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.k SCIF.NTIFIC ADVISORY BOARD to The Council for Tobacco Research-11.S.A., Inc. as of June )U, 1971 SIIFLIx)N C. SOMMERS. M.D.. Chairman Rrirarch Dirrctor, The Council for Tobacco Research-U S A, Inc. Director of Laharatorits, l.enox Hill Hospital Clinical PmJtswr of Pathology Columbia University College of Physicians and Surgeons New York. New York NOWARD B. ANDERVONT. Sc.D. Scientific F.ditor (retind), The Journal of the National Cancer Institute Bethesda, Maryland RICIIARD M. BINO, M.D. Director of Cardiology and lntrmnwal Mrdit inr Hunlington Memorial Flodpital, Paaadena, California Pro/rtsor of Mtdkine University of Southern California School of Medicine Los Angeles, California McKEEN CATTELL, PH.D., M.D. Professor Emcrltru oJ Pharmacology Cornell University Medical Colkge, New York. New York ROBERT J. IIUEBNER, M.D. Chic/, Viral Car+rinogenesis Branch National Cancer Institute Bethesda. Maryland I-EON O. JACOBSON. M.D. Dean of the Divirion of BioroRiral Sciences Rrgrnstein Professor of Biological Sciences University of Cfiiugo, Illinois CLARENCE COOK LITTLE, Sc.D.. LL.D.. LtrT.D. Scientific Director. The Council for Tobacco Research-U S.A., Inc. Director Enuritus, Roseoe B. Jackson Memorial Latxxatory Bar Ifarbor, Maine CLAYTON (;. LOOSLI. Pst.D., M.D. Hastints Professor of Medicine and Patholoty University of Southern California School of Medicine Los Angeles, California KENNETH MERRILL LYNCH, M D., Sc.D., LL.D. Chancellor and Professor En.rri(us of Pathology Medical Colkge of South Carolina, Charleston, South Carolina WILLIAM F. RIENNOFF, ltt., M.D. Profrssor Emeritus of Surgery lohns flopkins University Sdx)ol of Medicine. Baltimore. Maryland N~Y Q, ROBf?RT C. IIOCKFTT, Ptr.D. Acting Scientific Dbrctor m 1. MORRISON BRADY, M D. JOHN H. KREISIiF?R. Prt.D. 0 Asscxiatc Sci.nto/4c f)irerk+r Associatr Scientific )hrrrtor m VIN('FM F. LISANTI, D.M.D. tn rj ID Sc{rwN/Sc Associate I . (:LAREr1CE C(lOK L17TLE, Sc.D., I,I,.II., l.iu.l). 1888-1971 Dr. Clarence Cook Little, internationally known geneticist and cancer researcher, died December 22. 1971. lle had been Scientific I)irector of The Council for Tobacco Raearch-U.S.A., Inc. and its predecessor since shortly after the latter's establishment in 1954. 11e also served for many years as Chairman of the Scientific Ad- visory Board, an elective position for which only Board members vote. Former president of both the University of Maine (1922- 1925) and the University of Michigan (1926-1929), "Pete" or "Prexy," as he was known to colleagues and studenls, was a tower- ing figure as a man and as a scientist. Warm, dynamic, an en6agins personality with a sharp wit, Dr. Little was one of the fint scientists to discover evidence of a viral agent in eancer, an observation that led eventually to the generalized virua theory of cancer. He also did pioneering work in immunology and was one of the early re- searchers into the genetic eRects of radiation. Dr. Little founded the workf-famed Jackson Laboratory in Bar Harbor, Maine, in 1929. He served as its director until 1956 and as director emeritus until his death. lie formerly was Managing Director (1929-1945) of the American Association for the Control of Cancer, which is now the American Cancer Society, and was a Fellow of the Na- tional Academy of Sciences and a member of numerous other scientific societies. He uthortd many books and articles and his 1939 book, "Civilization Against Cancer," is still considered a classic for the layman. For 17 years Dr. Little gave The Council inspired scientific leadership and guidance. Ilis ccxHributions were many and important. He will be deeply missed.

Iritroduction CONTENTS •he Cancer Progam . . lCardiovaseutar Rcsearch I('hronic Respiratnry I)iseascs INeurophysiotogy. Psychc.physioloRy nd Pharmacology . Other Studic-t Abstracts of Reports . . . . . /Psychophysiological Studies JCarcinogencsis Studics . .C'ardiovascutar System . lRespiratory System . f'issue and OrRan Cul(ure . 6 . II 14 . 16 . IR 20 20 23 14 42 . . . . . . . . . . . 55 Studies at the Cellular Level . . . . . . . . . . 56 JPharmacoloRy and Psychopharmacology . . . . . . . 59 J Metabolic Studies . . . . . . • • • • • • • • 69 .rhcmistry and Biochemistry . . . . . . . . . . . 71 JEpidcmiolo6,y Active Projccts . . . Completed Projccts . 76 79 . 89 I Previous Annual Reports have stated the general research policics of The Council for Tobacco Researeh-U.S.A., Inc. as conceived by the Scientific Advisory Board. These policies, which continue to guide the program, emphasizc study of the etiology of those diseases that arc reputed to be related statistically in their incidence to cigarette smoking. Such diseases, especially eaneer, cardiovascular ailments and chronic respiratory afllictions, are not only leading causes of morbibity and death since the conquest of major infectious diseases but are universally recog- nized to be of multifactorial origin and to be strongly inNuenced by con- genital predispositions. The role of tobacco use in their etioko6y, if such exists, can therefore be defined or measured only within the context of a growing comprehension of the total etiologicd picture, invols•inR knowledge of the crxnple>< interactions between endoaenous and eaoRenous factors. As new concepts develop with respect to etiokgical mechanisms that may be involved in the genesis of these constitutional diseases, these con- cepts in turn suggest new biob6ical test systems tor determining whether chronic exposure to cigarette smoke or some ingredient thereof can con- trib ite to the operation of these mechanisms. In this way it is to be hoped that a series of progressively more meaningful test systems will evolve as etiological understandin6 advances, to supersede the crude and inadequate methoda of the past. All investigators in the Ikld are weU aware that scientific progress takes place "in slow motion." The description of progress in a singk year is akin to attempting to depict the progress of a baseball game by describ- ing one inning. Moreover, since the progress of studies in one single pro- gram such as that of The Council is Interrelated in a very complex manner with the progress of many other atudks throughout the scientific world, the report of any one program can hardly hope to present anything resembling an integrated picture of the status of knowbd6e in any particular field or area of medical science. ~ Recognizing these limitatiom, we have attempted only to meotioo in this report a few sekcted Bndinas that have emerged in published form in the year ended June 1971. These selections do not in any way minimize the potential importance of many contributions by other investi6aton that do not receive particular mention here. Since all these contributions have entered the "public dcxnain" of acknoe, they will br assimilated into the body of total knowledge and comprehension that occurs through the process of "diRestion" and anabolism by the great confratcrnity of investi- 6ators in the many disciplines involved. Roaear t:' Ikx Kc r r rn ~ Acting Scientific INrector m 5 ~ m cv w

I .- ri'he Cancer Program Viruses and Cancer Viral aspects of nncer, inciudina the human disease, are being in- tensively studied in many labor.tories throughout the world. Rcports of advances in this active field seem to appear alrm»t weekly as scientists strive to pin down esact evidence that human nncrn, or at least some of them, are caused by viral factors. Perhaps of greatest prominence in this field is the general vinl 6enome concept. This postulates that c C-type RNA viral Rcnomc exists in .11 mammalian cells but remains "switched oft" until, for some reascn or reasons still largely unknown, it becomes activated or "derepressed" and triggers the development of cancer in forms determined by genetic programming of the strain or specics. I)eoelopnsent o/ a Test System A Gouncii-sponsorcd study has been aimed at development of super- sensitive, virus-primed tissue-culture test systems for measuring ahc relative potentials of various chemicals, in collaboration with the virus, to produce "malignant transformation" of celis. For exampie, rat embryo cells infected with Rauscher leukemia virw have been treated with various 3ows of 7/12-D+methylhen:(a)-anthracene (DMBA). Morphologic traisforma- tions indicative of noopfasia were seen. On the other hand, there was no transformation in uninfeeted rat embryo cells similarly treated or in infected cells not treated with tha DMBA. When transplanted into newborn rats, the transformed cells produced subcutaneoui sarrnmas, but no tumors resuited from like treatment with the infected or DMBA-treated, untrarrsformed cclls. The work showed that in this nodel, at least, both chemical and virus were necessary for cell transformation. Aceordina to the irwestiRator. the findinRs suggest that the C-type RNA viral genome of the Rauscher leu- kemia virus provickd specific oncogene information for the malignant trsnsformation. 6 I I It must he recoanixed that this model does not duplicate real life situations. Rather it exaggerates certain faetors and eliminates others for the sake of supersensitivity. The effects of chemicals on cell transformation are greatly enhanced by priming with virus, while the protective effects of the in- tact animal's immunity system are eliminated. Hence the model can be ex- pected to show positive effects by chemical agents which, on the basis of earlier in vivo test systems, have been considered totally Inactive as "carcinogens." Such indications from the new supersensitive systems therefore do not simply or automatically imply that such substances are either "dangerous" or "safe." The model is only one rrew tool that provides comparative ea- perimental values on a single suk. From many such evaluations a relative "activity scale" or act of scales may develop that will permit more direct and more nearly quantitative comparisons of very feebly active compounds nd mixtures with thosc of high activity. Any attempt to extrapolate the findings from such a model to real life situations, especially the human, will require even greater care and discretion than heretofore. A hopeful potential for the model lies in the ultimate possibility of including human tissue cultures in the system for comparison and contrast with those from other speeies, under defined, controlled and closely anal- agous conditions. A more distant goal is development of a method for assessing the relative degrees of cancer susceptibility in human patients. Another virus-related study of The Council, completed during the year, sought to determine whether a relationship could exist between the occurence of cancers in humans and the presence of cancer virus in house- hold animals such as cats and dogs. 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 doas or to man or even from cat to cat. It appean, under natural corrditions, that feline C-type viruses are inherited as indigenous latent Senes which may activate in the fetus or later in life. The investigator cautioned that susceptibility of certain human cells to in virro infection with these 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 sarcoma virus can transform human osteosarcoma cells. This example of cell transformation by a non-host virus seems of considerable significance in virus-cancer research. Findings gained by this investigator in the (•nuncil-supp)rtcd project were applied to later research, funded by the National ('ancer Institute, in which human cancer cells were injected into the tetuees of preRnant cats Some of the cat fetuses developed tumors of human cells in which were 7

found particles similar to the known C-type cancer virus particles of several animal species. Present immunolo6ical evidence suggests that these may be the long sousht human cancer virus particles. If this finding is eonfirmed, it should greatly facilitate testing in man the many implications of the viral genome ccx+cept of cancer etiology that appear to present a rather wcU- integrated picture in several animals. It might also make possibk the addi- tiext of virus-primed human cell cultures to the in vitro test system that has been described. Other Ylrasal'..r+cer StrdlR. Lymphcxarcoma in r>,bbits, a rsre tumor In that particular animal, has been the subject of another Councif-sponsorid project. A rcxarcher studied one strain of nbbits amons..hich a number had developed lympho- saroomas. Ffe .nalyxed the pedigrees of the affected animals and found that inheritance indicated an autoaomal rectasive Sene conferring suscepti- bility to lymphosarooma. The flndin6s, the investigator rated, were con- ceptually compatible both with genetic susceptibility to malignant lymphoma and with vertical transmiaion of a virus. The neoplastic invofvement of various orRans in the rabbits resembled in many ways visceral lyrnphoaareomatosis of cats which has been proved to be caused by feline leukemia virus. According to the investi6ator, his findings on lymphosarcoma and its hereditary basis pmvidc a new and important model for studies of the pathoseneais of neoplasia. Still other studies being supported by The Council in the virvs area include: oncogeny and the antiviral action of interferon, eRects of respira- tory and oncogenk viruses in organ cultures of human respiratory tract tissue, and mechanisms o[ suppression of cellular immunity by carcinogenic hydrbcvbons. Smoke E:poaure Deolte. In its search for mexe realistic bioassay systems. The Council har for many years supported studies involving eiaarette smoke inhalation by animals. A major aspect of this undertakina is, of eourse, the drsi6n and production of a"smoke exposure device" that permits exposure of experimental animals to smoke inhalation in a manner and under amdi- tions that resemble human smokint sy eb.ely as possible. Previous Annual Reports of 7?w Councit have outlined severtl strict criteria for the function of such devices and these have subsequently been extended. The Council has developed a machine which has been undergoing tests in actual projects. While it has already demonstrated its value in several researches, a number of small but important improvements are being made to refine and define its operational characteristics. In using such a device, perhaps the most ditTicult problem is to measure how much of the particulate phase of the smoke actually reaches the lung surfaces of animals that normally breathe through their noses. Such measurements are being carried out with tagged smokes. The machine now being use-tested by several Council 6rantees has provision for insertion of a Cambridge filter that removes particulate material and thus permits comparison of the effects of whole smoke inhala- tion with those of inhaling the Ps-vapor phase akone. Handling and St.nd.rdisstlow of Anian.[. It is important to bear in mind that handling animals and confining them in a smoke exposure device ia very stressful to them. Hence "machine controls" that are subjected to the same handling and confinement in a functioning device, but without actual smoke exposure, must be included In experiments as well as unhandled "caae controfs." Comparisons of these two sets of controls can be expected to disclose sonx of the biobycal effects of these particular stresses. These, at leaat, can then be taken into account in the interpretation of smoke inhalation experiments in which handling and eon6nement stresses cannot be separated directly from smoke effects. Sitnificant biologicd effects of stress, originally observed in such "machine oontrols," have now become a subject of investigation in their own right as part of The Council's program. In connection with smoke inhalation as well as other kinds of studies. The Council has sought improvement in the standardization of animals. Animals used in most Council-supported research are delivered by cesarean section and are substantialy free from patho6ens. Alw, their virus profiles are determined as fully as possible aa well as the status of the C-type RNA viral genome expression. Many cancer researchera uae inbred strains of mice because of the great variety of strains with known congenital tumor susceptibilities. Ho.vever, because thert sometimes are advantages in using hamsters, which have larVr funas and greater blood volume, studies have been started with this species. Some inbred hamsters strains re now available. 8 9

Expo.ure of (;ultr.res to Srwo4e In one smoke study, three types of primary cultures from Snell mice- kidney tissue, cmbryonic lung organ and lung explants-and one establ•shed cell line from Swiss mice were used to assay the biological eRects, in virro, of the gas phase from charcoal-filtcred frxsh cigarette smoke. Repcated exposure to puffs of the smoke did not produce any significant chang:s in the Snell mouse cultures. The exposed Swisa mouse cells showed art en- hancemcnt of 6rowth, mitotic index, and cellular atypism. No morpholcgical cell transformation was observed In any of the exposed cultures. Such in vitro studies are mainly useful as aids to the interpretation of whole animal studies. Being by necessity "unphysio{o6ical," they cannot be extrapolated easily or directly to rsormal life conditions. The researcher who performcd this study under a Council grant had previously reported that Snell mice, with viral genome expressed, exposed chrbnically to inhalation of either whole smoke or its gas-vapor phase (devoid of the particulates or "tan") developed lung adenomas and adenocarcinomas of the same kind that they develop spontaneously. None of the animals developed squamoua cell lung tumors. Mice of another strain, lackins viral genome espmsion, showed a dramatically lower incidence of adenoma and ade+xxarcinoma under the same conditions. In a study of thc incidence snd appearance of lung tumors and pneumonitis in mice, a Council-supported scientist immunized mice with an influenr.a virus and then exposed them and control mice to sub-lethal and highly lethal nebulized clouds of fresh virus. The controls succumbed quickly to the lethal cloud of virus and had extensive and persisting pultrronup changes following exposure to sub-kthal clouds. Tlse immun- ixcd mice becsme only mildly ill and survived the lethal clouds, though large amounts of virus were found in their lungs, which soon returned to nornial. The researcher noted that immunization, while not preventing infection, was beneficial to the animals exposed to airborne influenza virus. It is known that many mouse stnins develop adenomas in the bron- chiolo-alveolar regions regardless of what Is, or ia not, done to them. Adenomas do rsot seem to arise in the large bronchi or in the trachess of these animals. Is there a difference in susceptibility of these tissues to chemical agents? Or is it that these Inciting atcnts, when used cxperi- mentally, do not reach theae different tissues in equal amounts? In n effort to learn some rnwen, The Council has supported work in which fragments of tiarue from lungs, large bronchi nd tracheas, re- spectivcly, of HAI 8/c/Cb/Se mice were impregnated with methyl:ho- lanthrene (MC) alone or mixed with Wc powder in crxtcentrations of i:10 i and 1:100. The fragments were then transplanted into the subcutaneous fat pads of syngeneic hosts- Rcsults indicated that the sensitivity of bronchiolo-alveolar epithelia to MC was higher than that of tracheo-bronchial epithelia. However, the latter were not wholly resistant to the MC since there was almost constant tumor growth after impregnation with the carcinogen. Thus, there does appear to be some difference in tissue susceptibility. A similar experiment with subcutaneous grafting of ltscheal, laryngeal, bronchial and lung tissues, followed by a single intraperitoneal injection o( urethane, produced adenomas only in the grafted lung tissue, showing a tissue specific cflect of thia particular agent and suggesting lhat the agent was Iransported by systemic routes to the locus of action. Other Cancer Stud:e. In other work related to caneer, The Council is continuing support of eRorts to develop "positive" rnodels for the production of squamous cell lung cancer in animals. Guide lines are few in this arca, but if some simple, easily reproducible method could be devised, it would be very helpful in many research areas. If lung cancer of the type reported preva- lent in man could be produced repetitively, at perhaps the 20 percent level, in an easily handled animal, it would then be possible to undertake studies to see whether many fadora-age, sex, hormones, irritants, diet, atrcu, infeclion, and others - might influence the kvel and rate of incidence of the tumor. Also being continued is a project in which a concentrated stream o( fresh cigarette smoke is being blown directly on the skins of mice of a strain previously used in a skin-painting test with tobacco-smoke con- densate. Among other ongoing projects being supported are: hetero-trans- plantation studin with human lung ancer, the pathogenesis of urethane- induced lung adenomas in mice, and host factors in lung cancer and other lung ailments. Cardiovascular Research Ensynae ReIatkd to Atlrtrosr[ero.t. A study involvinR an enzyme has turned up findings that may hc significant in regard to atherosclerosis. 7he Council-suppcxted project used II 10

segments of hunian iliac arteries incubated with human serum £amples were heated to inactivate the enzyme lecithinrholoternl-acyl-trar sferase (1-CAT). It was found that when LCAT enzyme was present in the incubation rmdium, virtually only free cholesterol left the arteri:l wall. However, when LCAT enryme was absent, only cholesterol ester teft the wall. The rcsults suggcst that a decrrase in serum free cholesterol, caused by a serum cholesterol esterifying ertzyme, possibly LCAT, might be important in promoting the removal of free cholesterol from the arterial wall. According to the investigators who performed the work, the results are consistent with findings that there is a tendency for LCAT act.vity in the serum to be higher In persons with hypercholcsterolemia Rreatcr than 300 mR/ 100 ml, which may reflect a nxchsnism for prntccting'thc arterial wall from exccssivc free cholesterol. The scientists said their findings may be particularly important because they have found that cholesterol esterification is sip,niixantly impaired in persons with acute myocardial infarction and chronic coronary artery disease when compared with age-matched oontrols. Thus, they said, a deficiency of cholesterol nterifying enzyme, possibly I-CAT, may be important in the etiology or rate of devclopment of atherosclerosis. Coronary Mitrocircrlation Continuing his work on total and nutritional coronary flow, another grantee has reported a new technique for determining the velocity of red cells in the capillaries. Ne has described apillary blood flow as thal por- tion of the total coronary flow involved in the nutritional function of heart muscle, while total coronary flow represents all the blood entering the heart eirculation. . To measure the velocity o( capillary red cetb, the investigator devel- oped a method showing the frame-to-frame pr)grr:s of individual red cells in moving pictures of the capillaries. The technique also permits measure- ment of the diameter of capillaries u it changes from frame to frame. Data from one part of the project iodicated that norcpioephrine re- suited in opening of capillaries, that nitrogfycerine slowed the flow in the capillaries, and that methacholine resulted in the complete arrest and even retrograde flow. While interpretation of theae findings will depend on con- tinuing study, the rtsardKr believes the work will provide new information bout the coronary microeulatbn. Another arpeet of the study wu a further elaboration of previously teported findings on the measurement of total and nutritional coronary I flow by means nf a coincidence counting system using rubidium-84. Workin8 with this system, the grantee found that norepineprine caused a dispropor- tionatcly greater increase in total as compared with effective flow, and the same result also occurred with nicotine. Isoproterenol, on the other hand, Icd to a proportionate increase in both nutritional and effective coronary flows. In another Council-supported study, mongrel dogs were cxposed to c~garette smoke inhalation and also to injection of various pharmacolosic agents. A reduction in aortic blood pressure during smoking by the anes- thctized animals was seen. This was attributed in part to the effects of nicotine on the central nervous system and in part to vauxfilation caused by the acticxt of rcleased catecholamines on certain receptors in the pcri- phcral vascular system. Kinina and /nJ[amnuttory Reactiona Another investigator has been studying kinins, polypeplides that are involved in inflammatory reactions. There is evidence of vascular permea- bility occurring independently of known mediation systems, and the kinin- forming system is being investigated as a possible humoral mechanism in the induction of vascular injury. Physical propertics of the components o( the kinin-forming system in rabbits re being studied. The characteristics of human components are comparable. It is hoped that this work will indicate the substance or sub- stances that may affect inflammatory reactions in the lung, particularly in hypersensitivity states. Framing/aam Heart Study The Council has made a ttant related to the Framingham fleart Study, effective July 1, 1971. This study was to have been ended for lack of federal funding, but its long-time director and several associates sought and obtained outside support to keep it going. 'iTre Council's grant is for an investigation of smoking elasses, risk factors and cardiovascular disease in the population being followed by the project. Other studies being supported include: nicotine and various aspects of cardiovascular function, carboxyhemogbbin and cardio-respirstory funetion, smoking and air pollution in human myocardial metafxolism, in- fluence of smoking and nicotine on lower limb cilculation, sensitivity of vascular tissue to nieotine, and the effect of smoking on rcRi(wul ccrcbral blood flow in smokers and nonsmokers. 12 13

Chronic Respiratory Diseases flyaline Membrane Dfuase A sianificant finding in regard to hyaline membrane disease (ItAf)) has conx from a Council-supported project that encompassed the anrlysis of 387 autopsies on newborn and stillborn infants. It was found that the adrenal glands were 19 percent liahter in infants with HMD than in those free of the disease. TTrose without the disease had a greater numb-r of adrenal cortical cells. Also, a positive correlation was found between the presence of infection arising before birth and the absence of IIMD. In connection with surfactant, which appears to play an important role in this disease, it is Interesting that anencephalic neonates who had little or no adrenal fetal cortical zorxs and half-siz.ed adult zones, were found to have only 45 percent the mass of osmiophilic granules in pul- monary type It alveolar cells found In non-anencephalic control inlants. These granuks reportedly are the anatomic representation of sur/a<tant. The investigators who eonductcd the study noted that the corticcnt,roid mechanism "oflers the ttractive possibility of relatively simple prophylaxis against hyalinc membrane disease in certain high risk gestations." But, they caution, "This temptatiixt to treat should be strongly resisted until the mechanisms in qucstion have been explored in the good experimental models of hyaline membrane disease now available. The need for such, caution is also supported by the observation that the doscs of cortico- steroids and ACTFf used to increase surtactant levels in the lungs rrf fetal lambs have induced toxic changes in other organs." AppaiIatAian Coa! Miners A quantitative morphdoye atudy was undertaten of lung and heart structure in 322 Appalachian minen who were classified by age, duration of mining exposure, rank of coal mined and smokin6 habits. Right ventric- ular hypertrophy as evidence of cor pufmonak was common after age 50. The volume of macular dust lesions, includin6 asxsciated silica crystals, fibrosis and focal emphysema, increased with age but these dust lesions were not deemed to be solely responsible for dyspnta since miners with dyspnea also had a gcneralired form of emphysema. Smoking was associated with a modest increase in bronchitis and emphysema in bituminous miners but showed littk or no relat;on to the extent o( such lung conditions in anthra- cite workers, and ninunioltins miners also developed these disorders. Ah)ve-ground air pollution may play a role since the wives of sonx bi- tuminous miners seem to be nearly as much*aReeted as their husbands by cough, phlegm, wheezing and breathlessness. The association of prxu- moconiosis with coal rank was found to be fortuitous. Microcirceelation o/ the Hurnan Lung During the year a Council grantee published a report describin6 the blood and lymphatic microcirculation of the human lung that provides a clear, concise summation of major findings in this particular field. The investigrlor, long involved in lung research, gave the results of correlated macro.arpic and microscopic studies o( the lungs o( humans, beagle dogs and mongrel dog.. The relxri was primarily concerned with angio-arehi- tectural relationships between the bronchial and pulmonary vascular sys- tems, and the author noteQ that the relationahips are distinct in each. The bronchial arteries are dirtxtly connected to each other, establishing a "parallel" vascular supply. 'I"he bronchial veins also form the peribronchial ven ws plexus. However, the pulmonary cireulation, the pulmonary arteries and veins form terminal, Intralobular branches. The bronchial and pulmonary arteries also communicate in the bronchioles through a common capillary network. The grantee reported he has been unable to observe broncho-pul- monary arterioarterial or arteriovenous anastomoses in entirely normal adult lungs of beagles, but said they seem to be normally present in the lung of the human fetus and infant. Ile said they probably vanish in child- hood but reappear in the adult lung with the onset of even minimal pul- monary inflammatory reactions or processes. The scientist also published another report in which he described cells with the ultrastructural characteristics of neurosecretory cells in the lung lobules of prematurely born infants. He had previously suggested the existence of these cells on the basis of light and fluorescence microscopy and noted that analogous celis had been reported by othen. Ife said the possibility exists 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 role in respiratory distress syndrome. Pulnsonory Al orofor M.croplsa6es What is the origin of the pulmonary alveolar macrophaRrs? "fhcre has been considcrable controversy as to the cellular precursors of these cclls, which comprise a major defense mechanism of the lung. A Council-sup- 14 15