Tobacco Documents Online

ported study has elicited evidence to indicate that at least some of the macrophsges originate from bone marrow. The study used genetically related mice and substrains to investigate the possibility that macrophages originate in marrow stem cells. Success of the experiment rested on the fact that the genetically re- lated mice carry a nonspecific, readily identifiable pre-albumin esterase marker. Lethal x-irradiation and injections of bone marrow from the mice led to findings confirming that at kast some macrophages originate in bone marrow. This particular work waa part of a project that is moving into the biochemistry of macrophagea. Another Council gantte provided a deacriptive report of the appear- ance under the ekctroo mkroaeope of alveolar macrvphagiea obtained by endobronchial lavage from smokers and eoeumoken. He said that in yeneral matrvphages from smokers contained larger and more heterogeneanly strucfured Inclusions than those lrom noo- smoken. However, there wu considerable variation in the number, size, and heterogenicity of indusions within individuaf macrophiges from smoken, suggesting that various stagra of phagocytosis were represented in lavage samples. Further, the researcher said, sorne substano-s that are phagocytized but not digcsted probably aecvmulated in the larger hetero- geneous inclusions of smokers. Other studies o/ lung macrophages have shown that a greater number are recovered by lavage from smokers than from nonsmoken, nd that the macrophages from smokers show unimpaired phagocytizing capacity in vitro. , Neurophysiology, Psychophysiology, and Pharmacology Nicotine and Memory Conao/1d.tlors For several years The C,oaroeil has been supporting research into the effects and .ction of niootine on eremorY eonsolidation. One researcher has found that rats put through a training regime (mase sdving and kvcr pressing) learn at a meuurr+ble rate. Fk+wever, if the animals are given an electric shock' after a training session, they tend to "unlearn" everything they had previously acquired. Apparently the shock caused an amnesiac condition and prevented consolidation of the karning process. When the animals were treated with nicotine prior to a training session, it was fuund that the subsequent electric shock did not affect memory conu.lidation; the animals largely retained what they had learned, apparently because the nicotine blocked any effect of the shock. The time of nicotine treatment was important in this experimental procedure, the effect being maximal some time after administration. Cotinine, a nicotine mctabolite, also was effective immediately, which suggests that the laltcr substance may be the active agent. Other parts of the project included testing the role of the serotonin precursor. S-hydroxytrypk>phan; age diffcr- cnces of the animals; Jifferential housing; reduced brain amine levels; and amine changes at the cellular level. In work in a related area, a Council-supported researcher found that chronic treatment with nicotine induced an increa-ud 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 animali brains. In short, the chronic administration of nicotine appeared to stimulate 7he brains of the rats, making the animals function more effectively. Sex Ilorrnone.a and Emplryaeina A potentially significant report during the year came from a Council grantee who has been working on the experimental induction of emphysema in rats. 1fe has sought to determine whether such induced disease would kad to pulmonary hypertension and cor pulmonale as in man. It was found that daily injections of progesterone (the female sex hormone) and medroxyprogesterone (in a dose 1/50th that of progcsterone ) prevented experimental induction of emphysema in the rats by a method that other- wise was successful. Another grantee, treating rats daily with nicotine injections, found an elevation in urinary excretion of catecholamines that peaked after three days. After seven days of continuous treatment, there was a marked fall-oft in the urinary Ievels, and by 14 days the ealecholamine excretion was essentially normal. TAis suggrsts a physiological accommodation or adjust- ment over a pericxl or time to chronic administration c>< nicotine. The scientist explored three poasibk mechanisms that might be reslxxr- sible for the return to normal of the ekvated urinary cateclVamines. He concluded that tolerance to the nicotine-indueed elevations of urinary 17 16

catecholamines resulted from increased metabolic enzyme activity that in turn led to faster metabolism of the catecholamines released from the adrenal medulla and adrenergic nerve terminals. Other Studies r.on6-Tern. Strdy of veter.ns The Council haa been participating In a kmg-term study that en- compasses periodic cxaminatiorn o( more than 2,0(X) male veterans. Pur- pcne of the projeet, which is supported mainly by the Veterans Administra- ticm, is to investigate a broad range of changes that occur in initially healthy persons as they age. One ultimate purpose of the investigation is to karn what factors may be predictive of longevity or conversely, of early decease. In this study the investigatcxs became aware of "secularity effects" as widely encountered, complicating factors in studies of human populations that extend over relatively Mng periods of time. While in well-designed anlmal experiments environments can be kept quite constant except for the independent variable to be studied, changing cultural and technological aspects of human Gfe introduce time-dependent alterations that are often not taken into account. In a book published in 1971. the two investigiton conducting the project noted that when they learned substantial numbers o( centenarians were heavy smoken, they gave serious thought to the possibility that smok- ing was secular, rumely, "that the earlier death of those that smoked more and those that smoked cigarettes was due to the fact that they were born tater and lived at a time when there was more smoking, rather than because smoking was hfe-ahortenin8." Their findings, they said, sugaest that the correlation seen between smoking and age-at-death may at kast partially be explained by the secular increase in smoking. They further twted that in a study such as thcin, "in which all the individrab die essentially at a single point in time, one can- not precisely rressure the effect of smoking on longevity since the prob- ability of a given individual being a cigarette smoker or nonsmoker Is re- lated to the birth year." Secularity eReets, the authors suggest, rsay influ- cnce the results of many longitudinal human population studits. Riocfremicof E/Jects of Stre» In a continuing study supported by The Council of certain biochemical effects of chronic smoke inhalation by'guinea pigs, a researcher was able to detect effects of stress and smoke inhalation on lung mitochundrial phosphorylation. l hc nostrils of the animals were occludcd with warm, molten paraffin or a quick-setting, liquid silicone rubber to insure mouth breathing. Sham-exposed animals were subjected to nose plugging, con- finement and machine noise without smoke. The stresses of forced mouth breathing, handling, confinement and noise resulted in losses in oxidative phosphorylation efficiency in the guinea pig mitochondria. ffowever, such loss of efficiency was considerably re- duced by cigarette smoke inhalation. Nicotine is not the active agent in this effcct. Twin Studies With financial aid from The Council, an international symposium on twin studies was held in San luan, Puerto Rico, December 1-4, 1969. A report on the symposium, titled "Twin registries in the study of chronic disease with particular reference to cardiovascular and pulmonary disease," was published in Acta Medics Scandinavica, Supplementum 523. 1971. The report discussed research into smoking that involved twin regis- tries in Sweden and the United States. It said the clinical twin studies "do indicate a presence of genetic factor in coronary heart disease and in variables which have been found related to it. For instance, blood prrssure, serum cholesterol, and triglycerides tend to be correlated between the members of pain, and in addition post-exercise ST-dcpressions of the ECG were the same in the twin pairs regardless of smoking." The report further said: "A statistically significantly higher mortality among smokers was shown in dizygotic male pairs, born in 1901-1925, but not in monozygotic male pain, or in femaks of either zygosity. No In- creased mortality was apparent among smokers in the older age-groups (1889-1900)." . Also in 1971, a sKcond suppkment to the 1961 monograph, "Tobacco - Experinxntal nd Clinieal Studies," was published. This was an update of the colkction, abstracting„ and analysis of the world literature on tobacco and includes published reports on both experimental and clinical studies. T.,e Council has supported this project throughout. 19 18

Abstracts of Reports Following are ahstracts, apDroved by the authors, of reports on new expcrimental research aeknowledging support from Thc Council that have appeared in scientific journals since publication of the 1969-711 Report. 7 he name of the recipient is in italics. The abstracts are grouped under these headings: 1. Psychophysiologi- cal Studies, I1. C'arcinogenesis Studiea, 111. Cardiovascular Systern, IV. Rcspiratory System, V. Tissue and Organ Culture, V1. Studies at the Cellular Level, VII. Pharmacology and Psychopharmacology, VIFf. Me- tabolic Studics, IX. Chemistry and Bioehemntry, and X. Epidemiology. 1. Psychophy.toloRtcol Studies PSYCHOLOGICAL ASPECTS OF CIGARETTE SMOKING IN MF:N: A CLINICAL EVALUATION Certain psychological factors influence smoking behavior patterns; psychological factors, the sanx or others, are also involved in the discon- tmuance of the habit. In this study, heavy cigarette smoking in men is theonlud to be associated with an oral-impulsive penonalily constellation. Clinical interviews with 130 subjects, representing non-, former, mild, and heavy amokers, supported previcws questionnaire findings that thc last named group is characterized by features of: defiance, rmpulsiverxss, danger-seeking, neurotic labaity, and oral preoccupation. In (his sampIc, heavy smokcrs' relationships with their fathen were more disturbed than were the other groups' paternal relalionships. Intensive follow-up interviews with a small selection of subjects indicated factors associated with starting and stopping smoking and an alternate personality pattern in heavy smokers previously seen as false negatives on the questionnaires. This subsample handled underlyin6 oral conflict with traits of obsessiveness, guardedness, aqd cautiousness. Former smoken seem able to discontinue the habi: when pcrsonally nxaningful, prn itive events occur and/or when their health is actually threatened. Bolh life events and factors of personal resoutcefulness are relevant in understanding why some men can give up the habit and others cannot. Jacobs, M. A., Knapp. P. l/., Rosenthal. S, and Fiaskcll, 1). P.tychotonfaric Medicinc 32 ( 5):469-485, 1970. From the F-Svision of Psychiatry. Boston University School of Medicine, Boston. SOME VARIABLEiS CONTRIBUTING 1-0 TIiF ONSE?T Ul' ('IGA- RCTTE SMOKING AMONG )UNIOR HIGH S(-FI(X)1. STttl)FN1S By analyring tlutknt resporues to  detailed questionnaire. thir dudy systematically expforcd a subject's perception of the conditions and forces present when hc smoked for the first time. The sample consisted of a total of 2,729 junior high scho students., According to their answcrs, rc- spondcnts werc ranked as nonsmokenol ertPerimental smokers, or regular smokcrs. Results showed that smoking by junior high school students was partly a function of smoking incidenee by their prevailing models since one of the bcst predictors for children smoking is slill whether or not their parents snoke. Regular smoking adolescents appcared to have thc highest proportion of parents and friends who smoked regularly. The sociaF nature of smoking became quite obvious when the data were analyzed. Boys were generally either encouraged to smoke or actually smoked with other boys whik girls maintained the same relationship with other girls. Neilhcr parents nor siblings appeared to assume any direct role in the instigation of smoking. The age at which the first smoking experience occurred varicd somewhat for boys and girls. By age 12 most boys who were going to try to smoke had already done so while most 4ir1s had al least tried to smoke by the age of 14. Girls re/rained from smoking because of the possibility of parental disapproval while boys were afraid of its potential effect on their athletic skills. Changea in students' smoking status occurred in spite of their Enowkdge bout potential harmful effects and their assessment of parental disapproval. Thus the meaning ascribed to smoking bX the culture and its place in the adolescent subculture was of maximum rmportancc to the sludents. Pafiner, A. B. Social Scirnce and Medicine 4:359-366, 1970. From the Department of Psychology, University of Toledo, Tokdo, O. VISUAL DEPRIVATION AND PAROTID RESPONSE TO CIGARETiE SMOKING Smoking while blindfolded slgniBcaAlly and consistently reduces sa- livary flow rates compared to flow rates associated with normal smoking. In this experiment, cigarette smoking signifkantly increased parotid salivary secrelion in eight smokers and eight nonsmokers. Obstructing vision by wearing opaque gogglca consistently reduced the salivary response to smok- ing in all 16 subjects. Unstimulalcd resting levels were lowcr when vision was blocked, suggesting a more general phenomenon than merely removal of the sight of the stimulus-objecl. Smoking cigarettes through a Cambridge filter assembly, which trapped the particulate matter and rendered the exhaled smoke invisible, had no effect on salivary secretion. This indicates that the salivary stimulation derives from irritating materials in Ihe gas phase of the smoke. PanirAorn, R. M. and Sharon, 1. M. Phytio7ojry and Behavior 6(5):559-561, 1971. From the Fkpartnunt of Food Science and Technology, llniversity of California. I)avis, and the University of the Pacific Schtwd i f Ikntiary, San Francisco. 20 21

SOME CNARA(TFRISTICS RELATED TO TIEE CAREER STATUS OF WOMEN PHYSICIANS Between the years 194R and 195R, 81 women graduated fmni ihe Johns Hopkins Medical School, often with grade records surpassing those of their male classmates. Of these 81 women, 69 were in active prac ice in 1967. Over one-quarter had ttained specialty certification and 219 held professional appointments; these two criteria were taken as a crude m.:asure of career success. Two factors related to career status were marital status and family size. BeinR married, especially at an early age, was associated with a less successful career, as was increasin8 family size. Althourh nearly 78% of these graduates had married, the most successful women, the "pro- fessors" 8roup, were most likely to be single. They were also more likely to be regular cigarette smokers and to have lower scores on "habits ol nervous tension" than their colleagues. In these two respects the) were similar to their mak medical school co(lea(Ives. Daughters of managers and proprietors had the best arades and most Qrominent careers; daugh.ers of physicians were rnost likely to be In practrce. It is suggested that f,art of the reason women medical graduates do not realize their full potential in later careers lics in the views and practices of society. Westlin8-Wikstrand. EI., Monk, M. A. and Tho.nas, C. B. The Johns IropAint Mrdk-al Journal 127( 5):273-286, 1970. From the Department of Environmental Medicine and Community Efealth, State University of New Yor1t, New York CSty, and the Department of Medicine, The Johns E(opkins University School of Medicine. Baltimore. PERSONALITY CHARACTERISTICS OF MEDICAL STUDENTS AS REFLECTED BY T11E STRONG VOCATIONAL INTEREST TEST WITEI SPECIAL REFERENCE TO SMOKING EIABITS The Strong Vocational Interest Blank (SVIB), a psychological mcas- urrment toof, was administered to Johns Nopkirsa medical students in seven consecutive classes graduating in the period 1958-t964. A total of 383 white male students with known snwkin8 habits at a mean age of 23.2 years completed the SVIB. Using the SVIB and smoking mcasurements, discrim- inant function analysis for two criterion poups was carried out by means of a multivariate program. Results showed that smokers and nonsmokers had significantly different personality characteristics as measured by the SVIB; this overall diRerence was highly significant. When single SVIB variabks were compared, light ciprctte smokers shared some of the main occupational interests of the heavy smokers. but had distinctive differences as well. Pipe smoken were significantly different from nonsmokers in regard to another set of single ocupational variables. In 1968 the smoking habits of the test group were rechecked and it was found that less than a third of the original group of heavy cigarette smokers had stopped smoking. 'Elsc group of physicians who had stopped smoking more closely resembled non- smokers in their vocational interests while in medical school than did those who were continuing to smoke. Thomas, C. B., FarBo, R. and Enslein, K. The Johni flop4ins Medical Journof 127(6):323-335, 1970. From the Department of IHedicine. The Johns Hopkins University School of Medicine. Baltimore, and The Genesoe Computing Center, Inc., Rochester, N. Y. CFfARACTERISTICS OF MALE MEDICAL STUDENTS RELATED TO THEIR SUBSEQUENT CAREERS This study of 724 1948-1958 male paduatca from Johns Ifopkin. Medical School shows that academic standing and age at 8raduation were closely asuxiated with professional careers. The t~re of practice, the attainment of specialty boards, and to aome extent the academic position of those on medical school faculties were all related, sometimes in a com- plex way, to class standing and a8e. Other factors such as tathcr's oceup.- tion, ethnic background, type of college attended, and son,c selected psychob8jcal and physical measures were not signiBcantly related to later careers. Marital status during medical school seemed to have sonre rela- tirxrship to later achievement reprdless of academie standing and age. In this study medical school grades were definitely related to later achievement for graduates. It is not clear whether or how grades reflect later ability but they do seem to influence careers. That grades do influence opportunities for graduate training and careers suggests that thest grades should be based on courses and training adequate to the variety of activities which physi- cians are now expected to perform. Monk, M. A. and Thomar, C. B. The Johns Hopkin.r Medical Jounwl 127 ( S):254-272, 1970. From the Department of Environmental Medicine and Community Health, State University of New York, New York City, and the Department of Medicine. The Johns Hopkins University School of Medicinc. Baltimore. 11. CarcinoRene.la Studies T()MORI POLMONARI DA IDRAZINA SOLFATO A DOS1 RIDOTTE IN TOPI BALB/c/Cb/Se OONADECTOMIZZATI Administration of hydrazine sulfate Increased the percentage of pulmonary tumon in Conadectomized, intact virpn, and breeding female mice. Tumors were Induced by hydrazine sulfate in the same rrequency in 8onadectomiz.ed mice and in intact virgins. Endo~e n ovarian stimulation associated with hydrazine sulfate induced in breedcrt pulmonary tumors more malignant than those seen in intact virgins. Without hydrazine sul. 23 22

fate, the incidence of pulmonary tumors in gonadectomhed 13Ai_fi/c/ C'b/Se mice was as low as it was in the controls. Bioncifiori, C. Lav. Anat. Pat. PeruRia 30(2):113-119, 1970. Other support: Anna Fulkr Fund. From the Division of Cancer Research. University of Perugia, Italy. T(1MOR1 POLMONARI ED EPATICI DA IDRAZINA SOLFATO A DOS1 RIIX)TTF. IN TOPI BALB/c/Cb/Se In these investigations, the incidence of spontaneous pulrionary tumors was low (24% in males, 4% in femaks) whilc that of liver ~unrors was urn. Ifydrarinc sulfate administered in reduced drnes increased the frequency of pulmonary tumors as follows: 0 56 mg (total mR R t), 65 % in males and 76% in fcmaks; 0.2e mg (total mg 42). 62% and 89%; 0.14 mg (total mg 21) 54% and 32%; 1.13 mg (total mg 32). RS 76 and 75'f6, and induced liver tumors: 0.56 m6, 7% in males and g% in fr males; 0.29 mg. R% in maks. When the average induction time of pulrnonary tumors was longcr, liver tumom were also observed. MorpholoFicr Ily the pulmonary tunxxs were adenornas and/or carcint.mas; thc liver :umors were highly vasculariud hePatocarcinomas. The possibility of ir ducing F ulmona7 nd liver tumors in mice with per-kilo dosts of hydrarine sul- ate, equivalent to thosc pcr-kilo derived from the adminisaration of isoniarid in man, is important for its applicability to the use af isomiarid in human pathology Biancifiori, C. L.ov, Anat. Pat. PeruRia 30( 2): E9-99, 1970. Other arpport: Anna Fuller Fund. From the Division of Cancer Research, University of Perugia. Italy. OVARIAN INFLIIENCE ON PULMONARY CARCINOGENESIS BY NYDRAZINE SULFATE IN BALB/e/Cb/Se MICE Alteration of the hormonal state of mice influenced the incidence of pulmonary tumors induced b7 hydravne sulfate (IfS). Daily administra- tion of IfS to BALB/c/Cb/Se female mice in various hormonal states varied the incidence and the average number of pulmonary tumors per tumor-bearing mouse as follows: in intact vir6ins, 90.0% and 3; in breedcrs, 1(x)% and 14; in gonadectomizrd mice. 60.0% and 5. Ftistologically, in intact virgins. 3.3% were carcinomas and 96.6% were adenomas; in brceden, 47.2% were carcinomas and 52.7% were adcrximas; in Rona- dectomired mice, 4% were carcinomas and 96% were adenomas. Many pulmcx+ary carcinomas induced in breeders infiltrated the thoracic wall and the mcdiastinal organa and rnetastasized to the adrenal glands nd myo- cardium. '1 he irx•reaud biologic and rntxpholoRic malignancy of pulmonary tumors seems to demonstrate that a greater ovarian hormone production. as occurred in breeders, accentuated the already existent susceptibility to pulmonary tumor induction in BALB/c mice. Whether this is asscxiatcd with an inhibition of the immunologic factors remains to be dctcrmined. 8iancifiori. C. Journal o/ the National Cancer Inttitute 45( 5):965-970, 1970. Other support: Anna Fuller Fund. From the Division of Cancer Research, University of Perugia, Italy. CANCER(x1ENFS1 DA IDRAZINA SOLFATO IN TRAPIAN"1I ISOrENI('I TRACFIEO-BRONCOPOLMONARI IN TOPI BALB/c/Cb/Sc Carcinogenic activity of hyorazine sulfate on the trachca, bronchus, and lung fragments of ncaborn BALB/c/(b/Se mice, transplantcd to the same strain, was studied ia this e><perinxnt. The lung fragments by them- selves showed 35% adencmas and 13% eareinomas. When the lung frag- ments were transplanted, )ydratine sulfate induced tumors, which showed greater malignancy, in a s7wrter time in the newborn lung fragments than it did in the lungs of the adult hosts. It would seem that this was caused by the marked susceptrbiiity of newborn mouse tissue to the carcinogen. Explanation of the findir.gs with regard to the divergent frequencies at which the trachea, bronc:ii, and lung parenchyma developed tunuors re- quires further research. Biancifiori, C. Lav. Anar. Par. Prrugia 30(3):137-146, 1970. From the Division of Cancer Research, University of Perugia, Italy. TRANSFORMATION AND PRODUCTIVE INFECTION OF IIUMAN OSTEOSARCOMA CELLS BY A FELINE SARCOMA VIRUS The studies reported here indicate that feline sarcoma virus ( FSV ) can transform human osteosarcoma cells; two lines (MT-1'SV and MT- FSV, subline 2) of transformed cells now have been established. When compared with the parent MT cell line, the FSV-transformed lines have, in early passage, an altered morphob~y increased sataration density, in- creased growth rate in 2% serum, and increased plating effxicncy in agar. The transformed cell lines contain C-type virus particks and feline C-type virus antigens not detected in the M'T line. Particles released from thc transformed lincs have a hoat range (do; and human cella) similar to that of the parent FSV. •Cclls of aubline 2 in seventh passage induced fibro- sarcomas in prenatally inoeulated kittens; the tumor cells, adjacent muscle cells, and submaxillary gland cells shed C-type particles. In a second set of experiments, the cells of the osteosarcorna cell Pne 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-transformed beagle cells). llrcx transformed cclls, as those in the first experiment, contained fciine ('-typc 25 24

virus antigens, shed particles with focus-forming activity on hcaRle and human cclls, and exhibited C-type vinis morphology and a density of ap- proximately 1.16 g/cc. McAllister. R. M, Filbert, J. E., Nicolson, M. O, Rongey. R. W. Gordnrr, M. R., Gilden. R. V. and Fluebner. R. J. Norurr New Biology 230(17 ):279-2g2, 1971. (hh.r.rpport: National Cancer Institute. From the Departments of Pediattica and Pathology. University of California School of Medicine, Lo. Angeles. REDUCED LYMPHATIC DRAFNAGE FROM HAMSTER CFI[iFiK Pfll>CH: A PROPOSED EXPLANATION OF ITS IMMUNOF-(X;ICAI.LY PRIVILEGED CFIARACtER To answer the question of whether or rsot a direct route exists Ixtween the hamster's check pouch and its regional lymph nodcs, the kft check M hes of eight golden hamsters were everted and injected with 0.1 ml of in. Serial sacrifices were performed at intervals of 2, 4, 6, and 24 hours post injection and the kft cheek pouches, kft and right su xnental lymph nodes, and livers were removed and histochemically stained. .\nother group of eight hamsten, serving as controls, received 0.1 ml of the ferritin solution intracutancously to the left part of their upper lips. These .nimals were sacrificed and their tissues processed as in the cheek pouch group. Histochemically demonstrable iron was prexnt only in a.few toc of the ipsilateral nodes in the group sacrificed at 24 hours post injection of ferritin in the cheek pouch. In eomParison, the same nodes already contained a greater amount and distribution of stainable iron at two hours after injec- tion to the lip. These results Indicate that while there is a direct route from cheek to lymph node, drainage via this route is reduced and delayed. Im- munolosically, this situation of  reduced and delayed drainage from the hamster eheck pouch affords foreign grafts in this site a decisive advantage for prolonged survival. Gofdrnbert. D. M. Exlxritnrla 26( 8 ) :907-90R. 1970. From the Department of Pathoiogy. University of Pittsburgh Sc',wool of Medicine, Pittsburgh. IIISTOGENETIC RELATIONSNIP BETWEEN CARCINOIDS AND MUCIN-SECRETING CARCINOMAS OF COLON AS REVEALED BY FIETEROTRANSPLANTATION A human colonic eeoplaun with morphologic characteristics of a carcinoid was successfully transplanted to cheek p~iuches of adult golden hamsters after a short ao}ewrn in cell-impermeable chambers in rats Al- though no mucin-secreting cella were detected in (he dimor carcinoid, the check pouch trsmplants exclusively exhibited mucin-seereting tumor cells of signet-ring type consistent with adenocarcinoma. This transplantable turnor, designated GW-77, has retained this appearance as well as expan- sive growth characteristics in xenogeneic hoats for a period of four years. The findings presented here represent strong biological evidence consonant with views advocating a hislogenetic relationship between colonic carcinoid and adenocarcinoma. GofdenberR, f). M, and Fisher, E. R. British /ournal oJ Cancn 24( 3):610-614,'1970. Other.rrportr U. S. Public Health Service. From the Department of Pathology. University of Pittsburgh School uf Medicine, and the Veterans Administration Hospital, Pittsburgh. RE[)UCE[) I.YMPHATIC DRAINAGE FROM HAMSi'ER ('FiEEK POUCH A transparent is+olation chamber permitting continuous observation of the hamster cheek pouch wu used to study the movement of injected India ink from the cheek pouch wall to the regional cervical ipailateral or contra- lateral lymph nodes. Th,e isolation chamber was constructed specifically to obviate the experimenta.^ error of dye leaking out of the cheek pouch proper to adjacent tissues. A brownish-black coloration of only the ipsilateral sub- mental lymph was first observed 20 hours after Injection; the coloration was definitely localized ¢ven though distinct lymphatic channels in the pouch could not be sa:n. Thest finding>t knd support to the thesis that there are lymphatics In the hamster cheek pouch. Compared to the time rsecet<sary for egression of dye from other areas of the hamster head, it appears that there is a delayed lymphatic drainage from the cheek pouch, by a factor of ten. In light of these observations, It is suggested that the so-called "immunolosically privileged" character of the bamster cheek pouch is related to a delayed and reduced lymphatic drainage from this site. f;oldenbtra, D. M., and Steinborn, W. Proceedings oJ the Society /or EsprrLnenta( Biology and Medicine 13 S( 3): 724-726, 1970. From the Department of Pathofogy, University of Pittsburgh School of Medicine, Pittsburgh. RETENTION OF HUMAN PROPERTIES BY A XENOGRAFTED IIUMAN COLONIC TUMOR, GW-77, PROPAGATED IN UNCONDITIONED HAMSTERS GW-77, a newly established transplantable neoplasm of human colonic origin, is capable of expansive growth In uneonditicxted, adult golden hamsters. l?tis unusual 6trowth-behavror of GW-77 raises a question as to the lurmx's spocics-idenldy. In the present study, this question was studied by immunofluorescent and biochemical means. Both the direct fluorescent antibody test and its lactate dehydrogenase isexnzymonwbJity 27 26

pattern rcvealed the human specics-specific character of GW-77. Thc rc- tcn/ion of its original sprcics•identity is consistent with GW-77's rclalivcly Icss malignant, only locally expansive, growth-behavior in various sitcs of the hamster. Goldrnhrrg, I). Af., Bhan, R. D. and Pavia, R. A. I'rocrrdinRs of the Scx rrly for Experimental Biology and Medicinr 135 ( 3): 657-659,1970. Other support: National Cancer institute. From the Department of Pathokgy. University of Pittsburgh School of Medicine, Pittsburgh. STATHMOKINF.TI(' EFFECT OF COLCEMID ON A PRF_SI1MPfIVF. IIl1MAN IIAMSTER IIYBRID TIJMOR, GW-47R -The action of Cokemid on the aacitcs variant of the (7W-47R tumor, originally a human stem-cell lymphoma propagated in hamster chcek pouches, was compared to its action on Fortner's hamster amclanotic melanoma A. Mel No 3. The two tumor types exhibited strikingly drflerent slathmokinetic responses to the alkaloid Colccmid. T-he percentage of un- trcaled sscitcs tumor cells in metaphase wa.s found to be 0.98±0 I' and 0.95!0.23 for GW-47RA and A. Mel. No. 3, respectively. The a-.oRee of inetaphasc arrest in the A, Mel. No. 3scites tumor cells occurrcJ at a dose of 60 mg/kg Colcemid, whik the pogee for GW-478A was at 20 mg/kg, These results, which were quite uncxpected, indicate that (;NI-478 ascites tumor cells resfu,nd to Colccmki more as human than as hamster cells. It appean, thercfore, that althcwgh GW-478, a highly malignant trans- plantable tumor in unconditioned hamstcn, predominantly has hamster-like properties, it lacks the S7rian hamster's genetically controlled resistance to this coichicine derivative. This further supports the hybrid character of this neoplasm and the usc of this trait as a genetic marker in hybridiza- tion experiments with Syrian hamster and other xenogencic cells. Coldrn6rra, D. Af. Experimental and Molrcular parhology 14(1 ):134-137, 1971. Other support: National Cancer Institute. From the Depa rtment nf Pathology. Temple University Health Scicnccs Center, Philadelphia. INNIBITTON OF MURINE SUBCUTANEOUS AND INTRAVENOUS BENZO(RST)PENTAPHENE CARCIN(X;ENFSIS BY SWEET ORANGE OI1,S AND d-LIMONENE Orange oils and d-limonene slow the rate of tumor formation following subcutaneous injection of benzo(nt)penlaphene (DBP) in C57B1./(i lax mice. 'fhes,e anticardnrrgenic rtia of the terpenes were discuvercd during the course r+f studies siEned to evaluate the pcnsiblc cocarcino- genicity of natural lerpcncs (citrus oils) and of pure d-limoncnc in sub- cutaneous injccticrn sites and in the lungs of mice. In the studies reported here, injections of orange oils with low and high lerpene content, d-limo- ncne, and a mixture of d-limonene and 6% of its hydropcroxidc were made into the samc site of C578L/6 lax mice 24 hours aflcr subcutaneous in- jections of 25 r.g DBP in tricaprylin. This procedure reduced the tumor incidence to Icss than 50% after 30 weeks (compared with 80% in con- trols receiving the carcinogen alone or the carcinogen followed by tti- caprylin). 'Ebe time of latency was markedly prolonged. In A/lax mice with spontaneous adenomas and adenomas induced with subcutaneous carcinogen, orange oils, as well as limonene, reduced the incidence of lung adcnnmas when given weekly for from 13 to 16 weeks. The accclcration of tumor growth usually observed following the transfer of multiple prxrlcd carcinogen injectirm silcs into new hosts was inhibited by orange oils IlomAurRrr, F., T reger, A. and Bogcr, Ei. Oncology 2 5:1-1 U, 19 71. Other support: American Cancer Society and U. S. Public Ifcalth Service. From the Bio-Rescarch Inslitute, Cambridge, Maas. I EINFLUSS CIIRONISCHER INHALATIONEN VON FRISCEfEIEM ZIGARETTENRAl1CII IJND DESSEN GASPIIASE Al1F DIE ENTWICKLUNG VON LUNGENTUMOREN BEI SNE'sE.L'S MAUSEN Chronic inhalation of tresh cigarette smoke and of the Fas phase alone contribute to the carcinogenesis of glandular lung tumon in Snell mice. In experiments reported here, one group of mice was exposed chronically, i.e., over the longest possibk time span, to total cigarette smokc, and another group for an equal kngth of time to only the gas phase of the smoke; a third group of Snell mice served as a control. Two t~pes of glandular lung tumon, adcnomas and adenocarcinomas, were observed in these animals. In the controls, the mak animals exhibited twice as many spcx~taneous lung tumors as the females. After inhalation of cigarette smoke the number of lung tumors was increased; this increased frcquency of tumors was particularly noticeable after inhalation of the gas phase. ll+e effect was more marked in mak than in female mice. It is interesting to note that in the controls, most of the tumors were observed only in mice which were nwrc than two years old, whereas in the majority of the ex- perimental mice turnon were found at a much earlier age. BrorKhogenk carcinoma, such as that which frequently occan in human cigarette smok- ers, was never observed in the mice. Since adenomas and adenocarcinomas were found in controls as well as in experimental mice, it seems reasonable to suggest that inhalation of cigarette smoke by mice enhances more or less celrular abnormalities which are already present in the lung of the mice. Leuchtrn6eran, ( : and Leuchtenberger, R. T.riuchri/t fur PravrnrlvmrdrLln 17:457-462, 1970. From the Swiss Institute for Experimental Cancer Research, I.ausannc. 29 28

7C. ~ ...r. ~ .... EFFECTS OF CHRONIC INHALATION OF WHOLE FRESI( CIGARETTE SMOKE AND OF ITS GAS PHASE ON PULMONARY TUMORIGENESIS IN SNELL'S MICE Does chronic inhalation of fresh whoie cigarette smoke conrainin6 particulate matter have the same or a different biological effect than that of inhalation of the gas phase of fresh cigarette smoke? To answer this question. 467 inbred Snell's mice were exposed to chronic inhalatton of puRs of whole frssh cigarette amoke or of its gas phase alone for ont year or longer. The smoking machine used for this experiment permitted ex- posure of individual mice to inhalations of pufls o( cigarette smoke alter- nating with air. Exposure to both whole ciaarette smoke and its gas phase a/one resulted in an earlier occurrence and a higher frequency of gla,.dular pulmonary tumors when compared with those of controls. The enhance- ment of pulmonary tunwri8enesis was particularly striking after exposure to the gas phase alone and was more pronounced in males than In fr males. Males exposed to the gas phase disclosed not only a significant shifr from pulmonary adenomas to ~nocarciramas, but the frequency of adc#xrcar- cinomas was 23%, that is, five times 6reater than that of controls, which was 4 7%. No bronchogenic carcinoma was observed in controls or in mice exposed to whole fresh cigarette smoke ot its gas phase. Leuchttnberan. C. and Leuchtenber8er, R. In Nettesheim, P., Nanna, M. G., )r., and Deatheragc, ). W., Jr. (cds.): Morpholoay of f:xptrinwntol Rtspirorory Corcinotencsis, Oak Ridge. Tenn.: U. S. Atomic Energy Commission, 1970, pp 329-346. From the Swiss Institute for Etperimental Cancer Research, Lausanne. EINFLUSS VON FRISCHEM UGARETTENRAUCH AUF DIE ENTWICKLUNG VON LUNGENTUMOREN UND AUF LUNGENKULTUREN BEI DER SNELL-MAUS TTThis report deals with the efiect of chronic inhalation of cigarette smoke on the developnxnt of lunt tmsors in SoeB's mice, and the influence of citarette smoke on alveolar gn growing out from lung explant cultures of Snell's mice. Results of these e:periments showed that chronic inhalation of whole fresh daarette stnoke, or of ita aas phase alone, occa- sioned Ure earlier occvrreoce and higher frequency of lung tumors in Snell's mice. This enhaneement of pulmonary adenomas and adenocarcinomu was particularly striking after espawre to the 8as phase alone and more pronounced in rnaks than In femaka; no broncho8enic carcinoma was ob- served. Lung explant cultures, which were exposed to whole charcoal- filtered ci8arette smoke fran which cytoloxic factors were nearly all eliminated, showed a aclet.tive damaee to the alveolar macropha8es. After exposure of lung esplant cultures to the 6as phase from ehareo.l-filtered cigarette seake, the alvedar macroPhases showed a aekctive atimulation o( DNA synthcsis. These results indreatt, on one hand, the importance of particulate matter for the Inhibition of cell metabolism, and on the other 30 hand the importance of the gas phase for the stimulat on of cell metabolism of alveolar macrophages. i.euchtenfrerger. C. and Leuchtenberger, R. SchwtiLtrischt MediZinischt Wochtn.rchriJt 101(38):1374-1381, 1971. Other.upport: Association Suisse des Fabricants de Cigarettes. From the Swiss Institute for Experimental Cancer Research, Lausanne. LYMPHOSARCOMA IN THE RABBIT: GENETICS ANI) PATHOLOGY • Lymphosarcomas are rare in rabbits. However, since 1962, 29 rabbits of strain WH at 1 he Jackson Laboratory have exhibited lymphmarcoma. Because of this unusual aggre6ation of lumors, the pedi8rees of the affected animals were analyzed. 'I he inheritance indicated an sutosomal recessive gene conferring susceptibility to lymphosarcoma; this sene was designated Is. The data were compatible with both concepts of genetic susceptibility to lymphosarcoma and vertical transmission of a virus. The neoplastic in- volvement of Iymphoreticular and other orsans, especially kidneys, cor- responded to a pattern observed in lymphosarcoma of other domestic animals. Specificallr, it resembled in many ways visceral lymphos.rtomato- sis of cats which has been proved unequivocally to be caused by feline leukemia virus. Because oC the vast amount of rnorpholo6ic, physiologic, and biochemical data available on rabbits, the simplicity of rabbit care nd breedina, and their large sixe, rabbits are of considerable value in biomedical research. The finding of 1ymphosarcoma and its hereditary basis provides a new nd important model for studies of the pathogenesis of neoplasia. Fox, R. R., Meier, fl., Crary, D. D., Myen, D. D., Norber6, R. F. and Laird, C. W. Journal of the Not{onal Cancer Institute 45(4):719-729, 1970. Ot14er.rpportr U. S. Public Health Service and Hycet, Inc., Houston. From The Jackson Laboratory, Bar Harbor, Me. MALIGNANT TRANSFORMATION INDUCED BY 7,12- DIMETIiIYLBENZ(a)ANTHRACENE IN RAT EMBRYO CELLS INFECTED WfTH RAUSCHER LEUKEMIA VIRUS Morphological alterations of cells and an abnormal growth pattern were noted 42-45 days after trestment of Rauscher kukemia virus ( R1.V ) infected rat embryo ( RE ) cells with various levels of 7,12-dimcthylbcnt- (a)anthraeene (UMBA) for seven days. Uninfected cells treated with DMBA and RI.V-infected RE cells untreated with DMBA failed to show any evidence of transformation. When stained with Giemsa, the foci of transformed cells consisted of randomly oriented eriss-cn.csinR spindle- shaped cells having much more rapid replication rates than the untreated and untransformed RE cells. The transformed cells were more resistant 31

m ~ r m to the toxicity of DMBA than were the untreated RE cells and aily the trancformcd cells were capable of producing local subcutancous sa •cornas when transplanted into newborn rats. When re-cstahlished in tissuc (ulture, cells derived from the tumors, like Ihe tumor tissue itself, contained group- specific complement-fixing antigens characteristic of the murine Icutcmia- sarcoma virus complex nd the C-type RNA particles. These results, which showed that both chemical and virus were required for transforriation, suggest that the C-type RNA viral genorne of RLV provided !pccific oncogene information for the malignant transformation. Rhim, J. S., Vass, W., Cho. I{. Y. nd Nucbner, R. 1. (Microhiologicof .1 rsuciarcr. Inc.) International lournal of Cancer 7:65-74, 1971. Ofhrr anpporf r National Cancer Institute. From the Department of Virus Rcsearch, MicrobiolrsRical Assr.ciata, Inc., and Viral CarcirnoRcrsesis Branch, National Canccr Institute, Bcthc.d.i, Md. POLMONITE INTERSTIZIALE CRONICA IN CORSO DI SARCOMA MURINO DA METILCOLANTRENE Ilistological examination of the lungs of 147 mice with mcthylcho- lan(hrcne-induced sarcomas or transplants of the same tunxxs revealed 24.5% chronic interstrtial pncumonia. Mice used for this study were of the C3H,B/Cb/Se. R111/I)m/Se, CBA/Cb/Sc, nd FI(C3f1.8/(_'h/Sc X RI11/Dm/Sc) strairn The pneumonia seen in these mice differed from bronchopncumonia, which is frequently scen in old micc, by reason of the age of onset, the ahscnce of alveolar exudatc, and the intense proliferation of septal cells. Malt7efl, N. (Severi. 1, / Lav. Anar. Pat. Prrugia 30( 1):1 S-2S, 1970. From the Division of Cancer Research, University of Pcrugia. Italy. I TUMORI I)El- POLMONE. DEL RETICOLO E DEI.LA MAM- MELLA NEI TOPI BALB/c/Cb/Se DISCENDENTI DA GENITORI TRATTATI CON URETANO NEL PERIOE>D NEONATALE: Two groups of BALB/c mice were treated as newborns with one and five milligrams of urethane respectively, and then mated. Offspring of these treated mice were followed in a study of the incidence of spontancous tumors. Descendants showed an increase of lung and reticular tunxirs, in male and female, virgin and mated mice. A discussion of the mcchanism through which urethane, inoculated into newborn mice, enhances spon- taneous tumorigencsis in the next generation is rcpcxtcd. Ribacchi, R. (Severi. L.) lav, Anor. Par. Prrulia 30( I):27-39, 1970. Fmm tlrc INvitii<,n 44 ('ancer Rexarch, University of I'crugia, Italy. 32 DF.TEC-IION OF A LUNG TUMOR AGENT IN IIALB/c/(b/Se IRRADIA'f E:D MICE In this inve-,tigation lung tissue from newborn mice was graflcd into adult syngcncic recipients previously panirradiated in an attempt to meet the most suitable cxpcrimcntal conditions for the detection of cndogenous lung tumor agents. Of the 29 recipients irradiated before grafting. 21 had recoverable lung grafts and five of thcm, or 23.8"6, showed alveolar adcnomas in their lung grafts. The number of lung grafts recovered from irradiated recipients was 44. No tumors were observed in the 43 grafts of newborn lungs recovered from 23 non-irradiated control recipients. A strong association was obscrved between leukemia in irradiated recipients and adenomas in the lung &rafts. Although four of the irradiated recipients died spontaneously of thymic leukemia and the recovery of lung grafts was not possible, four other mice were kukemic when killcd and three of these had recoverable lung grafts showing alveolar adcnomas. 'llasc results suggest that whole txxiy irradiation activatcs a lung tumor agent in BALB/c mice. Squartini. F. and Bolis, G. B. (Severi. L.) Lav. Anar. Par. Prrugia 30( 3):125-128, 1970. From the Division of Cancer Research. University of Perugia. Italy. DIVERSA SUSCF.'fTIBILITA DEGLI EPITELI A(-VEOI.ARE E TRACNEOBRONCEf1ALE DEL TOPO BALB/c/Cb/Se ALLA TUMORIGENESI DA URETANO NE:1 TRAPIANTI ISOGENICI Data relevant to the susceptibility of alveolar and tracheobronchial mouse epithclium to urethane tumorigencsis are reported. Grafts of trachea together with the lower section of larynx, of main bronchi, and of peripheral lung tissue of newborn BALB/c mice were subcutaneously impIanted in 2-moxtth-old isogenic mice. Five days after grafting, one group of mice was treated intraperitoncally with a single injection of urethane at the drne of I mg/g of body weight. Another group of untreated mice was used as thc control. Six months latcr, 86.4% of femaks and 96.1 % of males developed lung tumors of alveolar origin in the grafted lungs. No hyperplaslic, prcncoplastic, and/or neoplastic Icsion caused by the carcinogen was observed in the trachcal, laryngeal, and bronchial grafts No tunnors were obscrvcd in the controls. Ribacchi. R. (Severi. 1..) Lav. Anat. Pat. Prrumia 30(3):147-160, 1970. From the Division of ('anccr Rescarch, University of 1'crugia, Italy. 33 U CA A r

n ....rl 76, ...3. ~ 111. Crrrdiorasr•ulrrr System TH1: EVALUATION AND TREAI MF.NT OF C'ARDI(Xil'.NIC SHOCK This thorcwgh review paper discusses the clinical assessmcnt and therapy of cardiogenic shock and presents new information which coutd mcxhly n overall approach to the use of vasopressor agents in shocF. For diagnostic purpincs, shock is conventionally classificd into hypovolcmic (hcmorrhagic), scptic, and cardioglt:nic types. In each of these shock classifications, early diagnosis and institution of treatment are the l cy to improved survival. An cight-point, annotated schedule for Ihe assessment of the shock state is presented here. In cardiogenic shock, the goal of therapy is the restoration of myocardial function to the point where it can adequately provide the contractik force necesttary for the perfusion -4 the systemic circulatirx+. 'il+e use, as well as choice, cd vasoactive aRcrts for maintenance of satisfactory arterial prcuure in cardiogenic .:hock is u very controversial subject right now. Vasoactive agents discussed in dctai, here include I-norepinephrinc, isoproterenol, chlorprnmazine, mcterarninol, mctham hctamme, and dopamine; steroids and antibiotics also arc con- sidered ~rKny. Mucllcr, I(. S., Ayrri, S. M., Gregory, 1. 1., Giannclli, S., Ir., and (',race. W. 1. Mrdicol Timrt 98(7):137-152, 1970. Oth.r support: (1. S Public Hcalth Service. From the Departments of Medicine and Surgery. St. Vincent's Ilospitr:l and New York University School of Medicine. New York City. THE LUNG IN SHOCK: ALVEOLAR-CAPILI-ARY GAS EXCHANGE IN THE SNOCK SYNDROME In an attempt to delineate the effects of circulatory collapse on pulfnonary ventilation, this paper reviews certain physiologic considerations relevant to abnormal alveolar gas exchange in the patient with shock. Alveolar gas exchange in eight patients with shock revealed marked reduc- tion in arterial oxygen tension (PaO2) and increase in the alveolar-artcrial oxygen difference while they were breathing room air. Failure to adequately increase PaOt while breathrn6 100% oxygen indicated significant increases in venoarterial shunting nd demonstrated persistent perfusion of non- ventilated lung units. An Increase in the alveolar-arterial carbon dioxide difference indicated increascd alveolar dead space, suggesting that some alveolar units were undet'ptrfused. Continuous pressure breathing improved PaOn in six of seven patients but tendcd to incrcasc venous prescurc and reduce aortic pressurc. These obserraticxn suggest that alterations in lung functicxr are part of the generalized metabolic dccnmpencatiim seen in shixk I)ccrcascd pulmonary nutriticxr after decreased hkKK1 flow, incrcascd 34 Icft atrial preccurc, and pulmonary venoconstriction arc all implicatcd. Progressive pulmonary changes may preclude revcrsihility t+r thc shock state. Ayres. S. M., Mucllcr, 11., Giannelli, S., Jr., Fleming. P. and Ciracc. W. 1. The .1 mcricon lnurnul of Cardiology 26( 6): 588-594, a 970. Other support: U. S. Public Health Service and New York Ilcart Association. From the Departments of Medicine and Surgery, St. Vincent's liospital and Medical Center of Ncw York and Ncw York University School of Medicine, New York City. MYCX'ARI)IAL AND SYSTEMIC RESPONSES TO CARBOXYIII:M(XiLOBIN ' This paper reviews ceblain theoretical aipecls of systemic and myo- cardial oxygen exchange and summarizes a series of experimental atudies of the physiological eRects of relatively small amounts of carboxyhcmo- globin (COIIB). Measurements of alveolar-capillary gas exchangc, sys- temic hemodynamics, and myocardial metabolism were made in a series of h.tman and canine studies before and after the administration of amounts of either 5% or ().I % carbon monoxide sufficient to raise COILB satura- tion to between S and 25%. Arterial and mixed vcnous oxygen tcnsirms were decreased by administration of either concentration and changes could be identified with COHB saturations below 5%. Cardiac output and minute ventilation increased when COHB was elevated by breathing the higher concentration. The coronary arteriovenous oxygen difference was uniformly decreased and coronary blood flow increased when COIIB was raised to between 5 and 10% saturation with either gas mixturc in the human studies. Certain patients with coronary artery disease developed altered lactate and pyrvvate melabolism following elevation of COIIB suggesting myocardial hypoxia. Significant myocardial changes were seen in patients with ckvation of CO11B above 6% COHB. The caninc prcpara- tion, in contrast, was notably moro rrsistant to COHB and significant al- terations were not observed until COIIB saturation exceeded 25%. Ayrrs, S. M., Giannelli, S., Jr., and Mueller, H. Annals of the New York Academy of Sciences 174 ( 1): 263-293, 1970. Other .rpport: National Air Pollution Control Administration and Na- tional Heart Institute. From the Dcpartments of Medicine and Surgery, St. Vincent's 1{ospital and Medical Center, New York City. FIEMODYNAMICS, CORONARY BLOOD F1AW, ANI) MYOCARDIAL ME:TABOI-ISM IN CORONARY SLI(X'K; RESPONSE TO /-NOREPINEPHRINE AND ISl)PROTI:RI:NO1. This paper prescnls myocardial mctalxrlism and systemic hcrrw>dy- 35