina iaoproterenol, dio>lethedrine, metaprokrersol, soterenot, and sd
buumol .
Avldo, D. M.
lowno/ of Cl/nlcal Pharmacr>joty and the Jownaf of New I)raas 1(/(4) :
217-221, 1970 .
From the Department of Pharmacolo6y . University of Pennsylvania Schord
of Medicine . Philadelphia .
59

HORMONES AND PUI .MONARY EFFECTS OF TOBACCO :
CORTICOSTEROIll3 IN ANESTHETIZED DOGS
Pulmonary compliance and tesistance were measured in 36 anes-
thetiaed dop in this study of ahe interaction between corticosteroids arid
cigarette smoke . A sin~ m tion of either hydrocortisone or desametha-
u~nrc uused a sli6ht but nile faH in pulmonary resistance to low :r
kveis . These corticosleroids probably e:ett their Influence by local relasi-
tioa of smooth muscles of Ihe airways . Relaxation of the dog's bronchial
smooth muscles by cortioakroids could siot be anributed to potentiatiwm
of the sympathetic bronchodiiator weebritr or b inhibition of broncho-
constrictor mechanisms . Changes iM Ua rnoe#a .iat propenties of the lung
were elicited in response to Yoprolete~ol, compound 4d-d0 (a histamine
liberaWr), serotonin . histasdtae, iahalafiom c/ 5% oxygen in nitrogen for
two minutea, and inhalatiom d elpreNe rrwke. Inhdation of 4i6aretk
smoke, alone, increased pt.l.ronaty reaislarws i. .nesthelirud dop . The
response of the dogs 1o oordooatervids givew be{ore espowre to ci6aretk
smoke was so variable that it was Is.pasibk /o determine the relatirwnhlp
between cigarette smoke and airway sensitivity after corticnslerr»d therapy .
CarriMo, 1. . R . and ArWo, D . M .
Anrhivet o/ £nvi.onnrewref He.IrA 21( 2) :149-133, 1970.
From the Department of Pharmacoiogy . University ol Pennsylvania School
of Medicine, Philadelphia .
CARDIOPULMONARY EFFECTS OF PROGESTATIONAL
AGENTS IN EMPHYSEMATOUS RATS
Progesterone and medrosyprogesterone (in a dose 1/50 that of
progCsterone) prevent the development of experimental emphysema in the
rat . They do not, however, increase the rate of survival from the initial
esperinuntal procedures of tracheal ligation aad intratracheal injoclian of
phytoheeug$1 Winin . The studks reported here show that in the rat with
ligation of the trschea, which reocrved intralracheal injections of phyto-
hema;gn utidn but no progeslational a/aN, tAe following effects were ob-
served dler six weeks : (a) high fusctional residual capacity ; (b) high
perceata~e of airspaaes in histological sections of the lung ; (c) cardiac
outpul ; (d) awrwrat pdmosiarr arterial preswre and pulmonary vascular
resistance ; (e) extreme ekration of }ttle+o..ry, arterial pressure in re-
aponse to rapid iailusiaa of salise ; ud (f) nornW ekctrocardiopaphic
M era and normal thicteess o/ ratrictrl .r ..a/s examined at postmortem .
concurrent adsninistratios d pro~esteoone or nsodroxyprohesterone
prevented (a) and (b) but did swt n/fect tAe other factors . Rats with
tracheal occlusion aloas had high k .e1s of pulmonary arterial
pressure associated with hYpo>tia srd by inhalatian of high oxygen .
These rats had not propeased to the stage of chronic cor pulnwmnak,
althoufh those under (e) .bofe indiuted some change in distensibility of
the pulmonary blood vesaels .
60
r
Inoh . T . and Avradu . Q M .
ClKsr 59(6) :659-666 . 1971 .
From the Department of Pharmacofo6y. University of Pennsylvania Schcwl
of Medicine, Philadelphia .
INCREASED RETENTION OF NOREPINEPWRINE-'ll IN VAS
DEFERENS DURING NERVE STIMULATION
This study represents an attempt to determine quantitatively the im-
portance of increased uptake during nerre stimulation of the isolated
~yppslric nerve vas deferens preparation studring the action of drugs
known to block the resting uptake of catee murcs . Retention was in-
creased when isolated vas deferena of guinea pip were exposed to norepi-
nepMine-'11 during nerve dimulation of the hypopstrie nerve at a rate of
50 shocks/ser, 1 .3 msce pulse duration ; 4 aee/atin for 60 minutes . This
increase in retention of norepinephrhte-OH retaaisrcd waltered when the
program nf stimulation was prolonged to 10 aee/ndn or decreased to 2
sec/min . It was inhibited when ooeaine, desnxthylirnipramine, or phena .y-
bentamine was added to the orprt b .th 10 toinutes after norepincphrine-`1i .
These results indicate that uptake is increased in order to meet the need
irx replacement of catecholamine lost during hiRh-impulse activity . "is
increase was nol observed when monoamine oxidase inhibitor was present
in the orpn b.th .
Bhagw. B. and Zeidman, 11.
A rnerican Journal o/ Phyfioluty 219 ( 3) :691-6%, 1970 .
From the Department of Physiob6y, St . Louis University School of Medi-
cine, St . Louis .
INFLUENCE OF CIIRONIC ADMINISTRATION OF NICOTINE
ON THE TURNOVER AND METABOLISM OF
NORADRENALINE IN THE RAT BRAIN
Chronic administration of aicotine accelerates the rate of disappear-
ance of intraventricularly administered aH-nortdrenaline from the rat
brain. This is associated with normal levels of aH-norrnetanephrine sug-
Vstina an increase in intraneurvnal deamination . The slope of noradrena-
line decline in nocotine pretreated rats is sipiAcanUy greater than that of
control animais, while steady state levels of brain noradrenaline ara about
equal in both 6roups of rats . This su s arr Increased turnover rate and
utilization of noradrenaline Induced by akrotine treatment . Also, the
actinns of sedative, antidepressaM, and central stinwlant drugs In the ral
brain ane not allected by nkotine pretrea/meM . Amphelamine, reserpine.
and acelykholine si~n ifkanllr decrease the endogenous utecholamines
in the rat brain, but decrease fn amine level Is the same in nicotine treated
and control animals . The results of these esperiments Indicate that chronic
administration of nicotine Increases noradrenaline turnover in the brain and
possibly may increase the deamination of this amine .
61
Blha`al . B .
Psychophar.nxoloria ttT(4) :325-332, 1970.
Other r.rP' .rt : Nationa) Institute of Mental Ilealth .
From the Department of Physiolo6y, St . Louis University School of McJi-
cine, St . Loua .
EFFECTS OF C.IIRONIC ADMINISTRATION OF NICOTINE ON
DRUG-INDUCED IIYPNOSIS IN MICE
The present study wr usdertakea to determine the effect of thronic
administration of nicotine on fheJ~ ~at responsivity of mice to
selected central nervous system nts . Barbital, which is escreted
mainly un .hered, was chosen as an indicator for aateration of CNS sensi-
tivity on the rate of drrK entry irb the brain . Hesobarbital, pentobarbital,
so :azolanrine and ethanol wqt wed to lest the alteration in the drug
metabolizing en:rmes. Chmnie adraiaisention of nicotine in mice for six
weeks did not affect the dwNion of hypnosis induccd by pentobarbital,
heaobarbital, b.rbital or m:axofandne . The onset of barbital hypnosis
remained unaffected . These rstwka ar~ett that chronic administra-an of
nicoline did not affect the drruS metabp/rnnS activity of hepatic microsomes .
While psychotropic drtip siqwlkantly polentialed the hyprw .is due to
pentobarbital and hexobarbital, the degree of potentiation was the same
in both chronically nieo8ne-pretreated mice and controls . Nicotine pre-
treatment signi&antly increased the duration of aleepin6 time caused by
ethanol alo.e . However, when treatment of nicotine continued for a 1on6er
period of titwe, the duration of hYpnosis induced by ethannl returned to
control kal.
BA.tw . e . . dayer . T. and Lind, C.
Prychop/iarw..nokrera(Ber(.) 21(3) :2ft7•293, 197 1 .
Oth.r .∎Pp.rtf U . S . Public Health Service .
From the Department of Physiobgy, St . Louis University School of Medi-
cine, St . Louis .
SOME NEUROCHEMICAL CORRELATES OF ALTERED
MEMORY CONSOLIDATION
In this roundup daen+or~ oondidatbn e :periments, several neuro-
chesrical ehanSes attesrdia~ .herod reuograde amnesia in response to
ekctrnconvubive shock (ECS) are espla+ed and related to modifications
of the memory consolidatioe procesa• An iuitial series of experiments was
concerned with the extent /o which changes in brain aerntonin kvcl, as
aQprosimating those prodroed by ECS . would affect the Incidence of cnn-
ditwned response .cq~ tsNiow . Othet experiarenta tested the rok of 1) the
urotonin precuncx, S-hydrosrtryp/oph .n ; 2) ye dilfcrcnccs : 3) Jifkren-
tial housing ; 4) reduced brain amine levels : and 5) aminc changes at the
ccNular kvcl . The studies summarized here suHeest an important rok for
62
S-hydrnsytryptamine in the mediation of at least one phase of the memory
amsoliJatiun process . The relationships between changes in this amine in
whwrle brain, in rcEiunal sites within the brain, and on a cellular kvel, and
certain other cvcnlc implicated in other phases of the memory consolidation
proKCss (RNA synthcsis, prdein syn/FKSq, and their inter-dependency)
have been shown, under several experimental conditions . These relation-
ships may constitute a rrwdel within the framework of which serotonin
may play an imptxtant rok in normal memory consolidation and in those
cwditions wherein the memory consolidation process in impaired .
Esinron, W . B. ,
Tronsacrionl o/ the New Yor4 Academy o/ Sckncts, Series Il, 3 2( 8) :
94e-973, 1970.
Other .uPprt : National Institutes of Health .
From the Department of Psyehok+6y . Oueens College . City University of
New York, Flushing .
TIIE ABILITY OF VARIOUS NICOTINE AGENTS TO RELEASE
I ACETYLCIIOLINE FROM SYNAPTIC VESICLES
Nicotinic agents apparently penetrate the intracellular site of the nerve
endin6 causing Ihe release of endoFenous acetykholine (A( .h) ; non-
nicotine agents do no1 . Evidence to thrs effect is presented in this study of
the release of endo6enous ACh from synaptic vesicks, the body's primary
storehouse of endoaenous ACb . In these eaperiments, mixtures of rat
cerebral cortex vcsicks and niootinic and tion-nicotinic drugs were incu-
bated at S' C for five minutes so study the release of ACtt by these drup .
Nicntinic agents such as nicotine, letramethrlameanium, eholine, and
carbachal rekased ACh ef6icientlr . Non-nicobnic agents such as triethyl-
chdine bromide (TEC), hemkhdinium brornide (HC-3), and DMAE
among others faikd to show the tame effect . The ACh-rekasing effect of
nicdinic agents was not blocked by TEC . HC-3, or DMAE . These resulu
suggest that the nicotine ayents are taken to an intracellular site of the
nerve tissues in order to cause rekase of endogenous ACh from synaptic
vesicks . The antinicotinic agents block the rptake of nicotinic agents a the
membrone site but not at the intraceMular site of the nerve tissues . This is
demonstrated by the fact that TEC has been shown to block the nicoaink
e/fect at the ncuromuscular junction and autonomic ganglion in intact nerve
terminals, but not the release of ACh from the synaptic vesicles localized
within the nerve tissues .
Chiou . C. Y ., l .onR, l . P. . Potrepka, R . and Spratt, J . L.
Archives Inrrrnoriorwlrt de P/wnscolynanit et de Thhopir It17(I) :
11111•96, 1970 .
OrArr .urporte Il . S . Public Ifealth Service .
From the Department of Pharmacolo6y . University of towa Cotlc6e of
Mcdicinc, Iowa City .
63
STUDIES OF DMAE-INDUCED POTENTIATION OF TIlE
PRESSOR AND CONTRACTILE RESPONSES TO EX(Xif:NOl)S
NOREPINEPIfRINE IN NORMAL AND RESERPINE-TREATED
ANIMALS
While it has been reported that DMAE, a hemicholinium derivative,
enhances the presscx and contractile responses to exo6enousty administered
and endoBeno+nly rckased norepinephrane, the mechanism of these actions
has not been clearly de6ned . This paper presents evidence that DMAE-
induced potentiation of the responses to electrical stimulation of adrenergc
ncrves and diroct-actinB amines 1a mediated by an increased release of
neurotransnwtkr from adrswerglc nerve essi>itW . Usin6 control and M-ser-
pine-treated cats, blockade d the adrenerEk neuronal uptake mechanism
on DMAE-induced poleMiNion of the contractile and pressor respcrses
of the cat nictitating mewserane so exopenotdy administered and endesen-
owly released rKxepinephrine was evaluated . Cocaine pretreatment autat-
oni:ed the ability of DMAE so enhance the responses to esornous mxe-
pinephrine . DMAE-induced polentiation of thercsp~+nses to nerve stinwls-
tinn was unaltered after cocaine administration= lhcse results suggest that
DMAF rekases nnrepinephrine taken up by the adrencrEic nerve tcrminal
after dx administration of norepinephrinc .
Greentxrg. S. and Lon`, l . P.
Archives IMt•rnoriondrr dr Pharnfocudymmmir et de Thfrupic 191(2) :
365-375 . 1971 .
From the Department of PharmacoloRy, University of Iowa Collcse of
Medicine . Iowa City .
EFFECTS OF NICOTINE ON SELF-STIMULATION IN RATS
Nicotine facilitates sdt-stimulation in rats . In experiments reported
here, rats were trained to press a lever b receive intracranial electric
stimulation through a uereotaskally implanted bipolar electrode in two
different area of the hypothalamus . Nicotine was pven i .p . at several dose
kvels. The effects o/ ntcotine wet~e found to ee rate-dependent . Facilitation
of responding for se(f-stimulatton was observed at 37 .5 r`/kg and higher
dones of nicotine in rats with low response rates . In rats with high reapnnx
rates, nicotine had very little eAed or even caused depression . Nicotine
had no appreciable effect or unreinforced respmses and it counteracted the
depressant effect of barbiturates on r+elf-stiemlation . The facilitatory effect
of nicotine on self-stimulation resdwbkd that of amphetamine in many
respects . Facilitation by nicotine wr reduced or blocked by mecamylamine,
a tertiary ganglion blocking aprt, aaid could not be produced in animals
treated with rcserpine 24 hours earlkr . It la proposed that niawine, by
acting on a central nkotink<lrolinergic receptor . may indirectly cause
rekase of norepinephrine which . in lurn, produces the facilitatory eftect
04 acM-sri.wlatu,w .
64
Prodhon, S . N . and Bowtina, C .
The Journal of Phar .nocoloRy e .d Eiprritrsentol Therapeutics 176( () :229-
243, 1971 .
Other .upport : U . S . Public Health Service .
From the Department of Pharmacolo6y, Howard University College of
Medicine, Washin6ton, D .C .
EFFECT OF COI .D STORAGE ON THE RESPONSE OF
GUINEA-PIG TAENIA COLI TO CERTAIN CATECHOLAMINES
AND OTHER AGENTS
Cold storage aflects smooth muscle responu.s to sympathomimetk
amines and other active agents in several complex ways . In the present
experirnents, relaxation prvluced by plsenyksphnee, epinephrine, norepino-
phrine, and isopnNcrenol on guinea-pit laema culi was not nsodified after
cold storage of up to sis days . The responses of the cold stored strip to the
first three of these drugs were prevented by pretreatment with alpha•bkxk-
in` agents but not by treatment with beta-blockinB aBents; the opporite was
I obs.rved for the response to itaproterenol . On the other hand, the con-
traction produced by methscholsne, physostipnine, KC1, and Ba was
decreased after three lo six days cold storage . Similarly, the relaxation
produced by ATP and 3',3'-eye/ie AMP was also decreased after cold
storage. Incubation in low Ca medium had no eRect on the inhibitory
action of catecholamine used in cold stored strips but suppressed the re-
sponse to ATP and 3',S'-AMP . It can be seen that in this experiment the
cold stored strip still responded well b catecholamines but not to ATP
and 3'.S'-AMP ; mwxeover, alpha- and beta-adrenergic receptor blocking
agents did not modify the response lo exogenous ATP and 3',S'-AMP
while such blocking agents prevented eateeholamine response . These data
suggest that the relaxation mechanisms of ateeholamina may be different
from that of esogenous high energy substances .
SJilbett, S., Hattori, K . and Timnserman, D.
Ewopean lournof o/ Phrwtsnofop 11 :321-331, 1970 .
Oth.r s .pp.rtr U . S . Public Health Service and Ilawaii Heart Associa-
tion .
From the Department of Pharmaeology . University of Hawaii, Honolulu .
ADRENERGIC INNERVATION AND COCAINE-INDUCED
POTENTIATION OF ADRENERGIC RESPONSES OF AORTIC
STRIPS FROM YOUNG AND OLD RABBITS
The use of the rabbit aortk strip u a pharmacologic tool has become
very popular in studying adrenerBie mechanisms. In this histological study,
a catecholaminaspecific fluorescence was observed in the tunica media of
the aortae of young rabbits but not of old rabbits . After five days of cold
storage at 2' C or reserpine treatment, these specific fluorescent sub-
65
stances disappeared from all layers of the tissue ; such treatment decreased
the tissue norepinephrine (NE) content in both young and old rabbit
aortae . Checking the NE content of the tissues by a spectrophotofluoro-
metric method . the aortae of young rabbits were found to contain twice as
much NE as those of old rabbits . Cold storage blocked the contracfik
response to nicotine and tpramine . The sensitivity of the younS rabbit
aixtae to nicotine and arranwne was siSnificantly greater Ihan that of old
rabbit /ortae . DesPite Ihese disetenoes, NE-induced contractions were
potentiated by cocaine in strips of Sofh types . Cocaine-induced potentiation
could stiN be deewnslraled afler 3 days of cold storage . No cocaine po-
tenliatiorr of NE-induoed ootatt-Ilo . eouW be seen after incubation for
20 minutes in a Ca+ # -lree twedi.wm and treatment with MN++ antJ Co++ .
Cocaine potesitiated the Ca++-iadrotd contraction in a Ca+ +-(ree medium
with a high pdassiwn oonleN . 'ilrest tesrlfs suggest that adrenergie nerve
6ben penetrate into the smooth n+uade layer of the rabbit aortae, but that
the cocaine-induoedpo1entiation may not be dependent on these adrenergic
nerve tern+inals in the sortie anedia . E :terwal Ca # 4 may possibly play a
significanl role in the developwieat of eoeafne-Induced pi .lentiaticn, .
SAibar., S . . Hattori, K ., Sakrrid, 1 ., Mori, l . and Fujiwara . M .
I From the Department of PFurmacolob,y . University of Hawaii School of
lornwf o/ Phernscolosy o ./ Eiotrlwant.l Ther.p.uelcs 177 ( 3) :621-632,
1971 .
OrArr .rPr.rtr U . S . Public Health Service, Hawaii Heart Ass•xiation,
and Amcrican Medical Association Education and Research Foundation .
Fran the Dep.rtment of Pharntacology and Pathokogy . University of
Hawaii School of Medkine, Honolulu .
TFIE ECT OF COCAINE ON GTECHO40-
METH~TRANSFERASE AND ON THE RESPONSE TO
NOREPINEPHRINE OF RABBIT AORTIC STRIPS
Atthou4h the oosoeutratiom of 10's M and 10-• M cocaine caused
the polentiatron on the contraction of rabC+t sortic
sl n'pa, sreh eowonrtratious did .ot inhibit ealalrol-4-methyl(ratrferase
(COMT) from rat lirer . The ooeantratbns of 10 • M and 10 a M pyro-
plld which poleMlated the no~e~hrine-ledreed conlraction sisnifi-
caMy decreased COMT aeth~il7 arte, but not pyro6altol . paentiated
the phenpkphrine-iwdretd contraction of fresh strips and nore~rnephrine-
induced eontractioe d• days cold abted strips . The data indicate no
pouuve evidence to appott the theory that oocaine-induced potentiation
is mediated by the iiiibilory .ctbr of cocaine on the COMT enzyme
system .
ltattori, K . a.d SAi6w, S.
/ .p•nrir lownd o/ PA .wr.ro.lop 21 :59l-S62, 1971 .
Oth .r ..Pr .rtr U. S . lrblb Healb Serfloe and Hawaii Ileart Association .
Fram the Dcpartateat of Mlkrtaroolop . Univetsity of Hawaii School of
Medidne, Hawlulr .
66
THE RELATIONSHIP BETWEEN EXTERNAL CALCIUM
CONCENTRATION AND THE RECOVERY RATE OF AORTIC
STRIPS FROM NICOTINE TACHYPHYLAXIS
The depletion d eedoteeous calecholamine stores by agents which act
through catecholamine-rekase mecMnisnts is considered to be the mechan-
ism responsible for the devekaprnent of tachyphylaaia. l.n(ortunatelr, the
nature of nicotine-induced tachyphpla :is ia not clear. In rabbit .ortic
strips a repeated etposure to the same concentration of nicotine produced
tachyphylaxis . Compkte iecoverZ occrrred 50-60 roin following the wash-
out of the first application of nicotine . Incubaioa in medium containing
aorepinephrine ( f0 • M) or dop .mine (10-t M) did not modify the time
cou _rse drernvery~ Hish Ca++-medium halved the recovery time and low
Ca++-mediurn inhibited this pruoen . Thus nicotine tachrphrlaais does not
appear to be due to plechdamine depietion but rather to be a blockade
of the adrenergic nerve e!(ector site by depolarization which prevents nore-
pinephrine rekase .
Shlbaa, S ., Ilallori, K . and Sanders, 8 .
ErroP.an lo .vnd o/ PA.rwr.noJory 16 :109-112, 1971 .
Medicine . Honolulu.
CNS EFFECTS OF THE ALDEHYDE PRODUCTS OF
BRAIN MONOAMINES
Theprraent series d e:perlmenb show that S-hpdrosyindokaeetakle-
hpde ( S-HTA ) and isdok .ceWdehpde ( tryptddehpde ) are s k octing
and as potent as serolosti/t and tryptanMe in inducing ekct~ ruolobical
and behavioral eQects in e :perimeMai a .iarals. Other retated c• nds
are also phartnaooloCicaly active but hieher dosa ate required to ewww-
atrate their effects . In these studies, indoieacetaldehydes and indokethyla-
mina induced sleep in ne.d b.tched ehicks,1~pbpI~oI depreaad mwne
e :ploralory behavior, and hi~h do .a of phe.Ifteets {dehpde Induced CNS
in mice and cbkks. As tepirda rabbit photic evoked pdentiab .
S-ru enhanced and later depressed the slow negativity and en-
hancad the fast positive eompkt (siawilar e/lect to setolordn) . High doses
d S•hrdrosrtryptopfwi, S-hydtv :yindoleaoelic aeid, and senolonin de-
Preaed the slow neptivity. la contrast b hydroayirrdoka, tryptamine and
wtdoleactlaldehyde au~ np etNed slow nept{vity . The monoamine oaid»e
inhibitor, p .rplrne, duoed the effects of serotonin and S-11TA on pholic
resporrea, and phenyksoetaWehpde depression of ancwse exploration .
Further experimentation wriq be required to confirm or ruk out a sipri/kant
role for the cndoprwrrlr fotmed aldehyde derivalives of brain amines in
behavior and in the actios of rwononnlne oaldaae inhibiton .
Sabelli, H . C. and l3iardina, W.1 . (Oastee : !. E. P. Tonwn )
Bioloticat Psychiotry 2 :119-t39, 1970 .
67
Oth .r .u'prt : U . S. Public Ilealth Service.
From the Department of PharmacotoEy, Chicago Medical Schix,l, Chicago .
TIIE INFLUENCE OF INIIIBITORS OF AMINE METABOI .ISM
ON TIIE EFFECTS OF SEROTONIN AND ITS METABOLITES
ON PFIOTIC EVOKED POTENTIAL IN RABBITS
Non-anesthetized rabbits were used b test the effect of intraventricular
injection d serolonin (3NT) . S-h?dto~[ oplal (SHTOL), and S-
hydrotyindokacetic acid (SHIAA) o. the rc evoked potential . Fast
potentials were depressed by the throe S-h ayindoles tested at all dose
levels ; this depress was m ore prowounccd with SIITOL than with
3111AA or SIIT . S/ios IT reduced the slow wepdve wave (SNW) amplitude
at all doses tested . The onset of the SNW depression occurred 15-20
minutes after injection of 0 .03 tng of 3HT, and it was preceded by a
transient enhancement of the SNW . The pharmacological activit}~ of
SFITOL and SF11AA, togethcr with the de4y in the ansct of the SNW
depression induced by low daes of SHT, wWsts a possible participation
of SIIT metabolites in SHTs central action . The dose reap~nse curves for
the three hydrosyindoies showed that 311TOL and SIiIAA were as potent
i
as 311T . In addition, pretreatment with two diRerent inhibitors of amine
metabolism. N-benzyl-N-mNhylprop-2 ynylamine (par6ylinc) and tcora-
ethylthiuram disultde (TETD), markedly altered the cReets of SIIT with-
out influencing the effects d its metabolites .
S.belli, H. C . and Giardina. W. J . (Grantee : 1. E . P . Tomon)
Eiperlenrio 27(1) :64-65, 1971 .
OtAer .urprt : U . S . Public Health Service.
From the Dep.rtment of Pharmacology, Chicago Medical School, Chicago .
CHRONICALLY ADMINISTERED NICOTINE AND THE BLOOD
PRE.SSURE OF NORMOTENSIVE AND RENAL
HYPERTENSIVE RATS
Chronic adnriniattratiorr of eh :otlaie in the drinking water of rats, in
amounts rou#y oorreaponding to the e9uivaknt d one or two packs af
cigarettes darl , elevated the mesa systolic pressure . When this Ireatment
was proion however, the pressor eQect was reversed and a depossrrr
effect was ultimatelr obtained . With lar8e doses (three or lour packs of
eiprettes) only a depresaor effect was observed . Withdrawal of nicmine
during the deprrsaor phastpr odreed a marked, fluctuatins, and prolonged
~ressor response . In renal hrpertensive rats, administration of either Ihe
{ow" or the "high" doses d niooline lowered the systolic preuure below
control levels . This effect war sot observed until the neuro6enically-nuin-
tained phase of renal hypettension was established . An observation r,f
potential relevance to the tok of smoking In human hypertension was the
msrked pressor rebound and the prolon6ed period d recovery ∎frcr with-
68
drawal of the highest dose of nicotine . With such a prccsor responsc, it is
likely that the heavy smoker who attempts to break his habit may undergo
a prolonged period of elevated pressure .
Wenzel, D . G . and Azmeh, N .
Archives Inrernolionolrs de P/wvmocodynomie rr de Thrrupie 187(2) :
367-376, 1970 .
From the Department of Pharmscolo6y and Tosicolo6,y . The University of
Kansas School of Pharmacy, Lawrence .
A STUDENT EXERCISE IN CLINICAL PFIARMACOLOGY :
RENAL EFFECTS OF DIURETICS
A group of 122 medical students tested the renal effects of either a
placebo, hydrochlorodhiazide In four doses, acetazolamide, triamterenc, or
the combination of hydrochlorolhiar .ide and triamter=ne . The student eser-
cise was designed so that the following info.mation would be provided :
a) a comparative effectiveness of the various diuretics, b) a doae-response
relationship, c) information concerning di/krent sites of action, and d) the
efficacy of a drug combination . Results showed that there were no apparent
differences with respect to the incidence of side effects between the placebo
and the various medications . Also, there was no apparent relationship be-
tween the response of the smoker a . nonstrwker within any drug group .
Each of the medications was associated with an increase in urine volume .
In general there was a dose response rllalionship with hydrochlorothiazide
with the 6, 12, and 23 mg daes . Ilowever, the 50 mg dose of hydrochloro-
thiaride did not produce an increase in urine flow sreater than the 25 mE
dose . No advantage of the combination of hydrochkwothiaride and 1ri-
amterene was found .
Gilmore, l . P . . O'Brien, W. M., Brand, E . D ., Peach, M . J . and Wrsr/oll,
T. C.
Current Therapeutic Rtsearch 12(11) :739-769, 1970
Other a.rrort : U . S . Public Ikalth Service .
From the DePartments of Phar and Preventive Medicine, t)niver-
sity of Vir6inra School of Medieinr, arlottesvilk.
VI11 . Metabolic Studies
TIIE KININ-FORMING SYSTEM IN PLASMA
Since there is esistin8 evidence of vascular permeability uccurring
ind.pendrntly of knirwn mediation systems, it has become esxntial to
search for other possible mechanisms that inducx vascular injury . Among
the humoral mechanisms that must be considered in the mediation of such
injury is the kinin-frnmin6 system . In this study, a number of agents were
used to activate the kinin system .
69
 Three components of the kinin forming system have been purified in
precursor form . The 6rst, Nademan Factor, is a molecule of 90,(XX) datu .ns
which upon aclivation cleaves into subunits of 30 .000 which activate the
second component, prckaNikrein. The aclive Flageman Factor acquires
enzymatic activity . Prekallikrein is activated by limited proteolysis, being
cleaved into three and two subt .nit.. rrspectively, for human and rabhit
prekallikrein . Upon activation, kallikrein cleaves the vasoaclive nona-
pcptide, brad k'nrn, from puriAed kiairroken . Activation of Ilaseman
Faclw was acXieved on vascrrtar b ..enteat wernbranes by enzymes cleaving
arginine esterase activity and by .eptivelr charged particks .
Coclvaat, C. C. and W uepper, OL D .
Inrrrr.oo.eAolotr of !n/f .wrw.riow, Fsoetpta Medica International Con-
gaas Series No. 229, pp 137-145 . April 1971 .
OtA.r ..pp.rar U . S . Public HeaNS Servioe, National Multiple Sckrosis
Society and Aaxricaa Ilesrt AasneiNina.
From the Depanmc .l of Esperireentai PatAology, Scripps f'linic and Re-
search Foundation. l .a JoMa, Cal .
METABOLIC FACTORS AFFECTING PROTEIN SYNTHESIS
BY LUNG IN VITRO
The addition of glucose to lung sliees incubated with kucine-1rC
increases the protein specific aclivity of the acd-iruolut>fe material present
In the reaction misture . Glucose causes no increased degradation rd acid-
insolubk radioactivity rwr does it cause an increase in the tissue acid-
aotuble radioactive pool when kucine-I rC or o-aminoiuibutyric-I-I 'C acid
are the substrates . 'hr effect of glucose an kucine-I rC incorporation into
prolein is relatively greater under anaerobic conditions although total in-
corporatioa it eurkedly decreased . Gaiactose, fruclose, and ribose do not
auprent amino acid Incorporation into prdein as handily as does R1u«ne .
Neither p.lmitate nor wnNine added to the reaction mi .ture causes an
iscrease i• the arnino acid iacotporalioa inio protein, even though carnitine
doa'sipYieandy aupneat the oxidation of palmitic acid-r•C to I 'CO= .
Tkse effect of nralo++ic acid on protein syndtesis with and without glucose
is of interat as it may reAect on thr n+eclsanisw+ by which glucose auRma+ts
protein srntheait . Malonk acid markedly depresses formation of i'CO :
when tlucoa-6-r4C Is the substrate but causes only a modest depressi„n
of r•CO~ production when ~uooae-/-r rC is the substrate . This and several
related observations wggeet that the glucose effect is mediated through the
penloae phosphale pathway rather thaa the tricarboxylic acid cyck .
Maiaaro, D ., Sinwn. M . R . and Sieinkarnp. H .
l ow+w/ of Applied Physlolvp 30( I) :1-6, 197 I .
Orh.r .uPr.rrr Americaa Thoracie Society .
From the Pulmonary D'+vision, Veteraru Administration - Goor6e Wash-
ington University Medical Center . Washin6ton, D .C .
70
STRESS AND CIGARETTE SMOKE EFFECTS ON LUNG
MITOCIIONDRIAL PNOSPNORYLATION
Male guinea pigs were exposed to cigarette smoke on a 2'h day acute
I exposure regimen . To insure arouth breathing, the nares of these animals
were occluded with warm ewhen paraRw or with a quick-settin6 liquid
silicone rubber . Sham-exposed animals were subjected to the wme condi-
lions of nose ptugging, confinenu :nt, and machine noise without eiprette
smoke . The stress of forced anonth breathing and the superimposition of
cigarette unoke on this slresa caused losses in oxidative plwsplwrylalion
efriciency in the guinea piL lunt mitochnndria in vivo . However, b .a of
efficiency was greater in the nrouth-breathing air-inhalin6 animals than In
ciprette snroken under the aaree conditions . The "ti`hteas" of
phosphoryfation couplinS at nrilochoadrial sites 2(eylochrotne reductaae
kvel) and 3(cytoc6roase o>tidaae level) was seaswed In Ihese experi-
ments, using artificial electron gewexators or aeoeptors . The nquth-breath-
ing nonsnrokint animals Iwt ellkieney at both sites 2 and 3 . Moulb-
breathinS snsoken bst e/lkie*cy oa~l~r at lation transfer site 3 .
7lreae strca and cigarette smoke eAeets at Iea 2 and 3, respectively,
suggest that the wuscs d oxidative pfwaptwrylation efficiency arc due to
i diAerent mechanisms acting at specific loci within the milochondrion .
Kyle . J . L . and Riesen . W . H .
Archives of Environmental Health 21(4) :492-497, 1970 .
From the Life Sciences Research Division, IIT Research Institule, Chicago .
IX . Chemistry and Biochemistry
GEL PERMEATION ANALYSIS OF MACROMOLECULAR
ASSOCIATION BY AN EQUIUBRIUM METHOD
Macromolecular associatioa by gel perereation can be determined by
an equilibrium method. In this paper, a thermodynamic descri ion of the
simplest case, dimeritatiar, ia preaented in terrro of the equilibrium con-
stant for association and equrlibrirrn partition coefficients for species
present. The theoretical analysis yields an eqwtion relating the equivaknts
of nwoomer in the e:ter .u( phase to 1o1a1eq t.iv.knts, frorn which the
e~uilibrium constant for asaociatioe anaJr be obtained. Those parameters,
critical in experimental desip, ee) swel'int dnre, and cenlrifu6al collapse
point are determined for Sephadex /e11 of porosity G-2S to G-200. Appli-
cation of the method to human hemoglobin gives a value of Kr< = t X ttl •
for dissociation of o :yhctrwglobie at pll 7 .0 In 0.1 M buffer .
Carwrron, B. F. . Sllar, L., Greenfield. V . and Adkr, A . D .
Stparorion Science 6( 2) :217-22a, 1971 .
Other suPP•rtr Connecticut Heart Association .
71
From thc New England Institute . Ridseficld, Conn . ; Department of Internal
Medicint, University of Miami School of Medicine and thc Laburat,rics
for f(emaloiopcal Research, Floward Hughes Medical Institute, Miami,
Fla .
BIPIIASIC BLOOD OXYGEN DISSOCIATION CURVES IN
NEMOGLOBIN S HEMOGLOBINOPATHIES . SICKLE CEI-l .
HETEROZYGOTFS
The purpnse of this study was b tval.ate blood oxygenation in hemo-
n S heleraayBeNes (A-S and 1C) and, by comparison with bloud-hank
, to evaluate the effect of 2,3-diphoapfro8fycerate ( 2,3-DPG 1 deple-
tion on osygenalion. 1• order to do this, the oxygen bindr'n~ ctjrves of
whole cells of Aeteroxy/ous sickle tel ~n~~ thies werl mrasured .
Under the corditiorn d sneaaureetent (T=~~S•, pH=6 .4, pCO_=:0) the
curves are biphasic . Samples 1s whieh 2,3-DPO is very low or aheient are
monophnic, suggesting that there is a di/fertntial binding of 2,3-1)P(i to
S and non-S hemoglobin in oells d hetero¢ygotes . The biphasic curve has
been coe6rwred in ∎ htanotbbin SC patient, under physiuloRic conditions
(T=37' . Pff=7 .4 . PCOY=44 mm) .
Camnon, B . F.
Biorhrnuca/ and Biophysical Rrsrarch Cornrnunicarions 43( 4) : 888-892,
1971 .
From the Dcp .rtmeat o/ Internal Medicine . University of Miami Schoni of
Medicine trd the Laborabries for Hematolo8ic Research . Iloward IluEhes
Medical lawtuse, Miarwi . Fla .
PHOTO-0XIDATION OF BOVINE OXYMYOGLOBIN IN
FROZEN SOLUTIONS. THE EFFECT OF REDOX ACTIVE
INORGANIC ELEMENTS IN MUSCLE EXTRACTS
' The probiem of oatidNbn of snyogfobin in aqueoui musck extracts
is oompka. 7This .rork, done on bovine muscle extracts, emphasizes the
effect o/ redos active wbatanoa in trrwck on the photocatalyttd autoxida-
tion reactioe, prrmarilr at add pH whera the conversion is from the red
MbOi to the brow . MMb. 1n these studks, photocatalrud autosidation
of MbO, -. MMb in fro .en etlraettt was found to obey 6rst order kinetics
as found for MbO_ ; of sperm whale and horse . Formation of MMb-Oll in
crystallized beef MMb was studied . Its pK of ionization 8 .9() is cknely
similar to that of sperm whale and horse and differs from that of camcl .
Among the unbound ekwrcnts examined M beef muscle estracts, iron was
ment responsible for o-0nidatbn of MbOi . El)'f'A i iron caused
further increase in os ation ; EDTA alone, however, caused pracction In
a refated esperiment, a n+etmyo8bbin cationic reducing agent wac isolated
from deproteini:cd horse and bovine muscle extracts by ion-exchan6e
chromatography
72
Assaf, S. A ., Bratzler, 1 ., Camtron, B . F. and Yunis, A . A .
Compararive Biochcrnisrry and Physbloty 39B( 2) : 395-407, 1971 .
Other aw'porr : U . S . Public Health Service and The Michigan Agriculture
Experiment Station, East Laming,
From the Departments of Medicine and Biochemistry, University of Miami
School of Medicine, and the Laboratories for Hematological Research,
1'oward Hughes Medical Institute, Miami, Fla .
INTERFERON : EVIDENCE FOR SUBUNIT STRUCTURE
Mouse interferon was purided over 300-fold by differential precipila-
tion, centrifuption,pe1 chroatato8raphr, and a new technique of ekctro-
fotusinS in polyacrylamde pe4 ; hwsaw Mterferon, tubiected to the same
espernneMa/ procedures, was purified about 1 S0Wold . Both interferorrs,
althou6h initiaNy honwee.oua on gel ehromalopaphy, displayed two
wrolecWar forms (A and B) on ekct~aphwtaia in pll gradients . In mouse
interfero ., Form B( isoekxirie poiM ( p1) 7 .35) had a molecular weight of
about 38,000 and Form A(p1 ~ 1 S) whieh waacq wlly active, a molecular
weight of 19 .000. PwiAed Form 8 was dissociabk into Form A, but the
reverse reaction occurred to a much lesser extent . In human interferon,
Form B(p1 5 .60) had a .wlect,lar we*tt of abort 24,000 and Form A
(P1 3 .35) which may caetaie up to aS% d the total activity, a mokcular
weight ol 12,000 . Both formsappear b be equally active . The dissocation
of both human and mouse i .lerferos into wbunits appears to take place
during dialysis vs . low aak . The data are Fonsistent with the idea that the
native molecule exists as a dimer of similar or identical subunits . Dimer
formation, which probably occurs within the ee1M, does not seem to lead
to a measurabk cooperative effect between the subunits .
Crrrr, W . A .
Procrrdlnts of tJk Nat/onaf Academy o/ Scknces 67( 2) :620-628, 1970.
Other a.rp.rfe U . S . Public Health Service and American Cancer Sockly,
Maryland Division.
From the Departments of Medicine and Microbiolopr . The Johns Hopkins
University School of Medicine. Baltimore.
PURIFICATION OF MOUSE AND HUMAN INTERFERONS :
DETECTION OF SUBUNIT STRUCTURE
Mouse and human inleriervns, viral-induced, initially behaved as
single mokcular ap .ties In the studies reported here . Mouse interferon
was purified over S()0-fold by differential precipiution, eentrifuption, gel
chromatography, and isoekectrie focwinghuman interferon was puriHrd
about 1SMlold . At one step during purification (boeketrk focudn8), two
forms of each protein were detected . These two forms were characterized
then as to molecular weight . Form A(mouse) has a molecular weight of
19 .000 and Form A (human) a molecular weight of 12 .000 . Form B
73
 (mouse) haa a molecular wei t of 38 .000 and Form B(human) a
molecular weight o( 24.000. These data strongly suggest that interferon
exists as a dimer ol two similar, perhaps identical, subunits. The convenion
of Form B inlo A is pronwted by the esposure to low salt . In the presence
o( 0.05 M NaCI, little evidence for two molecular forms exists .
Carter, W . A .
Prrpwntlve Biochiw+ltrry 1( t) :SS-7S, 1971 .
OtAwr s .pp.rft U. S . Pubiie Health Service and American Cancer Society .
Maryland Divirion.
From thepep .rtments d Mediciee and 1r8avbioloay,''f7re lohns Ilrpkins
University School of Medicine, Bakiwore .
SYSTEMATIC STUDIES ON THE BREAKDOWN OF p .d-DDT
IN TOBACCO SMOKES
Aldroro DDT was reeaoved i . 1968 frow the list of recommended
compounds for tre on lobacoo~ tieau st .dies ow the pyrolysis o/ DDT are
rekvanN today beeatre dtey throw N*A on the aneehaniatns of the reactions
involved I . the deBndaliow of peatieides Its tobacco smokes . This paper
is divided in/o two sectios . Seetan t deala with the pyrolysis of p,lf•DbT
in a nitroNea aUnosphere at 900' C and srbsequent bdation and identifica-
tion ot its degradation prodrets . Meehanina for the formation of these
compounds are propo.od and on that basL prediction is made on the
formation of DDT degradation s when DDT-treated tobacco is
smoked . Section 2 deals with pyrolytic degradation of DDT incorporated in
tobacco. Methyl chbride, yl) methane . p,0-dichlorobenzo-
phenonee p.0-DDM, traes-p„f-dichlotvstilbene. p .0-DDE, p.d-TDE and
p.d-DDT were identi/kd r the pyrdysispr~ucb Based on the type and
nature a( pyrolysis obtaiaed, it was condrded, among other thin6s, that
hydro6enation is one ot the ewoA in .portant rradions taking place in the
smoking of lob.eco, prtwrmabl~ In the burning zone itself where large
amounts o( hydroNee are availabk.
CJbpr., N . At1 ., DoaaaN,1 .1 . and Onborse, N . B .
dslrMrr tw TaW/orschoing S(4 ) :167-174, 1970.
From the Department of Cheartistrp, Now•th Carolina Agricultural and Tcch-
.inl State University, Oteeasboro .
•1.. ~. .r..+~~ earf.. 1 a. ..w b .. . ...d r r d.., .r u . ~. ....a.4
a. ~ .f DCT . Ceraqr ..y. " rarkY. Y .r /. - .
SYSTEMATIC STUDIES ON THE BREAKDOWN OF p .d-DfYt"
IN TOBACCO SMOKE3 : I/ . ISOLATION AND IDENTIFICATION
OF DEGRADATION PRODUCTS FROM THE PYROLYSIS OF
p.6-DDT IN A N!TROOEN ATMOSPHERE
This hru rystewdic i.veatiptioe into the breakdown of p .d-DDT in
cigarette iwaia .Nrearo and sidsatream wmokes was started in the fall of
74
1967 . Two resultant papers already have reported the results and mechan-
isms of the breakdown of p,l ;-DDT in a nitrogen atnasphere, and in
p 0-DDT treated tobacco smokes ; this paper presents the methods em-
Pioyed in the pyrolysis of {t-DDT and the isolation and identification of
its pyrolysis products. p,~DDT was pyrolyzed at 900' C in a nitrogen
atmosphere and the pyrolyais Products were collected in pentane at -80' C
and isolated by tractional distillation and chromatography on alumina and
Florisil columns . The products isolated were : P.0-DDT, p,kDDE,
p .d-TDE, bis (p-chbrophenyl)ch{oromethane, bis-(p-chlorodtenyl)meth-
ane, p .d-dichlorobiphenyl, a p-dichlorotolrene, hexachltwoethane, chkmo-
benune, tetrachloroethykne, tricMoroethykne, carbon tetrachloride, chlor-
aform, and dicMoromethane . The soiid (first eight) pyrolysis products
were identified by gas chromatography and infnred .pecY raeetry, and the
liquid (the last six) pyrofyis products were identified by gas chrorea-
Io6raphy and colorimetric tesb.
CAopr., N . M . and Osborne . N . B .
Awdyrk.l Cltrrnistry 43(7) :E49-SS3, 1971 .
Frons the Department of Chemistry . North CaroGna Agricultural and Tech-
i ni :at Stale University, Greensboro.
EXCRETION OF NICKEL COMPOUNDS BY THE RAT :
BLOOD AND URINE LEVELS
Nickel and many compounds have been shown to be carcinogenic in
animals . Since the route of administration does not seem to be important,
this study was inaugurated to see whether nickel solubilizes in tissuea and,
if it does, what constitutes the route and rate of e>tcretion from the
experimenul animal . For this investiptiee, male Fischer-344 rats weighing
approaieutely 260 ` were divided iMopar pa of three each . The treated
rats were injected intramuscularly in both hind legs with 30 mg of nickel-
ocene, nickel acetate or aiickel powdex, aN suspended in 0 .2 ml o/ tri-
octanoitt . Control animals were injected with an equal volume of the
vehicle onl~. All throe - .ickel powder, the acetate, and nickelocene -
were rapidly solubilittd . Within 24 hours nicket ioes were detected in
moderate concentration in the urine and also in the blood during this
period of time . The serum pr'ote.ins were separated ekctrophoretically and
nickel was found to be bound to the albumin fraction . For detection and
analysis of nickel in biological material, a aolorimetric method was em-
pkryed using Quinosaline•2,3-0ilhiof as the reagent .
Chen, 1 . K. M ., Ilaro, R . T. and Furit, A .
The warw+ann Journal of Bioforr 29(1) : t-tS, 197 1 .
OrA .r .rpp.rrz U . S . Public Health Service, Carrie-Baum-BrowninR Trust
Fund and the de Martini Estate .
From the Institute of Chemical BioloRy, University of San Francixo, San
Francisco .
75
 X . Epidemiology
PREDICTING LONGEVITY : METIIODOLOGY AND CRITIOUE
This book has two main purposes : 8nt, to advance the state of knowl-
edRe of the methodology of longevity research and sec,ond, to increase the
understanding of multivariate data analysis methods for social research in
general . Aging is a process that iaternts aM of us, but the technology and
methodology necessary bsdeq~ . " study this sub~'ect have been woefully
4ckint for years . In this boo~ about lott6evily, chapten are devoted to
Review of the Literature ; Genetatiag the Data ; Univariate Procedures ;
Linear Discriminant a .d Repeasioe Procedrres ; Factor Analysis ; and
Nonlinear Procedures . The researdt reported here was undertaken in con-
nection with the Normative Aeiag Study of the Veterans Administration
in order to identify predictors of aging and longevity which could be built
into the prospective design of the study . The resulas showed subitantial
change in sipri/ka .oe of indepeadent variables as one went from univariate
to multivariate analysis, and froru linear to nonlinear analysis . The substan-
tive Andinp saaest that physipl predictors are tnore important than social
predictors to account for advanced ksngevity, while the contrary is true lor
moderate longevity . A maior problem is the control of the secular effcct,
and a secular-free, yet "one shot" design, is formulated .
Rose, C . LL and Be11 . B.
PrrdkNnr Lonrrvby : Methodoloty and Critique, Lexinglon, Mass . : D . C .
Heath and Company . 1971, pp 1-265 .
O/Arr ..rp..tr National Institute of Child Health and Human Develop-
ment and Normative Apn¢ Study . Boston .
From the Veterans Administration Outpatient Clinic, Boston .
COMPUTER BASED DATA ANALYSIS IN LONGEVITY
RESEARCH
This paper is primarily concerned with the application of multiple
~roadrres for data anal to a jiven data set in order to maximize the
aeard+ (or meaniet." The data studied evnsisted of the life history in-
formation gathered front nest of kin listed on death certificates of 500
while male deaths in Boston during 1965 . A total of 70 variables was
analyzed by zero-order oorrelation, multiple re6ression, linear discriminant
analysis, factor an.lysi., nonlinear discriminant analysis, and nonlinear
clustering. The rrsults show a substantial shift in significance of independent
variables as one proceeds from rnivariate to muhivariate and from linear
to nonlinear analysis . Variow perUub.tions in such studies are outlincd,
such as the effects of sectilarlty and bimodal distributions . Although social
variables are more vulnerable so seeularNy than physical variables, there
was some evidence of their being anore important than physical variahlcs
in accounting for moderate longevity .
76
Enskin. K . and R.,se, C. L . (Grantee : B. Bell )
('ompunrs and Brwnedical Research 3(4) :2E9-329, 1970 .
OtMrr support : National Institute of Child Health and Iluman Ikvelop-
mcnt .
From the C,encsce Computer Center . Inc., Rochester, N .Y ., and Normative
Aging Study, Vctcrans Adntinistration Outpatient Clinic, Boston .
PET ASSOCIATION WITH SELECTED HUMAN CANCERS :
A HOUSEHOLD QUESTIONNAIRE SURVEY
Two questionnaire studies, one done in early and (xte in late 1969,
surveyed the degree of fanwll exposure to domestic cats, doga, and para-
keets in 530 selected "indea cancer households and 530 control house-
hdds . Because lymphoma, lerkemia, and sarcoma reprcse nt the types of
cancer in animals known to be eaused by the C-type RNA tumor vrrwes,
"index" cancer casn were selected from theae dia tic cate~orin. In the
early survey, failure to match sets for duration 91 residence kd to a bias
which accounted for ae rewt excessive exposure to cats in families
t with Iymphoma . This sampling bias was corrected in the second survey .
Overalt, no difference in exposure to ea1s, dop or parakeets was found
between the indea patient households and matched control households . No
statistically sisni&ant diRerenoe existed in the number of families with
these pets, the average number of pets owned over the past decade, the
average number o1ycars that pets had been owned, the degree of handlin
of pets, or types d'illness In household pets . No differences were foun~
in the following eaditions of cats : abacesses, fever, fur balls, lumq ,
bum , mali6nancy, worans., and anemia . Also, no differences in similar
itions were found in . Of the family members with cancer,
70-R0% did not own cats . It therefore unlikely that cats are a causal
'ador in the 6enerality of humae cancers .
Hanes, B., Ca.dner, M . B . . Loosli, C. G ., Heidbreder, G ., Kogan, B .,
Marylandcr, II . and Huebner R. J .
lowral o/ the National Cancer Institute 4S(6) :1 I SS-1 162, 1970 .
Ot6.r .orp.rt : National Cancer Institute .
From the Department of Pathokogy . University of Southern ('alifornia
School of Medicine, l .os Angeles .
CURRENT INFORMATION ON FELINE AND CANINE
CANCERS ANI) RELATIONSHIP OF LACK OF Rf?I .ATIONSIIIP
70 HUMAN CANCER
It is most unlikely that cancer in cats causes cancer in man . While we
know that the domestic cat has a high natural prevalence of lymphoma
and of detectable C-type virus expression in the form of antigen and C•lype
particles, epidcmiologic and limited immunologic studies to date fail to
77
support spread of thcse feline C-type tumor viruses to dog or man . Whether
these viruses spread even from cat to cat under natural condirions is m» Active Projects
established . It appears that, under natural conditions, feline C-type viruses Following is a list of the principal investi6aton or institutions of
are inherited as indigenous latent genes which may activate in the fclus or projects under way or adivated during the year ended June 30 . 1971,
later in life . The susceptibility d certain human cells to in virro infection together with the respective project 6tla. Completed projects are listed in
with these viruses does not imply infeetiou in riva, However, this possibility a later section .
cannot be denied until inunMtwb- e swdies are done with serolo6ic reagents
of greater sensitivity and speci(k~M~, Tlle domestic cat nuy prove useful T'ZLIHC1rAL INYS4i1CATOti
oR IIn3TITImoN ntoPu :r ttn.tr
for study of the effects of ehestit .it, inddtr; those in the environment .
The newly found RNA-depeade .1 DNApd7we ras= may aid investigations DOMINC,O M. AVIADO, M .D ., lro- EReets e1 aioeliwe .M eipreue snwliiy
Irs .w of rArw ..roiorf. Uoivenil~ of On OlY/ostffik nItC1YlNYns in /Af "
in vitro d products of the felise C4ype .iral Kenome activation and its hewwsylswia Sctrool of Mediciwe. Mil- Tole.aaoe o/1Y.p to sosaoco siwte wit•
governing nwiecular mechanitu+r . .de1pIN. . special reterewoe to Nlw .ow.ry c+•pley-
Csdwer. M. e . fewr awd .ascvlar ocNwi.e ksioru
lownof o/ the Nationd Cancer l nstlnae 46( 2) :2 S 1-290, 1971 . bre.ctrovrcalr eAee4 of eipretk uwote
STFPHF.N M . AYRFS M D ., Di.enor, Measwwwewt of dvedar-arleri.l wilrot{ew
OtAar oaPr.rtr National Cancer Irtitute . CrLet..Jw.owrr I .~Y aeorrt. y . Viw• Ii/le.enot by pf ckon.aMorryAy
From the [kp~r,mcnt of ratholo~r . l/niversity of Southern Calirr .rnia «N'. ~la.~ .l, Nrw as CMy. Tha &WusMa cq .eNy of the alveolar
School of Medicine, Loi Angeles . a.ewMawe iw rYhns .ay ewyAysnwa
Rebliow of .ir pl ion b de .elopwne.1
o/ clrowk prlw.ow.ry di.case
TAc eReesf of saeasYred uwdl awrowNS of
carlosytuwoalobiw on cardioavir.•
lory fh.aiow im wuw
RELATION OF POVERTY AND RACE TO ANTENATAL Ef.et of lobacoo rsollna and coeYSY.My
INFECTION dr loNYtieo on twmta nyocsrdial
swnabolww
More children of poor families die during the few weeks surrounding
birth than do children of the non-poor . While undernutrition is a demon- qSCAR 1 . sALCNUM . M .D . N .uiq. Desenwiw.MS of the eouna of ewnpAy
Iro/rur of Mrdic .w. . Usivenily o/ sewa-lrowcleiti .
strated component of this excessive perinatal mortality, the present study SoYlAec∎ California 3e1od of Medi-
shows that antenatal infection is a/actor also . Anal~s of 1,0r4 consecu- eiwe . Los A.etele..
tive au~b on stillborn and newborn infanta in New York City showed FREDERIK t! . •ANO. M .D . raror Inleracilew ef .Mr.es wirA wweofs of IAs
that 27% of these b .bia had oon6e+tit .l prtetunonia or sepsis (or both), od CANnw .w. DrFawsrwr of rA .- nqirNory trtret. awd .w .e.lyfis of Ilte
primarily rebted b the aspiration of infected amniotic fluid . Infanu from f.coto~~, Tbe lobws 11opliws Uai.er.My eAecb of environneMal vari .riowe ew
Schooi ol Hysiewe rJ Public HeaNlt, the rwetiow of the rwucociliary fyanw
the ptwrest /nnilies had the IIi ;heM petcenta,e of chorio .rnnionitis, ptrcu- ttahiwwt .
nwnia, andspkni1ia . With each hRproremest in economic status the rate
tlENIAMIN fiELL M .D. DlrreN~ o/ Social PredinaC of Iayc .ity
of inffaetst.tiow decreased . Ra1a of ie0a.wnNiotl were highest in blacks IAr Nriw .ri.e Ariwr Snidy, VA OM-
awd lowest is whites : P.etb Ric .ns A .d rslea jtut .bove those oberred rekwt Clirtie. [kwto. . (LiNtled t•w4er
ia whites. Ida .es with a.trt+owie ..d e.htual evidesoe of Infection had a L. Rosc. )
mean Seatatbn.l ye d 29 weeka, and tho.u witlw.t Infection an age of SAMUEL IIELLET, M .D. . DMecAsr, DI- 'T1o ettett .t sicpiee on cardise ir.it .-
•isiow of Crliolorl . ftKadettibia Ge4' tiew M tlre y .esewoe of rescryisie. ad
32 wtxks . The infactcd infanb .rete pot Rtartkd in po..th, but they did
ersl Hoyird. rwiadclpRi .. the etees of wkotiue on co .ow.r~ blood
exhibit adrend4and abnorwalitb• adrenal 6lands were 19% heaner in (lvw i. dlop witA ooroarry iwsu/lkiewcy
I
the b(octed f.><ants, o..ing b Ineteared qbplasetic nwn of Individual Ell.qs of sdoolls ow the wnorpAolottr of
cells in the permanent aose d the dawd . wnrry trrNrks and sor1 . ; Aleinolrlk
dsals of alootlwe ow twww .w .wd .wi•
N.rye. R . L . aed Rlaee, W. A. sad /Iwse . ; eAecrs of cewNow of
Tlk New Ewgf.pe/lowrwdo/ Malkiwr 283(/1) :333-360, 1970. fw.liwR ow seeww ctYSkMerd k .els of
efr.nie fwwl<en ; rhe enecls o/ cipre/ue
Osll .r o .PP.rtr U . S . Public He.Nh Service . s.woLe on /re . fany acid k.els of suts
i.cts wib myoc.rdnl in/.rcuons
From the Dep .rtrncnt d Patlwlop, hyulaylrnnia State University College The eRM of wieotinc on various p .rwn-
of Medicine, fkrshey, and the Department of P .thology. , Columbia Uni- Nerf O~ c .r'dq..1tYIN rYrKIMM
reryhy College of Physicians tind Sargeons, New Yor# City .
79
78
 Bing SAB
FRINI :IPAI . 1N V F_`iT11:ATOR
OR 1NSTITUTNIN
WDi/D1 .V RHAaAT. MrD . rrnfr,sor
.l rAr+"NV. So . 1 o.ia U .iverai/r
icAa .+l n/ MeAuinr . i~ . 1 o•is.
RICHARD 1 . RIN(l . M D.. rro%aw. ./
Mrfirl/w. U•i.ersiry of Snulkerw C•li-
forwi• School ./ Medicine. / w AMeles ;
Rrwn A Awriw. ('slil.rnia lwMihA•
of Ted•.IoRy; DMr. /w YI CirIMlogJ
..I /auawrn/ Mdiciwr. HsMiwpoA
Memo.id HoyMd . ts.aAe.A Cal .
R1O•RESEARCH C()NSULTANTS .
1NC . . CamMidge. Mas. .
11sO-RESF.ARCH INSi17UTF, INC,
CaanMiJv. Mau.
RARRARA R . RROWN . M D . CAir/.
L'.prwwwud r.trAawr .. Verersns A,-
mi.niraliow Noyilal . Se'ulveda. Cal .
∎RUCF F . CAMF.RnN. M D . f N D .
No .rl N.[her InuYew. UniversNr
of Miami School .f MeMcine . Mnwd'
WILLIAM ALVIN CARTF.R. M .D
AaNu.M rrofiuor of Afrlk/wr ZJ
AIKIYaWIor/ . The )OIIM HopkiM U&
versiNf School of MeJiciwe . RaNiwsore .
ao
65100 6868
FRINCIFAL INVESTICATOR
FRA)El F TiT1 .E OR iN9T1TU1r10N FRo16Cr TI fli
The swecAanism of nicaiee-imhaeJ rc- IACK CNALON. M .D, A .uLrru h./ei. Rd~ .f ai .otNl& ekroiA, aM
kase of eaKeholamine . anr of AwruArMeloa . AR+a( Ebwein b /r~/.o•ry e'
ERecc ./ eie•re11e ueokiwg aed nicainc Colk" .1 Medici.e . New Yoet City. /~Mf wwosplfa•aRionsor-
.o Ihe Ailpsilioe of ealeaAolsmMea in
.e ~~ of the u•edeaReo.-
ea/eriweMM c.roeary •nay ierdfi- e~iid Ir
eiewef
SANFORD C110D06H. M .D_ Ass{awr Ctro.k M~o.eWla eaIMke
The eMed of rwokiry on 1Ae coronary h./rnw ./ MdiNnr. T.hs U•ivereNr
Mo./ R•W •wd eerlais PAa.es of uYu Sch•d of Mdieiwe. meal.a 11•MW"
earliel wel.~olism iw pMiewts wish srrea Mwrios Sepl. M.D. )
M/tti•adeeMk a STFerle .ave cardix .
radn Afaene
SNrlo M e•Rdar aysio/oRr of hesrr
Craighead SAB
NAITER M. CNOtRA.
as ./ CienMMr, . N.rN
Fw .D. "es-
C•rdi••
The dwdMMm of DDT . TDH awW Did-
a i.Nrs.
.Nrs.ww•ai ••/
aa•ada arR.rd s~.M TeeR.ical Su1e U.isa.~tFl, eiAeRet•w • .w[M w
Meaa.rsne. .f ooro.ary blood /low by OaeMeeo.
aeese .f cdcaive aRwrwl. CNARLlS 0 . COCHRANl . M .D .. The .•.wb. .f Y+•a.•leer iRb ., d
The efee/ of am•IIwR on axowarf liood ScrW. 1(.Mai~ e~ .aA r.rwb• (i...
Roer i. ptleAe srirL •eurio.ckrouc
beaet diatw a.M IAe eRM ./ swcdiwe
.w sr.rye .f awii .es i. 4ear1 swwck ALLlN Rran
1aR . COHEN . M .D. A.iw.r R.k of IRa Mw•. •L.Nar .•ce.pb .M
f3Ne N Mrliriee . U.i.asl/I et i.IRn p.tlawli.. .f as.obfwr•
Me•swawreM ./ o•ronarf blood Ro. .iNA ~ C.Ww.I• S•R Fr•.ciao..
• sysless sni.R ooi•eiikare cm .MiwY ;
IM eRect of aticorwe ar.d cA.w~e in ' 10HN !. CR~A/OH
.~l.AiD
.~. M .D. AandeN Ri•Lp .d a*/•/:(Ye aRsels d rea,ir•-
kar( rale on cardiac wwuAolimn aud IR1 ea/ ..o•«wie Hr .aes in wp•
re1Nel srAiests Va MeAk•I Sc~oe4 R .rR.M... 1admm of Mrr nsFir .~ :•y u•h
Slr/Ks on eNdiae rneiabollaw wML spe-
cia/ referewce lo mfocarJ.al awosis EFMReiW aR tr•rf.rwnliaw W erd-
The iwRrewoe of aicolme aw litiid cwnp+ . e+w /d.e1b. d Caf7e RNA vh. .a
waw .f .a.cular wall uf tbe eo .wurr
.esaels ; Ms e/lect on Jnudwlww of cw T. TIMOTHY CROCKER. M.D.. M Rie1Mk .eMvMr of MMoa . .eete c•r
owary Ro+ Iraa .r M MrhrMr . U.i.esilr of C•li- Ae.q1a .O resFirtl .rY e..c.a•
foraii• School of Melid .e. Sr Frr .1rft/
Evalua/io• af The goldcn Syrian Aamrer ciao. . .Aia~
as a wwdel ..imsl for Iossceo rnole .~ie Mdr~ ••rl•e
id.ltlion M .dies freee•Ii•s er Kvarl ./ •honMl a1MM
al re~ir•IM1 ~M••r MeA.w/ by
Cowprk•ft of Nretl mouse stin e .po ~• ~. c•wAesds a.A Mww
awe 1 . w~Ao/e. fresh cipreoe smole (a)Flr•.•
•d w••se ski• p•i•ti.g vri1A aw.ole
eowdeWAnea CARROLL E. CROSS. M .D. ArWrN ERae1a N etN .w.te on (Re F•Mw.
M/rau . ./ hwrwd MNkiwr. U•ivar- a .rr iwl•t fwewr
Nkolwr ••A wwfinR eReds o0 ekcdro- eiy of CaW .rwi• School •f MeAicYw
er+ce}hslo{raw correlucs of beAa .ior . D..is.
ew.oaie.al reyowsiveecss and vilaal
percepUow M cNs IOHN P. DlI.ANEY . M.D.. fif The 1•Rrn .ou d•iwdl" aw1 oia(i.a
./ SrCei7. Uai.aaily
.D,AawkhNe M circ+rlMian ia11Ne Iwa liaab
Esp/orMiow of 14 Jiffereaces in FF( : of Mi.wala, MMwFoli..
ptlla.- .rl1 edive rNe arrelalcs in
snsola ara/ wo.aeoler saAjeets ER.Aa .f /A•oe. a~wei~e a.A wkaiwe e .
EDWARD F. DOMINO. M .D, ftiNrr
.er .f lArrw.r.loRr. U.i.aul'11 .f Ma eenlral aer .ew afnem
Sptetr .pAo/orwepie asay of carbun mon
o .iwk aM wNrie us«k Aemoolol„n MitYRaR A.w Arlor .
NfSRT1AM lICNEL . R~ . . D.DS., Di- M.IaMIk kMre./MIweYM Aerww . ~ .
I rrrur. IwrMwr .f Sr+iw.ql.~kr/ Rew •aec. ea•b •d Ma 6. .w awowis
Onvoppewy, and /h •mivirsl acliuw of in-
/ec{aow .r.rcA. Scie.ea Resowoes F ..da11M. Mald•lie s*/ efhr-yeMlaRkddiewskal
1M .1eA.vR Mar. iMeerelali ..N11Fa ke( .eew wSaec.
eaw•Le •.A 1Re Mrw•w wrow.
el
'
r111NCJFAL INVESflCATOR
OR INSTTTVTtOf7
CARt.TON K . ERICKSON. hl D . As-
s/,.ewr Irofrs.o+ of rArw.erofory sw/
To ..rolettf. The Universily of Kawsas
Schod of tfwwacr. Lawre.ce .
WALTER f/ . ESSMAN . t•w D. Pro/es-
.o. of LfcAolorf . Q.etne CoNew d
the Ciry of New York . FLtWg .
THEODORE N . FINLEY . M .D. D6re .
rr of rdewwy RrsrrrA Leio..MrT .
Moaa Zien Hoyiral . Sa . FraecMotr.
( Forwerl? a1 The U.i.ee.Yy o/ New
Mesioo School of Mdicine, AIE+NreT-
!+e• /
DARY D . FRIFDMAN . M .D . Jmwie.
is'Rilriw/dec4r . Kai.ee Foa.ilio . Ra-
eercA Inrnwe . O.tla .dL Cal.
N HUGH FUDENRERO . M D rv.
/rs .w of M.NrMr. U .i.er.1t7 J Ca1L
foe .la School of Me1k:.e. !.. Frsy.
cieoe.
MURRAY 11 . GARDNER . M .D . Ass
riw h./rssr of lerAo/oly. Uni .ersil7
d 3wtle.a CaWau .r Schoat of Med1-
csae. t .. A+r.Ms.
DAVID M . OOIDtNRERQ1 k .D .
M D, Aa rriw lh+ki ..r q IrAe1-
. U_ .Lar+MT 11 ..M! Sd
e~wo~e. Ce
LEONIDe OOI .DSTt'1N . Dsc. Re .
awcA SrMnNU. Ic.w of Reurt A
1. Nrwlop . .I lslcAYrvT, New lar-
af . NewqsrcWtric 1.wM.k Rhoe-
Lw .
)OSet•H 1 . OUARNERI. ht.D. . Dr+r
sor. IrAwewry Ae.ei/olo~ tAbe*-
1oef. Deprrw.r+tt of MrNc~nr . 3a1wt
Vi.oe.l H.qital Wo .ces/ee, Mtw.
(IniMea .nder Orde .e A . La.eewe>t
11 D .)
NORMAN W . HEIMSTRA. M.D, A .
.erl .rr he/rsser o/ r Adery; Dl.ec-
Iae . D .l ..v I/rA. .ior Uni-
versiwf of Sourh Da&wa- v io ..
fTfIOJE(T TTTIJE
Mecfr .ienl of karninA facililauon by
•iwtti.e
Swdies of nicaine aclion uoon menwrr
cn. .olidation
Sea LaiwaR A . l .
Clrroc4.aks d .noAers and nornwwA•
en
CoMqeg aaR.odies in eelslion lo IAe eli-
ok{T of ewFArsnna
An evidemiological researcA program on
IAe ei .o/oRy of M .aue c .ncer
Hesesar .w.~ieMaiow Mud .es .wh bua.sn
luy cancer
A r .1y of bioelectric dilfcrences bet.een
niodlne-h.bilwled a.d eo .lubitwled
ory..iws by we of Aitf ewertr Pb-
piMe cwqouwde
TUe eRect of c .K ..cl ., ..nofe on the Im-
rw .wolo~kal sd rnrlabolic function of
aleeolat rrsacro96aRcs
E/<eete of .wrolind o8 wslained perfonn-
anoe Iw a sYnelared driving teN
An M.esliplb. of The relarion .Aip be-
L.ew ssndMy deRrivuww awd Y .eu
PJacte of YwoLlwg ew poiNeral vnusl
acvlly
Relatiews\ip hl .eea +poMeneous smo\-
i.lt and rndrocd mood c6ange
m e3
rR INCIt•AI . IN V ESTICATOR
OR INSTITtmON
IIT RESEARCH INSTITUTE, Chicago .
SHIRLEY L . KAUFFMAN. M .D .. Auo-
C.re Mrof.uoe of rer4afotr . Doww•
I
slne Medical Cen/er . Sule Uwiverw2
of New York . Broodlyn .
AARON 1 . LADMAN. nr D., ho/rser
aod CAd.w..e, tsrr..tewnr e/ AnaN-
mf. T1e l/wiveaile of New Meake
School of Mcdiune, AR" .erqre . (1ni-
Ilaed uwAer Tleodore N . Fitler. M .D .)
1 AUL S . LARSON . Itit .D. Higstp rro/a-
sor of IArmerologf. Medical CoMqt
of VirRia.. Ricttrwa.d.
GUSTAVE A . LAURENZI. M .D. CAMf
of Mrlkiwr . S.int ViuOtrM Hoqilal,
Worcester. Mar . 1Now M NesMOS}
Welk.ky Hospital. Newtoq Ma. .)
IOSErH M . LAUWERYNS. M .D., fw.D .
rro/ra .or e)rdwris /w Mtnwree/k
Awoe.ti; CA.rww, EirnMwwrd
t..AeretrF of Cr.Mer~rbrseraar~ ead
t:ewiw Pathology. WrvertilF ef t .er-
.eq LerveR RelsiwM .
RICHARD A . LERNER~M.D .. Sce111•
Cliwlc end RrsrrcA e .wdsrbw, ta
I )ellat Cd.
CECILE LEUCHTENREROER, f1t .D ..
Href. Drrerrwww/ of CyrerAensisw).
S.ise Inw ./we for F .reriwseaal Caw-
« r Research. IauYw . SwNarrt. .d .
.ROJIECT TIrtJ;
Rioe.ce~etic .ad ewdocrine drecte of
slres n.d tlseir iMerrel.tiowaMpa wi1R
the et acts of lobeceo ssnole inAalabew
Effects of tob.ooo rwot<e inA.lalion on
.Itedv rnacropAaRes and IunR sur-
/adw i . RnMed w.odeb
To Isr.eMiRMe the R .tlacigcoesis of we•
1A.ne•Idr.e1 IrrIR .drnanas in mia ;
yaciRawMf IRe ideaificalion of tAe uRs
wRicA Ri.e riee to the adesornas. sad
Ne R.e sumtw.l cAanRes in IResc aMs
irri.g .eod..l.
C.rci .osew-brAaed nllers,liowl iw the cell
efck d IAe Type 2 alveo/ar eoilrelial
oeR
ERetl of elRne/1e ewso\inR on IiRids .nd
snorFlro/oRy d alveolar Lnisy w.alaial
od snaeroRiyes
tlisw for rub/iealion of a bool eo
~dbiologic ayecte of /obacco and
The ptrille deet d 1, b .ooo tewoAe awd
oioe/ine on a.roelie .cid rwetsd,olirw
SrMidF /o . FrrblkNbw of a rppIr .neM
Io ttte w.orwrql., 'Tob .cco'
See Owrweri, 1 . 1 .
The 1lwyiaka of 1\e lunc ; their rok in
Rrid trasn'ort and ckar .nce of air-
•nrq /iN1 .CV/ale rnatler
Slydia oo Eer.Menl viral IntMiow
A eered.N1 t,hlolollkal . ey/C"rea! awd
t .scAfswkal MrdF of The Irae~eoerM•
ciW u .a of win . .roeed to ciprelle
.nmlie
Tr iwNrr.INMw belween Intauew vlrrs
Weclis.R earowre le ciearet/e .wwl.
. .d etAee factors In the rr .ek+pnenl
of wlw.eoarT and b.onAial ksione in
w+ioe
 Loosli SAB
rRtNI :/FAI. 1NVE.STICATOR
l/R INSTITIrf1ON
l . P . LONO, rn D. . Lole..o+ o/ lAer-
n..colart. Slre Ua.ersity of I ..re
Colk8e of Medicina, Io+ . Ci1y.
CI.AYTON O . LOO6L1 . hD. MD
N.WnRs /1o/ia.er o/ MedkMe ..~
te.w Scfool M~
.d1eMe.~L.w/~AaRdea
KENNETH MERRILL LYNrH, MD .
SeD. LL.D. CArsevMor sI r
.o. En.erker e/ rrA.MRf . Mediul
kp o/ Sorlk Ce.d1.s, Clarkre. . clo
a.ecialoe wkk Feeds A . Mclea. M .D. )
INES MANDI., r+. .D . A ..Irw hr/e.
.r ./ Ibr#endrrf. C.M .p of Hri-
cie.e ..d !ws ta.a, CoM.N. U.1.ee-
sMr. New Yor\ Ck1 .
Meier SAB
/OHN H . MANHOLD . la ., D .M D, rro-
/eunr .n/ Di .rctoe oJ ror .wf
Orrf D1.rww(s, New IerseL C of
Medicine ed Den/is", lerty City .
MASON RP3EARCH INSTITUTE,
WoeceMV . Mea
DONALD 1 . MASSARO. MD . Ao+ciue
f1'o/ew+ o/ ALdic/ne, OeerRt WaeR-
InRlo. U/~Lee.Yr Scfleol d Med41 .r,
W.rlw4eq D. C .
HANS ME1ER, D .V .M . Sre/ ScMrIM.
71e l .clson I .Aor.wr. Mr Herbr.
Me .
Mll :k(r .1oLOOtCAL AS .IOCIATl3,
INC . IIMdedk Md .
RICIIARD L . NAEM M D . h+/err
.wI CbLww . D.PS+ nvr o/ rrAel-
ooy, h .. .fl .sni. 9w Uo+wrs .1 Cd-
hye e/ MedieMr . Ner .~tr
94
Lynch SAB
rROHwT T1TI .R
CawWaive cylocRemicel, cylo"icel
and MMologKel MrdK7 of e.rl1 tnecH
of eilardle smoke Lhnle, g .s pA .se.
emwMMOeMS) in rwice and in Insue and
orps eultures (rom mice and lbum .ns
Caerrb.uwlar eReela of nicoline
F.rt•M• Mrdin eo .eerninR syenPelbomi-
wMie .ctioos of Riicoune
Ibw/@ re .ctioMs to .irborne (bemi-
aMd I/IO/ogKd yenu
FAni. .oeaal fs(ioss and ry~rnoa . .r dis-
eer : 1 . Aebcsao. dwl : 11 . AM.eMUS .wd
e.-oeeMoRena. vied end eden.ic.l
Tle rde ef brisdlwy e1.Mare InliAiloe
Idde•eI i. Ile eUdolf of Fulrnon.ry
emaolses,.
EleMdflic leeatdo.o in 1!e etioloql) of
pubme-7 e-0t'eemi+
SWdL of the pwForled retNio .rskiR Ae-
lwees a.okrwR Yd clenRes in 1wn .n
oed IisMr In rlvo by roWine w,icro.-
oW, di/rienli.l Mrinin/, and micro•
re8"owneue snetbdr, and furlhet M.-
UMtal ea.wwliow of I .o series of
dMW'resenlyI. 1!e principl in.es/i-
We+ 9 le. .crio.
Medrlnl sed biolollicel evs0u .lion of
wntl..ical de.ion for the noni/o.ed
ler.oos aaeoLeloo ~ds lo
CowelprNM rscW pevek.oc of clronic
w.«.'wr
Al.+dr oslM : lrolei. sad RIKo'rolcin
hia.f'wlkala
RoW. qakesis ed acrelion by Ire-
ckal mecaee
Owoarnreais 1 . IRe raslil : Renelk sur
oeMiOiW~. .enkal Inw.assiow of
vir.a .nd e .viro.weMal in/uewets
/n r4ir Md MI vlro Mrdias of Ike ln/la-
ww of .aor .ow waeride on .crww
Ilos o( {Men( C .IWe RNA .4u. .e
Srookaq .wd 1Ae pulmons.v bbod .es-
seM : e 9uanlilsawe . maIP41oloRic Yudv
I 85
1•RINCJ rAl . 1N V FSTICATOR
OR INS-11ITUTION
ALRERT H . NIDEN . MD, lro/easor of
Afefwinr Dirrcror . rrln.owrj Diansr
Sr- n w. Dep.rtment of MedicNre. Tesn-
~1 1 tniversily School of Medicine .
Ffrl .Je/0.ie .
JOHN W. PARKER. M .D . Auarlw
rro/e,ior of r.rlloloRS. UmivessM~ of
Sowbeew Cdifo.ni. Seoaod of i/cdi-
eiwe, Loe Anqeles .
MARY STPJIRNS rARSHLEY, M.D.
AuiiLn/ rro/easar of Anwo_sn~ in OI'-
.Kracs onf Gf .'doltl. C•~M •e
rfy.itiw .M 5++~cowa. CoMrli.
Uarverrly. New Yoet City.
3 . N . /RADNAN, M .D M .D. f'ro(es-
.w ./ tArw ..eoto~~. ~~lo..ed Uwi..r-
Wr Colkp of Medrd.e, W- I.dreq
D. C.
rROCPS3 AND INSTRUMENTS COR-
PORATION. Rrooklm N .Y.
WILLIAM REOEISON, M .D . M/ewr
.wI CA.Mnree . Drr.nn.nsr o/ Medfeef
Oneofop . Medical CdkRe of ViqideL
Riclwod .
RORPRT C. ROSAN. M .D . Asoeiw
rrde..ar o/ hdlelop .nd redirrict,
31 . Law Unive. .Nr Medical 3elted.
S( . Lo.ia
CHARLI'S L ROSQ A .M . Senlo . D1rr+c-
ror, Veler .ru AdminiMrMloo OWpMieM
C/i.k. SoMow .
JOHN R. ROWLAND3, M .D., Sr/
SekN1M. Sow\.es1 Reseac! IwMi1.K
Su Antoeio. Tea .
ULRICH H. SCHAEPPI. M .D. DLeAw
of NerqA .rw .oroloff. M .ee. Re
a .rc\ Inne/we, Wo.aeler. M .r .
rROIECi' TTTtE
ERecu of ciprelle Mwoke . drnRs and woa-
iotis erwes on Ike lermine1 .ir.rers
with apeei.l reference to the lermi ..l
Ero.cliioles
MecV.fMSw of wwppresaioe of eell .l.r iiw-
∎wnilr by eua .oRenie Rrdroe .rborM
ERect of tiowMR .crs of losecco MnoRe
ott awr.w .l and rMdign.M bwnew re.-
FirMOry erAreliw . In vitro
ER.d of lols.ooe awwle on rwr.n.l ano .a
111ea tI.MI.
E1ed ef wfeaaMe ow be6 .vio.
1'aed d .IooUwe ee bek .vior and ke In-
b.el/ew .kR drvp
C.a.Me .disM of .w eaperin.eM.l drvfa
foc Mre .Noeed eapwMe of rn .R ea-
Rala.eMN ..iiwNe to tobacco swral .
~dnio .
RES furlelior; iwlor, indudiow and gro.1`
Mo.Aoprwo..ry dFqi.sie
Se. .el1, a .
A d1a1wiIM/ L..MI~MIow of Ihe nMrr* of
Ut n.atbw bl.esw!ido~ kal waerl-
u/e ad .area~eck eowuwi.. .(a . .i.y
e1.cVew pr.wy .elic .e.od ..dneo
qlkd q.eMe.eoRic 1ccMi~e.
L .erlplb. ./ 1he direct Mlwwlaion of
~aef./Mb11e nerve krwriw .ls !f
NIoMMr aiwl.iMrNloo to roM. .l e.es
of 16e .aa 4rV : eff.cts .pn I:h(1 and
ewe.ashk e?wem
C1 .~yse 1∎ e190 and eervlo. /nsuwr
oi1~ lr peMteud Inlrevenous .dmin-
IMsaiom of ./w.Il do.es of nicoline in
.wralnined eeU
PRInCIPAL INYRITICATOR
oR 1NSTiTtm01'1
Sommers
MAURICE SSAB
. SEOAL. MD C1Wnd
r.o/.s.er of M.Iai.r. Tnfle llai .enily
School of 1re~ .ci.e : Dhicro. . Depowra
wnw of IwA .f.rie. TAe. .,p . . . 1losloms
City Hos*:1.1. RoMO ..
LUC1O SF.VERI . MD . DLec1a . lwr4
rwr e( Moi1ll AwuawJP ad Bssw/-
UD a''`o
.I" r1~i ..R.~ w~y.
30011 SHIRATA. M .D . PM.D . Aw
cire ea .w rtr.. ..c lJsll
. School of . Modkbn
He.aWr. H
ERIK SKINHOI. M D. CAie% Dy.rr-
ul. Co .eN
. .e.en,`~O'De..nrtN~+
OEN@ M . SMITH . Pw .D . A1a1rw rr.`
/. .asr o/ rsnAokry . Hanarl Melical
Scfosd. Mer.cfranls Oeoeral Hospil-
t.L Ro.loa
LOU1S A . SOLOFP. M D. rnOr.w . .l
C/lwk+d MeJkM.r anI CYr/. DhLM. .I
C~ wlw), T..~FIe U .i.w.Mr .ItHe
SHELDON C. SOMMERS, M .D, C1W-
:, fterfeamor e .d r"'./""' C
1 . .i~i
Ud .sd11. N.. Yer4 City .
SOUTHWEST REtPARCH INSTI-
1VTE. S.. Anl .r.r . /eL
DAVID M . Sr. .aN . . M .D Dbeevw, De-
~tw..v .J r.Nr,i.., .'sl . Rr.ea.de
IloyMal Cew. RrwdlTM N . Y.
c'AROl1Nlt RPDt'Ll . T110MAt, M D.
r ../eaa.r Eww.par ./ lLlk/wr. Tl .
/eMe Ho~i.e U.F.e .iy 3ded of
Medicine . dlimmor . .
86
PROILCT TnTIZ
Sa C\odoekS .
Aa aMro.c\ to t\t strdf of internal fec-
~ ~ carciW\e .eus : influenoe
slowed-I ~carc,.qes iw .rorse tu/l\
SLIF d eerili .Mf of .eecrlar tiswc to
slkolir
Vogt SAB
ne eere eba a( . .o .r. ..c. .eao . .l
areMd Mood Ro. 1. .wders ed
aur .. .lan ; 1\e eled .( some Pifeio
IsRical .11.di s>!e" cerelrsJ !MmW Ro,
b .a.tan a" sweters
TIr relMbwe Le1.tee rwo\in\ ..d Fer.
eowdily
Tb eleet o1 lolvze sa.oli .y on eur-
(en..lv sreciic Iry eciAr, urdiec per-
Iam. .a ewl oetaboll .w of .`vore
twre
SpciRc aRade of aweftly e . .focrAW
.eeh .ic>l rloearrid ..elabdilem ea/
.. eoe~ee a .d Iorwel ek..ers of
1\e e1ee~
HaM Lclors im chronic plwowarT "n .-
ar/lol . ew'\/w.a ed 4wng aanoer
SEeWoeoo*k ttr/p of efleds of lobwoo
~ole coOMilYule ow t•aw"onaliu tim .
wte
h\i.o..r, pre.c\rnal slk+elioes ie u
-orssd-
w popluiow as re•
M ye. se∎ r+wd ew.iroawweM.l
6icsore
Tir riF.rca.oe of dMere./ Md . .ldu.l p/ •
Mew. of eihevl .loef reapoww lo eig.-
rM/. ..oki"
StdMe d genetk diRere .ees Eei .een
=OtiQ1 .nd nOMnOltff
PRIN(yPAI . IN V ESTICATOR
OR INSTITlfT1ON
1AMFS F . P. IOMAN. rw .D ., rn./eee.r
and CA.1.ws.w of rA.rwrn./Ky. C11-
c .~o Medical Sc\oe1.1/~ai1.1e for MeAi-
cal Rex.rcR CUic.p (/ece.ee0.1Co+
Iiwrel rwdec Heesor C . S.leMl, M .D.)
UNIVERSITY OF SAN FRANCI9CO .
Saw Francisco
ELLIOT S . VFSlLI. M .D. M(easor
.n/ CAdrw/... Dqwraaaw ./ rAMwrW
C e~Rqe e hf ediciwe. H ~ en\e~U. ~wf
ROMEO A . VIDONl, M .D . Asaarlre
rro/.sae, of r.r y. Y .k Uai.er .
eitr Scbd of M Ne. Haver;
CoRD.
PETER K . VO(3T. hM .D., esaar e/
MMrolbfop . Udeer,itr f Wa .\iq.
/ow School of Medklwe . Sertk .
1O11N V . WPII . . M D .. Aa+lauwr rro/.s-
sow of Mrfiriwe . Uwi .enily of Coloo-
rado 11edocal Cerec . Dew .er .
SIMON H, WFNDP.R. PuD., R .sw~rA
hof.uor of IiurMiwiwl. Ur+hersily
of OMI/Aowue . Nonwaw .
THOMAS C. WPSTrAI t . ALD . ./•
aa due r.../.. .ew o/ rAr .wcdoffy, UaJ•
versNy of Vwgiwia Sctww/ of b1eAwiwe .
C\aolol/e . .ilk .
87
IrMOILt .T TI?=
Sllrdiee of P . \oloRhal diAererwes !e-
Iwaxl en ead wonsnoters r
.\olrs by corwprieow of Ra.re dre.•
i.p
P.tc\elvieal cMracleriwicis of 4aA\?
fes1.4 aRr/le .wd 1\eir siol"ical iw•
Flieauo .• a cae~.i.ri.R s1.d>• r. ~q/R
with specid re/ere .oe rs 1\e pecw.on
of 1yperlerisa MA corowf \e .rl 4kir
e .w awd to emoliry \ .bile
A ~ ~~ a,.r of \>}esleoeie .
Cyrwle nwolisg oulerss orer tiwe :
preffiles o
~ eM . iwi rrw en ~t ew~ .o.
M.cli ..i.we e1 tM pyc\olrovic efew
TM eoft of aaiom of wicoaiwe .p .
ceMlal q awd ils correluiow .A\
1\e N.eciwnm of acliow of behavior .
.Mf K1i.e drrp
Id.cliem of e«a.wum oeY carcina.a of
the swy Is wip
R.diol.rw..o.way for wicoline
Hiaec\ewielry of etsil\elid rawcfwe in
carel.mwe of 1\e lung
A.im Lmmor virr .es in menwndia. \oMs
EAeets of cipre/te rnok ip and of chronic
aitvaf obelrvdioe on hyposic aai•
Iuary 4i.e in nun
Med of eiprelle rnot<e and ils conpoo
wcaU on free poline in aewesd /iwK
eraNrres
Acllon of wlcollne on wAnuul .r siar{•
MNlow of ee/ecAolea.ines and .erulonu
MM Mein .wA \eer/
Infl.ewcr of nkalae end relaleA Irrr
on 1\e v/lale, ssoraee. rekese e .d
Wt.dle~ of c .1eC\OIaT/MS in QMfal
enA'[r/pAefal tlssUe
rRINCJrAL INYGITICATOR
OR iNSTTrilT7ON PROIE(T TITt .lE
DANIEL H, WISEMAN, M .D . . AuWw Ien1.le.y rlewn..f dr+lunctioe foltow•
' Completed Projects
r.efi ..or e/ %Ii.r.ki. Ueiva201, e/ iwR yeed4 . Iv.er rcaprNoly dne . .e.
Sofwher• C.li/orwi. : CAi//.ew i d- L .i .* cfildAood Following is a list d the principal investigators or institutiotn oI
non. Los Awfek. Coury Oewnd Nof projecu Ihat havt been oanpkled prior to the period covered in this
pd .i. La. AwKks . Report. Several ol the itdividuals named are deceased. The tilta .nd
affiliatioro listed art those in tQect .t the tirne the work wu oompkkd .
CLARENCE M . AORFSS. MD . Aas-
cW. Cli.kd rre/e . .u. .f MeIkM...
Uei.eniy et C.Ida ..l. Mdic.t Ceti-
1n . Lee Aqda.
ANTHONY A. ALRANESf'. FM .D. DI-
nc+«. Mwr/N.w .wd M .r.tdk Re-
.erc A Dhldow, Tb -.r1. ReWYYa-
Uo. (ka1e+. rVtiw rt.iw< N. Y .
ANTHONY P . AMAROdt', fTr.D, fo-
re:ur Drr.rrwvwr ./ OfM .w1em swd
c~wec.~et_ _~, Tiw Allrh Meicyl GI-
Iqe s+/ lleiw U.i.+nM1. Afteovf. N .Y .
E . T. ANOELJ1KOd. M .D . li. .D. Ir+
.a.o . ~r[tysi./.p,R U.i.n .lt~
D . MURRAYM•AA e AlOi•~ EV1NQ M .D . U.t-
veni e[ wiroori. SeAed d Merl-
d... G..1 .am
RRODA A . RARNPM M .D ., laD . h.-
l...r (./H1.re) .a rA'ai.l.,. Cel .•
..b swe ur.e. .,. Fert GRM
FREDERICK W. RARNEl, la, MD .
Arerfre rrolemr ./ Meddwr. T1e
ld. . IIoNYr U.i.ea.My 3cfed .f
Me/iciec. aaNiwo...
T . C. RARNES, D.Sc. Rnnrs# ScirsAr . , OBOPPR~•flY L RRINKMAN, M .O . Ar-
Mi/.idrih S1aN Ho.Fil.k Mildd-
!bia•
R . FREDERICK RESCKER . PwD. AoF
ef.re rrole. .er o/ AwM.wy .d DY.r-
.... u. .ra., .l r«in.w sa+..r..
D.t. UMi .er.Mf Mcdinl Cselsr. D..-
h.w. N . C .
RALPH S . RECKeR Pu D . . sear •/
Hwraw.
1(MIN A . RF.VAN . M .D . A r.r N
rA.re. .c.+of,. Uwl ..r.wy .f i~,dw.r
.oa/ .f Medklw. . Le. Aq./ee. .lwtid
CESARB RIANCIFIORI. M .D.. Dl .1+lm.
./ C.wce+ Rex.nA. Uei er.k1 of
l4rvtiR rcrvlik 1t .1y .
aa 1
HYLAN A . RICKlRMAN . M .D .. Ado-
.wt rr.f• ..w .J Me/1dwr. ..l ALVAN
L RARACH. M .D. C.w.r..wr 1w MeL
kdar. CeM.t+i. Uui..r .fy CaMep .t
M1sideme .W S.rna .., OaY.Yer
Mew.rid Hetlilak New Yort Ciy .
FRED O. RO(.'K . Fw.D. Aper/.rr Crrer
Re.r.cA ldewNr, Ifdo* kvf Swl.r..
Re.wefl Part Mewro.i .l iw .lil.te,
SFrkR.Ylti, N . Y .
HERMAN V. t80l .'NIO . FirD . . Nmd.
C IbrA.wrlw.y D.~.r~
iwr~f. Spiadbelm Reac.rci Cawer, lsa•
+ ..4.. . r.
IAMPS P. RONNER. rM .D ., rro/e.rw of
R1ebp. C.lilard . IwrNwe of TeA-
.d.Mr. P. .dea. .
MALTER M . BOOKER. PICD ..rnk+u
. .wf et*4 Drp+ rwwwr of rAo,...
Ho..rd tl~iwwr . w ..tiy
~: C.
TOM O . t1lO1Yl.RY. Pw .D., re.rkYe Ar.•
ddw Labarwe+f. CAewd" Deparl
R' wr~ r~NeN Ceroliw . SuN Ca11qe.
.re1 rr rh.J.aw. ./ ALdirdwr . w.~
luir Uei..niy iclool o/ Mebci. .,
Dw.k.
RAYMOND R. BROMN, hu.D. rr./e.•
wr ./ CNwh.f Owedo67~U.i .a .Mf •f
Misosirl. Mdkd Scboo1. M .di.o..
IOSFJ' RROttK. Pw.D . hv/. ...+ .W
CA.iww . Dvrrvwrrwr of rrrcAelet) .
LeYab Un+q ..+rr. HeQde .ew. Pa .
SUd RVCRINOHAM. M .D . A .drrv
rrok...~ dJ re.w.+r.. c~ta a u .l -
vw.Y1 CtiR.R. .f M1dd.we ..w S.r-
p.w~ Ne . . Ypt CM>.
BENJAMIN BURROWS. M D . A,.oc1 .a
rro/ta.ar of MedkUr. Uftiveruir of
Cwcyo. Cfaicaso .
89
 E N RUTT . M D . CAkJ r.uAowbr,
lp Aqeks Courf Oe.o .l Hoy'iul.
l .oe Ayein.
RICHARD U . RYERRUM Pr .D, ho-
/r, .or o/ CAr ..rarr . Mj*c~.. 3rM .
U .i .er .wy. E.. tr.i.R.
SISTER M . EMILY CAHILL PtD .
CAobwow. CAaw/sny D.P .rewr.r,
ReRIe CdkAe. Wealer . M .w..
WR11AM H . CARNEI, MD. Ud ..r-
eYr d UW Co1Nrm d Mdhi.ik !dl
L.t. CYr.
MARCUS N . CARROI .l. )a. P&D,
CAW. D/dien o/ fA.rwunbfr7 . Ti .
M..LLM H.rPil.l C. .rr. Rrslllq
N. Y.
I .P.OIOID R . CL'R'CPDQ Pw .D. M
/.uer o/ ~ .oc~rwdw7 ..I N..rYl.~
1f .i..r.rf d PrM . Rk. Sel.d .t
MNid.a, S .. l.er .
WiLUAM O . CLARK. P.D . DAvey...
IrnAoFA. .w. .rr/n~ Jlr.e+cA 1 abo.r
Iw7. VNnw All .d.lr(rMlw Haoit .i,
serA...e . Cr .
HANS T. C'LARKE, D3c. . hel.ra+ of
//.cAriw/rrry, CoArM . U.F.erti1 Ca4
Mv d rff.ki... . .r SrKowk Ne.
York Ciy .
JAY D . COFFMAN, MD . S.crfwr Neol.
IMpAer+l Y .ar.i. Deprtwwwr. U.L
.etrtl Ho .FNd, fasneo .
DANIEL COI/EN . D .V .M . M.P .H . A .-
d.a.r A+leun of Yrwrk.ry EIi4~w
Miory .oI Lilk NrdrA, Uai .ani(7 d
/rw/l• schow ~d Vawia .rl
.iel~i.
IUUaNUSd• COMRO!!< la. M .D. Dion
Hr., Pt-
w. Gn.lon. .rdr 1[.,eateA 1..Nrw.
Uwiarr( d Ca/iNrda M .Na/ Cef
ae, S+n f rsaeia+s .
DEAN M . CONNOR?, MD Ai. .ei/e
DNrtiw. D•po.r iwrwt .J
M .Ikrwe . S1 . M .ry'. Haq1Yl M./Y.~
Wk
PHILIP COOrER, MD . CRakd rr+l.o-
p. ..r o/ Srrery ow/ DLMe .
..lo. .e.r~ .N Cew .. r~y
.,v~f .
r ARiert Ei.MeAa C.Rqe d M.Mciw'
m CAkI. Srrlcd Srrdr+ . Wle+tr AL.
B mfoietrarioa HeI it .L t<rws, N .Y.
m 91
rp 90
J
(J
ROSERT L . CRAIN. PH .D . Ane-/.wr
tro/raaor of Socwforl. Unia.rity of
Cbicyo . Chic.p .
CE(1L E. CROSS. Rrv+rcA Dr'.rrw.rnr,
St . lo .rEi Ho.'ir.l . RrrrM. .k . Cal .
ALUERT DAMON . Ph.D.. M .D .. lec-
d.w a . Awrboplogy; Rr.rorcA Aua
siYe ir Medical Awrliropbrl . h .Aody
Mwilk Harvard U .i .er.irr. C .w-
hMK M.r.
R. P . DATYSON, Pw .D.. ho/rnnr n/ R.w-
•y, COlu1abi . Uim/ltefllV, New i ~ N Cowcrr CA.w.oeAmry RrarrrA,
CRT.
ANDREW S. DIRNER, PuA .. FJKYIIN,
P.}cAtR.rr.reA, Tle ARe Ctmer d
1400 Rms1.A Lc.. Rorea
RALPH L DORPMAN, Pw .D . Dlrrr/e.
Mr Ft}wine+UlWtlol ~ S~ru~
Mr.
JAMES 1. DYAR. PM .D. A. .ls/ru Ao-
./ Iblerl . ReR.rwia . Cotlqe.
1 ooi.eiKe. Kf .
RICHARD H. EARLE, M .D. CAk/, ld-
rwrl Fr.niow l..bwwory ; Aalrowr
h.feawr o/ Mrt.rlnr. UwiveniN> d
cs.r..., Ci+e, .p.
JOHN W . ECKST'EIN . M D . Auljroat
ho/r . .w of larrw.l Mrlwiwr . St .le
U.i.ereit7 d lo. . Co1kY. of Mediciwe.
km . Ciy.
HYMAN ENOFISERO, M .D ., Atrrnl-
~~ yiiti .'w . ~ ~ s d Lcsano. 1{ae-
HCNRY 1 . PSRER. Pu D. Re .rreA /w.-
wrweleir4r, Mwo Reacarci Iwilru,
Mwewer. Mue.
HANS L PALK. PaD. AI/rwn Aiwci-
.w h./..or.p.~.rtw.e .r y rrAdop .
U .l~.rd1~ of Sorl~era C .llforwi•
SeR.el ef Mc4id .e. La. A.relce.
DANA L. PARNSWORTH, M .D. Nr+~
L . ONs Pre/r..w o/ Nsrkw ~ DI•
~ of
raN vwrre.,Y, HedrA srrrkrr.
H.r .ri U.i.enMf. C .wlM/eee. M .n
FRANK C. FEROUSON . 1 . . M D.
CArY+ww . Drrorriwewr of IAor+ ..rol-
V T1. Alb.ny Medied ('otlege d
.ie~ Ud.enitl. Alp .q . N . Y .
WILLIAM 1 . FISIISFIN, M .D . . CA4/ o/
t~-~orr . CAic.p dwre of HedlA.
C yo.
RUSSF.LL S . FISHER . M.D . Usti.eni~r
d Mryl.wd Sclool d MeAieiwe, /.M .-
wore .
R . L. FREEDLANDFR, M .D . Dkraor
of Cowcn Rr .e.rcA, Momme j.iow Has-
Fi1el ..A MeAital CeMer. $.. Fr.s-
ei .co.
FREDERIC A. FRENCH. A.1111 . DAWrr
Moa.( Iio. Ho./il .l ../ Me/ical Ct.-
1s . S.. Fr .wci .eo.
JACK FREUND . M .D. A.MMwe he(ea
.e. o/ rA. .w..rblsrF. M.dleal Celk*e
d Vksl.i. . RicMod .
01t 10F.RT H . FRIYOl11, M .D, CAkI
o/ rrAolo.~. 11 . VMoe+t Ho.'i(.k
Worcetin, ~Lr.
ARTHUR FURST. Pr.D . DY.rwr, lwol-
rre o/ Chemical Neim. U.i.ntYF d
S.. Fr ..eireq Sao Fn .ci.os.
GEORGE O . OEY, M .D. Dlre,crr,
Fiwwr"o.rM Cowrrr RrparcA t .b-
.r.mry ; Assori.ue hole»er o/ Sr-
m TAe laAw. HaEiine Uwi.ee .Mr
d d Mediciwe. fadlb.or+ (de-
oe.") .
THOMAS M . OOCKE, M .D . AuxAwe
h%i.or of f'.rrewN .e Mr//Nwe owf
Co+wiwrnirr Health. NeW l .nq SIMe
CoMqp of Medicwr ..d D.MiMry,
leney CMy .
PAUL GOLDHARE DD3. A».d
.re Harvard
3e"feel d D~e.( .1 MMkl.e, M.ro..
IRA OORE, M .D. . Ae/..s. .J LeAd-
.~, faalo. uwi.eni( Sef.d a M.Y-
eae : CAkI ol L.Ta.rae7 Je..kv.
Ve(ec .r Adwin/eunlo. HorFiut, Ma
R.aA.rF, Mar .
OERTRUDE Y . OOrTT]i..'HALL, rwD .
AWn.w Iro/euor ./ I/oeAr~NMry .
CelrwAi. Uwi.a+.M> C..MeM d MT•i-
cl ... ..e Srr.ro.L Ne. . Vrt Cwy .
A . Ci .ARK ORIFFIN. rw .D., Ne.f e/
IbcAriwl.rry D .p.rrw .rwr, M . D . Aw
Ae.+ow Hoyied .w/ Twror IwrMwe,
U .i .enMy of Teau Medkd Ce.kr .
Hawow.
ARTHUR L . GROSS . M S . . S.n/ar Rio•
cArwrir, SoWARe .cwc\ 1n .1i1ae,
S. . Aato.io, Te . .
MORTON 1. GROSSMAN, PM .D_ M .D ..
Aarsdre C/iw/nd rro/e ..a o/ Nr/1-
c+... Uai .e..i(r d C .lifoewi . Me/ic .l
Ceaar, La. Aqele..
CARL C . ORUHZiT. Pw .D., M .D, A .+o-
d.rr M rASiie/sgl .w1 tArwucoiop .
Uaii.enil of hwmarLawi. Gr .A.ue
Sded ol Mead.., ' W .ed,.i..
FRANK 8 . OUTIIRIE, Pfr .D ., Ire% .wr,
aM ERNEST HODGSON, Pw .O_ A.-
aipw Rraweh ho/e. .or, Drr.rrw.ewr
o/ r,R~ f. NoM Caroluu S(w
H . .C Me
.HAAO, M .D. lro/e . .or . rA.r .
~Melicd CdleRe d SfeAi./.,
F. l . HADOY, M .D. . M .D .. Iro/r..or
Mf CA+bw..w, Dep.rrn.ewr of rAydol-
orl. Uwi.er .ily d Oql .bow.a Medical
Cewwea. Oll.ttor.a Ci/y .
JOSEPH H . HAPKENSCHIEI, M .D,
Alfllenl De/.rrnyN, S .nd02 t fMm.-
aewiedR S .w Fr.ad.co.
RICHARD 1 . HAVEL, M .D. . Au/ .ronr
!ti'%+uar N Alrliriwr, Uwi .er.ily of
Califorai. Medicd Sc~ool, S.w Fr.w-
ti.o..
HERBERT R . HAWTHORNE . M .D_
CA.Yww, Drp .rw..wr o/ Sr~.ry
Sded N Medki~
.., HPW.41~~
CLARK W . H6ATH, M .D . . Ao/eur o/
M#/k+/wr .w/ Diirenero/ NedrA Srr.-
kr.. Trfl . Uai.enllY. Mdford. Mr .
PAULINS HlJ2ER, P+M .D, Rem .eA A.-
MciMr b Cyeo/o/, on/ C)r«Arw.isir7 .
! .r Pwrcho. IM1Nwe of Medical Ssi-
aoa.K R. . Fra.ci .os.
LAWRENCE L. HFSTPR. 1., M .D . Ih.
/.e..r wf CArMnw . Dr^ .nw.rnl ./
OAMMIei .oI O7wrrolor, Medical
C.R .w d lw1A C. .rdiwrv (b.rkNOa .
l119E CURTIS HOFP, Pw D. . M .D . hr
/.aw rd CA .Yrw.w, D/rlalow o/ rrq-
eAWrie Rr.nreA, Medical Cdkp d
Virgiftlik Rkfrwwrd .
 RUSSELL L . IIOLMAN . M D . Loriiiew .
Suu Ueieeery School of Medic ..c,
New Orkw .
OLE A . HOLTERMANN . MD . Rr-
•r.rcA Scwwr4+. LoA .r .f L.lsore.l.
U .ieer .iry of Noare D.we, No1n
De.ve, led .
FREDDY HOMNUROER. MD, hw/.
/rwr owI Dfacrw . Ris-RwarcR ler4
hts . l.c . CawMidp, M .r.
ROBERT W . HULL. P1r-D . ho/lra.es of
I..ioek.f Jclnarr. FMrid. Sl.r Uoati.
.ae.irl. TeReb.eme.
OlAROE IACOt.lON. M .D . M/e».r
owI Hr.4 Derw+wner of i
U.ieereily of So .rMrw Cdlf .e.
Sckool of Modkir. L .e Aaydu.
/F_RRY HART IACOf3D!!, MD, Dbre,
M. D/ .1ai.w f7ecwoMlr/d.Ry. New
Y .ef E)e ..d Est LM .r7. Mew Ywt
CLI .
)UUUS H . IACORSON It, MD. Aw
eirr P.ofea.or of sr.r..f owf D .eear
o/ srticof RrerorcA. Usiver.itf of Vet-
woa College e+t M.dici .e. F .ii.po. .
MURRAY Q IARVIK, PILD . Awclue
f tio%aan of If-.or.kfF AR~.n !i-
wi . CrMp ef Merldr . ~.+.ti N . Y .
OAWALD R . /ONM MD . 31 . LaLe1
HampieeL New Yeat C)ti.
n ANDREW A. RAN t+rD .
s.y sclnw.. Tie l.d .. . .
«-~ o.r He.ia .. Me.
ARNOLD R . KAPLAN hLD. Dieero. ..
/
L Y~~
rMerFi~
r h"Cii .erk LrYw
G w
Cle.el.d.
...3.
,..~' HRA7CH KASPARIAN . MD . Aad+e.w
Dirrro.. C..Ms.rrcoir /.rAorororf :
/+. ..
I.rr.cbr /w Mrflciwt. HaA .ewa.r
MeAicd CoRqe .d HoWiraL rlila-
dr/piia.
EI .1NU KATZ, hr D . A .asciHvfro/scmel
. Uwi .veilf C1ir .Mof
Chicyo .
ANCEI . KEYS, fMD . DMecoor. Wor+
re.7 of 1 A'a/doFkd Hlflewr . U .i.ee-
eYf of M1wwe+da Scbod e/ hblit
4iullb . Mi.w.apolra.
92
(D
J
A
IOSf:hH S . KIRSNER, M D ., Iro/ruar ol
Mrlkiwr. Ur .eruy of Clicago School
of Mcrictiwe. CAicap .
PETER H . KNAPP . M D .. RruorcA 1'ro-
/ruer o/ Pq cA .orrY. 110610111 Uni.endy
School of Mediciwe, Souoa.
KENNETH P . KNUDTSON, M .D . . Il.i-
satiry of M~a.Aiiylow Medical Sc6~wl .
ALVIN 1. KORAK . Pw .D. Asaociur Iro-
k+W of CAr../4ny. New Yort Uwiecr-
dtT, Nw Yo.t CMy .
ROBE,RTA . KUHN . M .D. . A>rsor/ .re f.o-
IteM.. DMdow o/ Nerop.lle" . New
la.ey l1Me College of MedicrR lereey
Cily.
MARV1l1 KUSCHNER, M .D .. New Yor!
U.iwnRy MMkal Ceeice . Now Yo.1
Cln .
CHARLl3 W . LARELLQ Pw .D . A„be.
eav ho%ar of EeNrow.wwr.f H~-
M/tw.. Depnt~eal of Pre .ewUw Medi-
ehe. )eHene . Medicd CoNege . Kila-
4/ f111.
ZHOMAS C . LAIPPLY. M D . . LoJriaor
of PoAdopNpliwnler• U .irertiq
Medical Se`ool ( .'Aicyo.
ROOdR K . LARlON, M .D . CAIr/ o/
'ew, Cal.Frear Cowf Hwpwal,
AVERILL A. LIEROrY, MD. . CAobww.
Dep ..ewr of lrAoferF, Y.M U .i-
w.dtFldoe, of Medici.e, New Ila.eti
C.. .u
lsTpl/ O. LMDQaTlI. MD . rw .D . SI .
1.eelR1 H .qMel Rae .rI! L.Aeralory,
!1. r.r~ Mi.~
RODlRT H . LINNELL, M .D . As+ocl.rr
fti.{.wr of CAnwtarf. Uei.a.irr of
Vec.ntl. R.rii.slo ..
HlRBERT L . LOMBARD. M .D .. M .P .H ..
ANwr. Cb.oer ReaweA laaiwwe,
}le.w paslad Deacowe.e No.riid . dpr
IM.
DONALD B . LOURIA . M D ., Auoel.ee
I1ofeai.r ./ Med4 .wr . CorneR l/.i.er•
iF Medical Corqe. New York 1'ry .
DAVID IL MANN . M D . Ar .ocl ./r Lo-
/tuor .( rArw ..colop. ?re.~1e Uwi .
.eetif Scbd ol 1'tierl .acf. Mu~adel•
phi-
JOHN P . MANOS. M D .. )ouwrne . Iw
YwoGrf) owd S .rrrr.ofop . Medical
College of Souib Cuoliw., Cberlerow.
CHRISTOPHER M . MARTIN, MD . A.-
afar.wr rro/ea .or of Mr/irlwr owI Dine-
br. Dirlrbw of Is/ecrbeu Di .rrwo,
New ler.ey S/a1e College of Mediciwe,
ler-er Ciry .
CHARLES C. McARTHUR . hMD. Psp-
eAoloRw ro eAt Uw/rrr.lry He.lrA Srr..
kn, H .r.ard Ueiver .ilF. Car.lridge.
M.e. .
CHARLES R . McCANTS, rw.D. Aiao.
efrr IroJea .or of Soilr. NortM Cuoliw.
Su . College School ef AoitrMwe,
R.killl .
HENRY C . McO1LL, /. ., M .D ., ArN~
Head. Dtf.rrw.ewr of %rAd.Rf to.~-=
si... Sreq Uwi.er .Mr School of Medi.
el .e. New Oekw .
HENRY D . MdNT06N. M .D., ho/ts+sr
of MedkMe .wd Dhrcrw. C.rd(sw.
ed. . 1.Ae..rary. Drke Uwi.etfilr
Me1iW CeMer. DrR.w4 N .C.
EDWARD MeKEF- M .D . his/euw .wf
AcNall CAebw.rr. Der.te.ew/ of f•o.
NWot7. Medical CoNep of SeMtt Car-
di.R Ch.rleflo. .
KE ./. MCKEL', M .D Aa.erirt ho~
fessm LLY T
3e./ Caali.k C1rkles C~ of
HERRERT McKENNtS, 1. PwD, f1r-
ft .ao . N rAesw..nJofT. ;dkd Cti1-
IrRe d Viryi.iA, Rici.ad.
VlCTOR A . MeKU51CK . MD. h+/e.-
rr of Me/kiwr. Tie /ir Mi.
U.i.enwr Schuol of MerkMe, /-
oere .
RORS L. McLEAN. M D, Aaadw M-
/tasor of Mdreiwr. Eeaoer U .i.eni~r
School of Medicine . Allaw..
N7LLIAM F . McNARY, 1 . ., rw .D . Ar
ltocbrt hs/ruor of A ..rowr. BoMow
Uedeer .Nr School of MedicMe . moaow .
NEAL L . McNIVEN, Pr, D .. The Wer-
aerer Forwdalfow fo. F. .'erYweMal Ri-
oloef. SMeweE.ry . Ma.e.
JULIA MEYER . rw .D. Aa.ori.u h.(ra
ior of Orol rorAofesr. U .ieenllr of
IRiwois College of Demi.lry. Cbicafo .
93
sERNARD 1 . MILLER, M .D . Auiuau
Pro/t.wr. The D.wirl RnrRA Iwimra
of AwMOwv. le/lenoe Medual Colkge,
Kil.dt4Ve.
IAMES O . MILLER . M .D . f N D ., ho-
Iruor of f yrAf.hr ow/ r,ycAola~7:
Dntccrer Mrw/ol Heo1/A Rr.reacA )w.
a.ir.rt. b .i .eniq of MicAipw. A .e
Arbr.
HUGH MONTOOMERY . M .D .. Auoc1.
.M hofiaaor of MeIiriwr. Uei.erwq
of = .awi. School of Mediciwe .
P . .y..MOttTOOMERY
O'1./ .1. . . M .D.. Pno~
Teue ~ . 'Mcdica~l ~Sclool.
D.Rea
OEOROH e. MOORE, f N .D . M D . Di .
rrclor R.e .eR hr Mew.oral IwMi-
t.w fi.t" N . Y .
KENNETH M . M06ER, M D. . Ad,rowr
ho/taror of Mtliclwr . Georfcroww
U.Lardly Mdkal School . warAiay.
lo66 D. C.
HURLEY LEE MOTLEY, M
.rrte.D,IropwaMec/ndDf ., Crlio-
R [ah.rora.~~ U .Lasir~ ef
3o.He.w CaW.ewi. Scroei a/ MeN-
ol .e, L« Aqa...
EDMOND ANTHONY MURPHY. M .D.
seD. A..ewe hNe.••r of Rw•ado-
Mrs .uI M.AkMe.. TR. loM .HopkM.
w.~rs hF .a nl~j~ .1 U.i.e~f~e
. R.R1-
. .M Medical Cewler . Deoeer.)
rV1l.L1AM S. MURRAY . ScD.. Jrnta.
S+./ Scie.r/r. Tie lacieo. L.borNory.
.Jn Haia. Me .
DONALD M . rACI; M .D .. ho/tawr of
I~~ .wf Dbtcror, Iwa/rrrr /or
CtNW.r ittar.reA, Uaieee .iq of Ne-
Ar.ie. Lj.ool..
ALBERT B . PALMER . tMD, AN/INM
ho/.rM, Drp..tdwtw/ of f atcAoloF1 .
U .i•er.Nf of Toledo. Tokdo. 0 .
ROSe MARIE )ANO01ORN, 8 3 . MS .
Aarlatowr Food TrrAwe/. .fl,r owI L.r
rrrl. Dr/Mrwwwl of Food Scirwcr .wd
TteAw)o*f. Ua.er .iry of Ca/do.mie .
D..is .

EDWARD W . PE1.IKAH . M .D ., CA.ir-
w . .w. Drr.rsw.rwr of IArw ..roloRy owd
ErPrr/w.rwf TAr.+yrwk; Bw/ow Uwi-
.cr.iy ScRod of Medicirt, RoMa . .
OTAKAR 1 . POLLAK . M .D. hrD,
EIKMLv Dwrrer. Do.ee Medid R ..
.c.rcf Crwcr, Iwc . Do.e+. Dd .
MORRIS POLLARD. 11rD Mrctw,
Le1wf Lda..rary. U.i..e .111 .f Nek.
D.wK Ndr. D .ww. l .d .
C . M . POMERAT. NrD . Di .rw. ./
• Rrar.rrk P.so•wr Pwrb-
riow or Medkal Re.eard . f'...de.ti
C.1 .
/1 . R . f RATT-THOMAS, M .D . Dww .wd
ho/rar.r of f'.do1Nf. Medid C.L
kRe of So+rb Cr .Y.R C>trkrw.
MARTIN S . rROTLl1. •s, DD3 .
CA4l. Drr...w.rr .{ O.r I ,
Ne ...t CrlHoyi1.~ N. ..ril N . I .
WALTER REDtlC7L M .D Awei .a
Pro%a.r M CMnkJ MejkW, Ne.
Yarl U .i .v .My Scfoo/ of M.YeMrR
and NYU Re.erc! 7er.loe. Odd .Mn
Ma.orid Ho>!i(aL Hr. Y.r! Cln .
HOlART A . REIMANN, M D . P*.kr
so. of MrluMr. H+rrarw edlealM
CotleM sad He .pU.k Efi .delRW .
ROLLAND C . REYNOLDS, MD, As-
Muowr of 1'.rA./qt. U.F .er-
.Mr .f Tear Soar .+wr. Mdie.l
ScloaL D.M .L
VICTOR RICHARD& MD . CW/ N
sYrir .y. Ihesykrir M .Nk.I C..w .
Su Fn.cYw .
W1LLL4 H . RIESeN, A .D SewY. N.-
tArpdrr. Lllr scfr+.ces ald.MR IIT
Reae .rd IriNMe, CrioR. . (lakle"d
•wder A . W.i .Mect . I'f .D .)
R . H . RIODON. M D, Ir+/ea.or o/ L-
thelmy. U.iwsiy .f Tw. M.dicd
Rranck O .1.eM.w .
SYDNEY C . ~R.frTE~Nr.T.RERO Fw .D, I'1n .
~SowMr . ~ ~ C al~fw~i~. l.c. A~
. ROfy MD ..RENSOH Asa.r/re Ir.-
/ruer ol srrery: CAkI. Crlier S.n
U.1.u++1 d C.Mfer.i. ScMsd .f
14.d~cs.. . S.. Fr . .da ..
• Rf
I
JOSFMI H . ROOFRS, M D ., Iloly Namc
of lew Hoapiral, Gad.dc .. Ala.
SENIAMIN A . RUBIN, PwD . Assirr .nr
1're/rssor o/ f dlir NrohA . Raflar
U.i.enAr Colkge of Medicine, Ho..-
M"
HQNRY 1. RUSSEK . M .D., F .A .C .I.,
Nrealdrr, Tte R ..ael For.dNion . Iwc .,
llalc. Idarl, N . Y.
W . C. RUSSFII ., M .D, Uei.er .ilr of
Tom Medicd CeMer, HoLwow .
1'SY!!l P . SAUSRURY, M D, 1'w .D . .
Be+d, lrrwa/ee Trr.rw.rwr Crwlrr . S.iwr
1i Hospwal, R.rAa .t. Cal .
PAUL SAI.TMAN, M D ., Aasisr.w Iro-
/rrr. D.prrw.ewr of ApbrArw.Lory awd
NrUM, U.i .wdly of Sowkr . ('ali-
br .i. Stl.d ef Madid.e. Los AaRrln .
IOROEN U . SCHLEOeL, M D . . M .D,
hNeawr and CArrwvw. Srrr .ow of
Dvprnwrws of Srrrisy . T.-
Iw ai .er.w7 Sc6oo1 of tdrd .ciwe,
New Orkar .
ALVIN R . SCHMIDT . rw .D . Dbrrtos
o/ Co..srMy. Tw/t . Uwi .e. .mV . Mcd-
/ord. Mua
ISAAC lCHOUR, D.DS_ 1'+R) ., DSc .,
Dr .., Co/kRr of DriuWry, Vwi .er.isy
of IRiaoM, C.ics. . .
CARL C . SELTZER . fw .D .. Rru+rtM
Fer.r M IAvska/ A .rMoploty . Nu-
..rd U .Fv M'. C*.Ariye. M.aa ; De-
prrweor N Niw.*bw. Har .ard Scbol
.f FMlk Ikdtk Rowo ..
CHARLES ti SHERWOOD. M .D, As-
aWrt Ao/es .er of R ./iob~f . U.i.er-
dty .( R.clewa Scfoel of Medicine
.d DarWT. Racferar. N . Y .
DAVID L . SiMON, M .D . /wsrrrctor. Dr-
pnt.vwl N Lw.wd Me1kMr. Ciwcia-
WI Oewrd He*itd, Cl .d.eaul .
OEOROE W . SMETTERS, M .D ., As .orl-
~ .M M t.rA.terl, Nortbvwmnw U .m .q-
aiy Mdkai Scfod, CSkaRo .
LUCILE SMITH . I1r D . . ho/rosor o/ s1o-
rhr..Wry. Dw1 .+aA\ Medical Scbool .
H ..wrr, N' o1
94
ERNEST SONDHEIMER. Pr.D, Asss I'_ D . WARNER . M D. Irolrssor o/ M-
riae hNrs.or of IlorArwdrry. Co11cRt Sule Uwi .ersiry of lo.. Cd-
of Fonnlrf. SeMe Ur .afily af Ncw IsM Mediti. .. lo. . City.
Yal, Syr .c.rs .
SHIELDS MARREN, MD, DHrcw . o/
T . M . 3ONNESORN, I1r.D. DlsNw- LbnModes, C.wcer RrsnrcA /wqqry.
twaAef Ser .ire ho%uor ol 2..1ogy . Ns- Eql ..d Deaoo.n. Ho7itd, Ror
Iwdi ... U .i .enilV. Rloooi.pea. 1m
SAM SOROF, fw .D, Nr.d. DrR.rwwwl
RARBARA K. WATSON, h .D, Aadar-
of Af.rtoa .drrrlr CAew .i ..r /R.curtdaRlr, M . .reMud(a Oet
.ry, l r Iw" rihM for Cancer Rescarck t Y .dA- wtt t1erlil.l; Resr.rrA Asrociw. De-
phim, /wriwtwr N parwrdology and L .aarw-
ALEXANDER SPOCY(, M .D, Asdaawr op. Hrr.rr Mdic.1 Roe1, R.ma
rro/easor of rrdir .ics, Dd,. U.her.Mr
Mrdkd Ce.1n, DwR..% N. C. 1OHN S. MAUOK h1 .D, hNea .r .1
CAnw/arr7, M ..nel~ .eu. Lai(w d
FREDRRLK 1 . STARB, MD, In/essw TaR.daRf', CrRrYM .
of N .wM/e., H.r.rd U.iwr .Nr SAsol
e1 Is.~lk He.ll lm. RaMe. . RICHARD L WBCHSLE MD C/l./.
er rAy,I.I~,., M F~arlMr
C . HAROLD 1TP , M.D, DMcwr L.INw .f IEe..pcR Mn .bwd .
of t. ..w«1rs~ dedM H.r•wadt.
Mrw*bi.. RUSSt1.L W . Wf'11lR, M.D hdld .,
t o/al. Ms.eHd HeWiu1 ei CRewr
JACK P. ST7tONO M.D Assec~lw Inr
/raao . N lerl~ap. ;.aii.b.. S(.Y C..rf, W.w cbea.r, h.
Uwi.erd(r Sc>,oel d Ioadid .R Nsw
DUANE O . WENZEL, Ai .D. . f'r./ear
O.kw. I !~ Se`eol ef H .r.ue1,
MARION R . SULLEROER, MD, ho- U .i..nY~ .f Lawra.o..
/raao. .w/ CA.iwsr, Deprnwrwr oJ
Dr.. .noron .nr sy.hM,. Ne.. FREDERICK Iw WHISKIN, MD, C .M,
Db .ersr. D/ ./ak+ . of Nn.hA ad Irn
Yert U.ioenN7-MRevw Ce.-
kr, Ne. York Ci4 .
.f l~Ie . l~I~
.w/, I .e, Rowe~ Ca~
RENATO TAOIURL 1'wD.. Aard .re
holerw .1 r Ot.iMe ROOlR 1 . WiLUAMS, IrD, ho/rsn .
Sdoel of Mriss ~ .Uor4, Dlrvrar, Cl.rea l:'ws
Har.rd U.i.enilV, fier.a 1/.c ~ IwrMwe. T1. U .1_
•. .Yt J T. ..a, A .rl..
IHROME F. THOMA7, lwD,
N s.Mrry E .R/wrwi.r, Usirwarawy ol 1 . lDMIN WOOD. M .D, /wrn.rMr /.
Mrdkia. Rope. Uri.enily ScRoal d
Califerwi.. Bertdry .
Medid .ti Doo . ..
IANET TRAVE MD, Assrniw M-
of Ct+.~ rn.r+~.~.+.~ . c«- SUMNER WOOQ 1., M .D . AsM.r
/.eR U.ner.Yy Medinl C.Rq., N.W f'hNerw. of r.M.lory. Tb l.It.. Hor
York Ci(y . Ur U.i..nYL Scfoal .f Medkl.q
R.Mi.a..
UE SHA TSAI. nr .D, Rras.eA Are1-
orr, Drp. .rwwM of rrM1.R). Yd . JOHN r. WYATT. M .D . lre/rs.ar o/
Uwi.eruly Scbd of Mediciwr, Nc . f'rAeisRj, Si . Lori. U .i .v.M y Scfwol
Ha.en. C.aw. of modici.n, S(. L.oYis .
95