Tobacco Documents Online

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MA ~deatibe lldvboiy aoud, e.~otlr ao.aittie+)< of teD .cientists and ; ~ i:. dt3tton who tssalntaln tbdt rcapoctlve Inatltstlioosl tt~'iliatlons, has full t^••. 1'' reapoesibility for rerearch polky and propamMIGff; Aa. Hoard it does not ~:' dimcOr COpa I* reacarch tor The C,ouocll, .5C 70q~ Ibe Council itself ~~,+Mw jaz~~~ ~~;~ j.-~--~ ~ research ,h.~~..j.,,•, . i :Orants-laaid for research are made b~.• . 'ZL/hu wbo are asaured eomplete scienti8e fr • z- .•~` r~atc~. Grnetcey alooe ue responsibte for reporting or publisbin` their ~ t±'!L ~tp In the accepted acientific manner - through medical and scientific ~ ~ • tu-A -4Ct1. e1 VM ~ • " .:Ibrout3s June 1970 research projectt have been approved by the 41 i h i '~a O inat ,- ties and researc atd to 249 kayestipfoA Ia 189 boapitab univers iB ~... 12}aut/oa4. These tiwarda MhOed =17 262 000. ` : , , , : pro}ecb ouPPated bv ' Ibe Council is Included in litt of ruearth %A ~~'.'a . ~.U>J•'Repott'Alw induded ate abatraets ~d 93 research papen, accnowl- ,, 1t ,~ ~t'drlnt Coupol support, that have appeared In ndeati8c }ournab since the '~pryvlotr jteporl and through June 1970. A total ci 821 such paprn has been publisbed by grant recipients. W. T. Flort Exrcutl.e 1)Ircetor t TIIF. CnIIN(7L FOR 'i'nBA(:C(1 RESF.AItCII-11.S.A. 110 F.ast S9tb Street, New York, N.Y. 10022 .o..' . . ApW to independent i 1rj cooductin3 their I ANNUAL REPORT o/ the SCIENTIF IC I)IRECTOR CI.AItEiNCE COOK L1TT[.E, Se.U.

S(:IENTIFIC ADVISORY IiOARI) to The Council for Tobacco Research - U.S.A. SI IELDON C. SOMMERS. M.D.. Chairman Research Director. The Council for Tobacco Research - U.S.A. Director of Laborotories, Lenox Hill Hospital Professor of Pathology Columbia University College of Physicians and Surgeons New York. New York HOWARD B. ANDERVONT. Sc.D. Scientific Editor (rrrbed), The Journal of the National Cancer Institute Bethesda. Maryland RICHARD M. BING, M.D. Director of Cardiology and Intramura/ Medicine Huntington Memorial Hospital. Pasadena. California Professor of Medicine Univenity of Southern California School of Medicine Loa An6eks, California McKEEN CATTELh Pw.D., M.D. Professor Emeritus o/ P/rarrnarolory Cornell University Medical College. New York, New York ROBERT J. HUEBNER. M.D. Chief. Viral Carcinosenesis Branch National Cancer Inuitute Bethesda. Maryland LEON O. JACOBSON. M.D. Dean of the Division of Biological Sciences Regenstein Pro/rssor of Biological Sciences University of Chicago. Illinois CLARENCE COOK LITTLE, Sc.D., LL.D., Ltrr.D. Scientific Director. The Council tor Tobacco Research - U.S.A. Director Emeritus. Roscoe B. Jackson Memorial Laboratory Bar Harbor, Maine CLAYTON G. LOOSLI, Pn.D., M.D. Hastings Professor of Medicine and Pathology University of Southern California School ot Medicine Los Angeles. California KENNETH MERRILL LYNCH. M.D.. Sc.D.. LL.D. Chancellor and Professor Emeritus of Pathology Medical College of South Carolina. Charleston. South Carolina WIl.I.IAM F. RIENl1OFF, Ju., M.D. Pro/tssor Emeritus of Surgery Johns llopkins l)nivrrsity School of Medicine, Baltimore. Maryland I ROBERT C. H(X.'KETT. PM.D. Assor(att Scientific Dirertor J. MORRISON BRADY. M.D. JOHN FI. KREISHf?R. PH 1). I Associate Scientific Director Associate Scientific I)irecror VINCENT F. LISANTI, D.M.D. ! Scientific Associatt

CONTENTS fntroduction . 5 Status of Current Researth . , - , - . , , , , 6 /The Cancer Program . . . . . . . . . . . . . 6 x'ardiovascular Res+carch . 9 Chronic Respiratory Diseases . . , . . . . . . . . 12 .1leuropharmacobgy and Psychology . . . . . . . . 13 Other Studies . . . 14 Abstracts of Reports . . . . . . . . . . . . . . . . 16 1 Psycho-PhysioloRical Studies . . . . . . . . . . . 16 Farcinogenesis Studies . . . . . . . . . . . . . 18 Cardiovascular System . . . . . . . . . . . . . 25 Respiratory System . . . . . . . . . . . . . . 32 / NeuroQhysrobgy . . . . . . . . . . . . . . . 45 J'issue and Organ Culture . . . . . . . . . . . . 50 J Pharmaoology . . . . . . . . . . . . . . . 52 l Metabolic Studies . . . . . . . . . . . . . . 63 ~Cbemistry and Biochemistry . . , . . . . , . . . 65 JiRe views . . . . . . . . . . . . . . . . . 67 Recipients of Active Projeet.s . . . . . . . . . . . . . 69 Recipients of Compkted Projeets . . . . . . . . . . , . 79 i I Iiitroduction The research program of The Council for Tobacco Research - U.S.A. continued to move ahead in 1969-70 with additional support for studics into smoking and health. The Council's eRort to help develop mote scien- tific data was further expanded during the year with the inauguration of several conlracls for research with institutions and laboratories geared to petform the required work in the shortest possible time. 'Me Council, by augmenting its regular gant-in-aid program with research contracts, is re-emphasizing its desire to speed up the search for the answers to lung cancer, heart diseases, chronic respiratory ailments, and other diseases. The process is naturally stow and painstaking because these diseases are immensely complex and have been afflicting mankind for hundreds, even tlxwsands, of years. While bits and pieces of information about them are rcported by scientists almost every day, the time when the numerous parts of the full puzzle will be assembled into a cohesive picture cannot be predicted. (.'laims Ihat the puzzle has been solved are totally unrealistic by scientific standards and misleading to the public. There are far too many questions that remain unanswered at this time. It is noteworthy that in 1955, one year after the Scientific Advisory floard to The Council began its research program, a progress report was issued that said in part: "The history of cancer research is a record of slow but steady progress. There is every reason to expect marked advances in the prevention, treatment and cure of eaneer. This also is true nf the other constitutional diseases, such as heart ailments, which are our grcatest present and future health challenges. "But this will take time, and we cannot count on shrxtcuts. Neither the generating of unnecessarr fears, nor the arousing of unfounded hopes, witt hasaen the coming of significant discuveries. "1'roFress in the battle against these great health prubtems has dependert and •will depend on solidly planned and wcll- cxecuted scientific research. 'I hcsc words are still true today. 1 hc Council for Tobacco Research - U.S.A. will continue its rescafch program in the belief that valid scientific conclusions can conic only from unbiaced and complete research. • 5

Status of Current Research Since 1954, when The Council for Tobacco Research - U.S.A. began to support studies by independent investigators on tobacco use and heaith, reports of its activities have been made annually to the scientific and lay publics. Tlris is such a report for 1969-70. Through the yran, the staff of The Council and the membcrr of the Scientific Advisory Board have seen the research program devciop and mature along lines and Into fields which give an opportunity for much more objective results. It remains clear that the complexity of the origin of different cancen, cardiovascular diseases and chronic respiratory diseases is very great and still littlr understocxi Ifence, as heretofore, The Councii's emphasis is still upon the etiolofy or pathogenesis of these diseases, since any possibte effects of tobacco use can he interpreted only in this context. A summary and overview of the current status of The Council's pro- gram are briefly prescnted in the following sections. rI'he Cancer Prograrn Virruea and Cancer Several present studies are directly related to the recent theory that cancer is one of several possible expressions of a latent C-type RNA viral genome, or genetic potential, found in all mammalian cells. The frenome, according to the theory, is normally repressed and inactive, and there is a complex interplay of internal and external factors that determines whether, when and how the rcprcssiim control mechanism is somehow broken and active expressicxt occurs in the form of cancer or uncontrolled growth. One study in this rea is aimed at developing nKxe realistic, as well as more sensitive, test systems to illuminate the interactions between exter- nal agents and internal Influences affecting the susceptibility of the biological substrate as determined by the state of the viral genome. Hiological test systcnn for this purlxne are expected to be of three kinds: ( 1) in vhro studies of cells that are controlled and standardized with respect both to source and state, (2) skins of intact animals in vivn from standardized, controlled and state-defined strains, and (3) lungs of intact animals in vivo from similarly defined and standardized sources exposed to monitored inhalation of external agents. One imnrcdiatc objective is to develop rapid yet realistic test systems that may "magnify" the effects of external agents so that the systems can be used to guide fractionation of complex mixtures and isolation of the ingredients most likely to be active in a suseeptibk host. Such assay systems should also provide new information on the components of host suscepti- bilrty through study ot step-by-step modificatiorn in the substrate system. An ultimate hope, of course, is to contribute toward discovery of methods for inhibiting or dclaying dcrepressian of the latent cancer genome as a means of preventing or deferring cancer in the human population. Other Ccwncil-sponsored studies are aimed at filling gaps and round- ing out needed basic knowkdge about the nature and applications of Ihe virus-cancer hypothesis. These include studies of epithelial cell transforma- tion and carcinoma induction by C-type RNA viruses; the behavior of avian tumor viruses in mammalian hosts; and oncogenesis in the rabbit in terms of genetic susceptibility, vertical transmission of virus, and environ- mental influences. The Irnrnunological System The concept that cancer may result from virus activity has renewed interest in studying the body i complex immunological machinery to see whether stimulating it will help prevent the induction of cancer. Research supported in this field includes studies of: the action of interferon as one type of virus-repressing substance; the function of the reticulo-endothelial system as it may be related to tumor induction and growth; the possible effect of tobacco smoke inhalation on the immunolotjcal system in animals and man; and how carcinogenic hydrocarbons may possibiy suppress cellu- lar inrnrunologicat mechanisms. 1'olxrcco Smoke Studies Sn.okinR Machinea . After an extensive period of experiments'and tests, progress was made in the last year toward development of inechanica! devices for exposing experimental animals to thc monitored inhalation rif wholc, fresh, normal 6 7

cigarette smoke under conditions simulating actual human exposure as closely as possible. Previous Annual Reports have described the numerous and complex criteria necessary for reaiistic smoke inhalation studies. The aim in the design of such machines is to generate the smoke ur der defincd conditions and to permit delivery of the whole smoke to the res- piratory tracts of the animal in the same physical and chemical condiiion as that which reaches the respiratory tract of a human. Mechanical and biological evaluations have been made of several such devices developed through the years by various organizations. Also, ana,yti- cal data were obtained for the gasean and particulate phases of cigarette snroke generated by each device. Some of the machines are now being used in preliminary studici by various Council granteea for inhalatkors tests with animals. Full descriptons of these devices will be published with operational details as soon as the progress of these preliminary tests and trials justifies. Exposure oJ Anim.l@ to Smoke In all cancer-cxiented projects invoiving direct exposure of waole animals to smoke, including viruslancer studies, some of which involve work with tobacco srrxike, it is now Council policy to require defining, standardizing and controlling the virus content of all animals being used. In one investipation aimed at elucidating the possible significance of freshness and physical state of smoke, a concentrated stream of whole, fresh, normal cigarefte smoke is blown directly on the skins of mice of the sitne strain that had been used previously in a conventional skin-painting experi- ment with tobacco-smoke condensate. All components of the smoke inrpinge on the skin and many of the constituents condense upon the surface. The treatment is being carried out with and without acetone, which has been gencraily used as a solvent for "tars" in skin-painting work, and in one group of animals a"promotin6' agent is also being used to intensify any possible "carcinogenic" effects that may exist. This experiment has been under way for a year. While the study still involvcs the "wrong tissuc of the wrong animal," it docs use natural smoke in the condition encountered in normal human smoking, and it should pro- vidc further insight into the widely prevaicnt mouse skin-painting with stale, artificially prepared "tars" in a sdvent. No Squamous (:elf Tumora Found In a long-term chronic smoke inhalation experimcnt, two strains of mice are being expcxed to smoke with the use of improved equipment. Mice thus exposed to inhalation of whole smoke, or of the gas phase alone, have developed only the types of lung tumors - adenomas and adenocarcino- mas - that develop in the same mice without any exposure. No squamous cell tumors of the type considered by some to be associated with smoking have been found in any of the hundreds of mice that have so far been exposed and then subjected to pathological examination. To study the incidence and appearance of lung tumors and pneumo- nitis in mice, a Council-supported researcher exposed three inbred strains of mice to prolonged inhalatjon of ambient and filtered Los Angeles air. Mice in the ambient air group showed no lung pathology whik lung adcno- mas were found in one strain exposed to filtered air. Autopsy examination of the animals' lungs showed that kngthy exposure to the ambient atmos- phere seemed to be associated with an increased susceptibility to pulmo- nary infection but not to an increased incidence of pulmonary neoplasia. This particular project is relevant both to cancer and to chronic respiratory diseases. In studying the effects on the lungs of mice of chronic inhalation of several pure gases that are present in polluted urban ir, and certain mix- ~ tures of these, the same researcher has developed a remarkably elegant technique for infialing. fixing and diRcrentialfy staining the lung tissues. Among the gases studied were oxides of nitrogen, ozone, carbon monoxide, and sulfur dioxide at various dosages and over various periods of time. Other Cancer Studies Other studies related to cancer include one dealing with host facton, especially abnormalities of the endocrine system, aa they may be related to lung cancer in humans. Another researcher is eompkting a study of bladder cancer in man. This particular project has produced findings to the effect that, contrary to some reporta, there is no paralklism between reported disturbances in tryptophan metabolism In bladder cancer patients and reputed effects of nicotine on the same metabolic function. Support is also being continued for research on the mechanisms by which urethan affects cells in the alveoli of certain mice. Cardiovascular Research There are now two key problems considered to be of first priority in regard to cardiovascular ailments and any possibk relationship to cigarette smoking: 8 9

1. Since arteriosclerosis, including atherosclerosis, is widcly considered to be thc hasic factor underlying most of the cardiovascular diseaus that are the leading causes of death in the United States, the ques- tion of preveming, delaying or reversing the process is paramount. As regards tobacco, a prime question is whether smoking and/or nicotine have any effect in speeding the development of artcrio- sckrosis, especially of the coronary arteries. Tlwugh there ar-- many studies that question whether smoking can affect the process, there is a need for mcxe research. Still lacking is a really satisfactory animal model for reproducing the human eoronary disease under reasonably physiological conditions and such a model is being sought. 2. Once artericxclerosis or atherosclerosis has been established, par- ticularly at an advanced age, another questiort is what factors or influences may possibly trigger an acute event such as a heart attack or a stroke. f lere too a prime question Is whether smoking or nico- tinc can be involved. Especially important are the basic differences between the kinds of people who like or need to smnke and those who do not. The issue is confused, particularly in epidemiological investigations, because people predisposed to cardiovascular disease may also be of the type cx types who feel a need for tobacco and, consequentrf, sepa- ratic.ns of populations on the basis of smoking behavior may produce statistically non-equivalent groups. Various twin studies have sup- ported the concept that epidemiological studies have generally pro- duced and attempted to compare non-equivalent groups. Method for Meaaurirsg Blood Flow The Council has helped support research for several years from which a method has been developed for measuring blood flow in the arte ies that feed the heart muscle without inserting tubes or resorting to surlery. By this new approach, it has been shown that nicotine does not reduce blood flow in normal arteries that supply the myocardium, but generally increases it after the manner of mild exercise. In addition to an increase in "nxchani- cal" coronary blood flow, there is an increase in "nutritional" flow as well. This method, repcated and confirmed in the past year with tests on animals and humans, has important implications in the entire field crf heart disease. The same research project, with continued support from The Council, is now approaching the athero.ckrosis problem by studying human arteries in tissue culture by perfusion methods. Tbe purpose is to determine whether nicotine affccts drposition of fatty materials in the artery wall from serum or plasma. The conditions are made to resemble those in life, with control and variations in pressure on the vessel wall and in the concentration of alhumin, cholesterol, free fatty acids, ete., in the serum. Blood flow in the microcirculation is also being studied to see whether it is affected by nicotine. Among other studies that have been contributing knowledge in various phases of the complex cardiovascular problem are: one suggesting a nega- tive effect of nicotine on thrombus formation; the relationship of blood- sugar level to nicotine effects; measurement of carbon monoxide in the biood; the interrelationship between carbon monoxide and oxygen clution from hemoglobin; the degree of fibrous thickening of blood vessels in smokers and nonsmoken; and possible prediction of early heart disease by longitudinal study of precursor conditions. 7hese arKl other interesting findings of The Council's grant-in-aid program are presented in more technical form in the various summaries ol research included later in this Report. Predietora o/ F,arly He,.rt Diaeaae Being continued is a long-term study of medical students to leam what characteristics, measured at an early age, will turn out to be predictors of early cardiovascular disease. Part of this project includes determining the patterns of measurable characteristics that correlate with a family his- tory of cardiovascular disease. During the year, the investigator conducting this study reported that 16 of the mature men originally studied as students had developed clinical hypertension by 1968 while 89 others had exhibited transitory hypertension. In 62.5 percent of the subjects with clinical hypertension, both parents evidenced hypertension and/or coronary disease as compared with 21.9 percent of the parents of the control group. Another development reported from this study was that there have bec 1 31 premature deaths amon& the subjeets, 14 of them from suicide. The other 17 deaths were due to accidents, coronary heart disease, neo- piasfn, chronic alcoholism, nephritb with hypettcniion, acute ulcerative colitis, and subacute bacterial endoarditis. Statistical evidence was reported that certain precursors of suicide, accident, fatal heart attack, and fatal stroke are already present and can be identifkd In youth. Uther research is being supported to karn whether changes in eakium ion mobility, induced by nicotine, play a role in addition to that of catecho- Iamines in bringing about the short-lerm cardiovascular changes that follow smoking; and to measure the short-term effects of smoking upon regional blood flow in the brain. , 10 II

Chronic Respiratory Diseases A hasic problem involved in the study of chronic respiratory diseases, particularly in determining their cause or causes, is the lack of generally accepted clinical distinctions among the various respiratory difficulties. These include emphysema, bronchitis, asthma, and even certain heart ailments. Inadequate definitions and the lack of uniform clinical distinction of these conditions have confused attempts at epidemiological studies of causation or aggravation. Further, It appears that diagnostic uncertainties and doubts, as well as changes in the popularity of such terms as "emphy- sema," may have resulted in a fictitious increase in reported prevalence rates. Nence, The Council ia supporting a long-term study in a pufmonary disease clinic where comprehensive and repetitive observations can be car- ried out on many chronic patients over a{ong period of time. T[x hope is that numerous bioehemical, pathological and radiological observations can eventually be correlated with the clinical course to produce better definition as well as imp.oved diagnosh and trcatment of chronic lung disease entities and also provide new etiological insights. Metaplaais in Nonamolrera A Council grantee examined the bronchial epithelia of 500 apparently "healthy" adults who died suddenly and unexpectedly, after living and working in an urban area noted for its air pollution, but who had had no known disease history. Metapfasia was found in the lungs of both smokers and nonsmokers. (x great importance, however, was the observation that various degrees of roetaplasia were present in a surprisingly high proportion (50 percent) of "healthy" adult men who had never smoked ciMrettes, cigars or pipes. There were no cases of carcinoma In situ In either the smokers or non- smokers. Thus. In the study of lung tissue t autopsy, it is important to distinguish between patients who die suddenly and those who die following wastingor chronic ailments in a hospital after being treated with drugs and other therapies. The Council has supported several studies through the years that have contributed evidence showing that a deficiency of alpha,-antitrypsin appears to predispose to emphysema. Other rrseamh includn: the eHecta of hypoxia on function of the respiratory system; the bioebemkal activities of sputum cells from patients with various types of chronic lung disease; and how lung celis and Mher products recovered by lavage from normal smokers and normal nonsmok- ers may differ. One investigator is studying the cyclic changes in the structure of lung cells of young women, recovered by lavage, that correlate with the men- strual cycle. An investigator is conducting a long series of studies on the effects of cigarette smokc inhalation on lung function, especially pulmonary resist- ance, in several species of animals. He has found short-term effects that differ among species and that a female sex hormorse, progesterone, reduces or blocks them. No permanent changes of the kind that occur in emphy- sema have been found in these chronic smoke inhalation tests. Additional experimental studies include: isolation of functioning ribo- somes from the lungs of animals and relating the speed of their formation to certain ksions produced in animals by high-oxygen exposure known to cause such lesions in humans; the effects of smoke exposure on the pul- monary macrophages; clarification of the relationship between lung lym- phocytes and pulmonary macrophages; and the lymphatics of the lung, their structure and role in fluid transport and in ekarance of airborne par- ticulate matter from the lung. Neuropharmacology and Psychology Most of the pharmacological studies currently being supported by The Council are concerned with the effects of nicotine and/or smoking on the central nervous system (the brain) with the object of learning more about why people like, want or need to smoke. These should help reveal the basic differences between smokers and nonsmokers, which previous work of other character has shown to exist. In a Council•supported study of high school and junior high schcrol students, a psychologist has reported results quite similar to those found earlier with adults, namety, that there are personality differences between smokers and nonsmokers. Brain Waoe Patterna An ongoing study deals with the effects o( nkotine or smoking on the brain waves of human subjecta. By use of computer methods to analyze these electroencephalograms, the meanings of the wave patterns In tenns 13 12

of "deep slecp," "arousal." "awakc but in rrpose," etc., have become known. One siKnificant observation ftom the study so fat is the irnpl-cation that heavy smokers may have a different basic prevailing brain wa.e pat- tern from that of nonsmokers. The investigator bclieves that thic (,attern may be congenital and that it antedates and influences the adoption of tobacco use. ConJerente on Nirofine A conference on the effects of nicotine and/or smoking on the central nervous system was held June 1, 1970, at The Council's oftice. In addition to staff and menttlcrs of the Scientific Advisory Board, the following scien- tists participated: Budhdev Iihagat, hh.D., Professor of Physiology, St. I.cwis Ilnivcrsity School of Mcdicine, St. Louis. Barbara B. Brown, Ph.D.. Chief. Esperimental Psychiatry. Veterans Ad- ministration f lospitaf, Sepulveda, Cal. Edward F. Dcxnino, M.D., Professor of Pharmacology. University of Michigan, Ann Arbor. Walter B. Essman, Ph.D.. Professor of Psychology, Queens College of the City of New York, Flushing. Leonide Gofds,cin, D.Sc., Research Scientist, Bureau of Research in Neurology and Psychiatry, New Jersey Neuropsychiatric Institute, Princeton. Henry B. Murplrree, M.D., Associate Professor of Psychiatry, Center of Alcohol Srudies, Rutgers Univenity, New Brunswick. N. 1. S. N. Pradhan, M.D., Ph.D., Professor of Pharmacology. Ifoward Uni- versity Colkge of Medicine, Washington, D. C. Ulrich N. Sehaeppi, M.D., Director of Neuropharmacology, Mason Re- search Institute, Worcester, Mass. '['homas C. WcsNall, Ph.D., Assistant Professor of Pharmacology. Uni- versity o( Virginia School of Medicine, Charlottesville. Other Studies The Council is contributing to a projeet that is supported mainly by the Veterans Administration. Its aim is to make numerous periodic exami- nations of a large group of male veterans, with a high initial level of good health, in order to describe the changes Ihat corne during normal apng. Support is being provided for a study of certain biochemical effects of chronic smoke inhalation by guinea pigs. Using a smoking machine, the investigator has it:c>aated the mitochondria from lungs of eRpcned animals and is studying the electron transport system in these cell components. The Co'incil is continuing sponsorship of a project that has been of great benefit to researchers and others interested in smoking nd health: the collection, abstracting and andysis of the world literature on tobacrn, including experimental and clinical studies. A second supplement to the monograph on this subject, titkd "Tobacco - Experimental and Clinical Studics," first published in 1961, is expected to be published soon. 14 15

Abstracts of Reports Each recipient of a grant-in-aid from The Council for Tob:,ccn Re- search - U.S.A is responsible for the initial presentation or publicatiom of the results of his rescarch t scientific mectin8s or in appropriate scicntific journals. Following are abstracts, approved by the authors, of report; rin new experimental research acknowledging suppo rt from The Council t!iat have appeared in scientific journals since publication of the 1968-69 P eport of the Scientific Director. The name of the grantee is in italics. These abstracts have been arcwped under these headings: 1. Psycho- Physiolo6ical Studies. 11. Carcinogenesis Studies, 111. Cardiovasc alar Sys- tem, IV. Respiratory System. V. Neurophysiok>Ry, VI. Tissue and Organ Culture, VII. Pharmacolo6y, VIII. Metabolic Studies. IX. Chcmtstry and Biochemistry, X. Reviews. 1. P.ycko-Phy,ioloRtcal Studies FFFECTS OF SMOKING ON PERIPIfERAL VISUAL A('UITY A total of 40 male university students, 30 smokers and ten non- smokers was tested on a modihed Ferree-Rand Perimeter in prdcr to determine the size of the pcriphcral visual field as a function or various combinations of smokinR, amo~in6 dcprivation, and smoking dcnicotinizcd cigarettes. The experimental design encompassed two control and two experimental test groups of ten subjects each: one group (CS) smoked regular cigarettes throughout the test period; one (CNS) never smoked; one (ES) smoked standard cigarettes preceding the first two peripheral vision tests, were deprived from amokin6 for the next eight test sessions, aqd smoked again preceding the last two vision tests; the last grou z(EDS) smoked standard ciaareltes preceding the first two tests, smoked denico- tinized cigarettes prcctdina the next eight test sessions, and smoked stand- ard eiauettes asain PtocedinR the last two vision tests. Results indicated that there were no significant long-term effects of smokin8 on peripheral vision by a comparison of smokers and nonamokera on the initial two test sessions. However, the relative change in performance from the initial tests produced a significant difference between the esperirnental and control groups. Specifrctlly, abstinence from srnokiq increased the size of the visual field. After aper{od of abaGnersoe, smoking reduced the size of the visual field. The major chanaes In peripheral vision were on the temporal meridian. Further, performaex.~e ot the two experimental broups, i.e., those who were deprived from srrsoklng and thoae who smoked the denicotinized ci6arettes, was identical. Thb indieated that the effect of smoking on periph- eral visloo may be attr(buted b the nicotine component of tobacco smoke. Krippner, R. A. and flrirnslra, N. W. F.Bccts of SnfokinR on Peripheral Visuaf Acuiry, The University of South Dakota: VermilGon, 1969, pp 1-57. From the Department of Psycholo6Y. University of South Dakota, Ver- million. A NOTE ON RESPONSES TO ETHYL ALCOHOL BEFORE AND AFTER SMOKING Differential taste sensitivity to ethyl alcohol was measured before and af ter smoking a cigarette by ten smokers; ten nonsmokers served as controls. Usi: ,6 a paired comparison rnethod of differential sensitivity, subjects evalu- ated eight paired sample sc:a consisting of 8% EtOH vs. 4%. S%, 6%, 7%, 9%, l 1%, and 12% E10111. No si8nificant differences were observed between smokers and nonsmokers or before vs. after smokin8, although slightly higher overall correct responses and correspondingly smaller just noticeable differences were obtained tor the nonsmokers. No practice effects were noted among the control group between the first and second set of samples. The findings confirm previous results which had been questioned recently. Martin. S. and Pongh.+rn. R. M. Perception A Psychophysics 8(3):169-170, 1970. From the Department of Food Science and Technolo6Y. University of California, Davis. RELATIONS BETWEEN PERSONALITY AND SMOKING BEIIAVIOR IN PREADULT SUBJECTS This study of 562 high school and junior high school students has yielded results which are strikingly similar to those found earlier with adults. In both studies, smokins status was assigned on the basis of self- report information, and personality scores were derived from peer ratings. With the preadults, as with the adults, amoken scored significantly lower on measures of "ABreeableness," and "Strength of Character," and scored significantly higher on measures of "Extnvenion." In addilion, the smokers (in both studies) scored si8nifkantly higher than the nonsmokers on the variable "crude," "happy-8o-lucky," aqd "trant." Amonj preadults, mul- tiple discriminant analyses permitted stl~rrokint status to be assigned with accuracy ranRm6 from 65% to 79%. IthouBh most information eoncern- in the psychodynamica of smoking has been obtained from studies of .ults, the present study supports the use of such Information in work with prcadults. Smith, G.M. Journat of Conrultrnr and CUrrkof Psycholoty 33 ( 6): 710-71 S, 1969. Other 8rawtor.r American Cancer Sodety and U. S. Public Health Service. From the DeQartment of Aneatheala, Massachusetts General lfcnpital, and Harvard Medical School, Boston. 17 16

SUICIDE AMONG US: CAN WE LEARN TO PREVENT 11? Dcaths reported in the course of a long-term study of students at The Johns Hopkins University School of Medicine point out the need for suicide prcvcntion. In the Study of the Precursors of Hypcrtension and (~uromary i)isease, many characteristics of the students in 17 consecutive classes were measured and recorded; all subjects are being followed through annual questionnaires. Among the 1.337 students enrolled in the study, there have been 31 premature deaths. Of these 31 deaths, 14, or nearly half the fatali- ties, have been caused by suicide. The other 17 deaths were due va;iously to accident, coronary heart disease, neoplasm, chronic alcoholism, nephritis with hypertension, acute ukerative colttis, and subacute bacterial endo- carditis. It is widely reeogrtiz,ed that psycho{ogical and stress factors, as well as somatic characteristics, play prominent roles in the evolution of most of the disordcrs from which the 31 former Johns Hopkins students died. It seems likely that the suicides and sorne of the other premature dealhs have certain kth.litr factors in common. With this in mird, the degree of personal Involvement In the wbjoet's own death was rated for the 31 fataiities, and other studies of precunort of suicide and risk i actors in coronary heart disease were examined. These studies provided statis- tical evidence that certain preeunon of suicide, aecident, fatal heart attack, and fatal stroke are already present and can be identified in youth. When more of these characteristics ore identified, it is hoped that not only single risk facte+n, but meaningful psychobiological patterns will be found, which may lead to nxxe effective methods of prevention. Thomas, C. B. loluu HopAint Mrdlcallourraf 125(5):276-285, 1969. Other Sr.r.tor.: National Hcart Institute and the Hcart Association of Maryland. From The lohns 1{opkirr University School o[ Medicine, Baltimore. H. CarctnoRene.Ia Studies }IEPATOMAS IN CBA/Cb/Se MICE tutd LIVER LESIONS IN GOLDEN HAMSTERS INDUCED BY HYDRAZINE SULFATE Intact virgin CBA/Cb/Se (CBA) mice and golden hamsters of both sexes were used to test the action evoked by daily administration of scalar doses of hydrazine sulfate (LIS). The daily administration of 1.13 and 0.56 mg of FIS was urdnogenic for the liver of CBA mice of both sexes. Such carcinogenk activity was reduced with 0.28 mg and was nonexistent with 0.14 mg. llistologically, the tumors were hepatocarcinomas. No mor- phologic differences esisted between the neoplasms induced with 1.13, 0.56, and 0.28 mg of the dru~. Four mice that received 1.13 m6 IIS daily also had lung metastases. 11S administertd to intact virgin golden hamsters of both setes caused liver rtticuloendothelial cell proliferation and cirrhosis, bile duct proliferation, and degeneration of fibrous cells in the hyalinized sclerotic tissue. These results are of importance since the liver tumors and lesions were induced by a drug that is the principal metaholite of isoniazid and that is widely used in the prophylaxis and therapy of human tuber- culosis. Biancifiori. C. Journal oJ the Nauona! Canrrr fnsrirutr 44(4):943-953, 1970. Other Rrantor: Anna Fuller Fund. From the Division of Cancer Research, University of Perugia, Italy. PATHOLOGY AS RELATED TO TRYPTOPHAN METABOLITIi EXCRETION. OCCUPATIONAL HISTORY, AND SMOKING LIABITS IN PATIENTS WITH BLADDER CANCER A combination of tiutx .ection examination, tryp(ophan metabolite aasay, and interview analysis wes employed in this initial attempt to asccr- tain the relationship betwcea the histology of bladder tumors and 1) the presence or absence of abnormal patterns of tryptophan metabolites in the urine, 2) (he occupational history of the patient, and 3) the history of the patient with regard to cigarette tunokin6. Results showed that there were no significant differences be:ween the bladder cancers in 39 patients with normal urinary excretion of tryptophan metabolites and those in ten patients with abnormal metabolite excretion patterns. Neither were there statistically significant differences in hstdogy between "occupational" and spc~n- tane wi ' tumon, nor between tumors in patienta who had "ever artxrkcd" cigarettes and those who had "never smoked" eitarettes. Nowever, in both the "occupational" and the "ever smoked" 6roups, apparently greater num- bers of carcinomas were either wholly or partially composed of squamow ekments, and further study of this point in larger series of cases seems indicated. Frirdrll, G. H., Burney, S. W., Betl, 1. R. and Soto. E. Journal o/ the National Cancer Institute 43(1):303-306, 1969. Other Rrm.torr National Cantxr Imtitute. From the Cancer Research Institute, New England Deaconess Hospital, Boston, and the Department of Pathology, Boston University School of Medicine, Boston. I MULTIPLE MALIGNANCIES IN THE URINARY BLADDER FOLLOWING A BY-PASS PROCEDURE A case with two separate transitional cell earciqomas of the bladder in which neither tumor was evident six monthsprim to resection is reported. In April. 1965, a bilateral uretostomy through an ikal conduit had been C riormed on the described patient. Microscopic examination of the distal tt ureter showed chronic ureteritia with foci of atypical epithelial hyper- plasia. Six months later, eatcinoma was noted; an anterior exenteratiun waspe rfortrted. 'lhe my ty of recent studies of carcinoma in siru of the bladder either state or imply that, just as in carcinoma of the cervix, the 18 19 '

natural history of bladder cancer often includes a slow progression from cellular atypi through carcinoma in srru to frank invasive carcinoma over a protracted period of time. In this case, although the exact date of devel- opment of malignant changes cannot be determined, the progression seems to have bcen very rapid In addition to the two large tunwrs, alm„at all of the mucnsa showed proliferative changes, including hypcrplasia, dys- ptasia, carcinoma in tiru, and multiple small papillary tumors. Ikspite the extensive cystitis cystica, no areas of adenocarcinoma were found. The dcvclopment or progrewicxt of invasive cancer following a by-pass proce- dure is of particular interest because it is decidedly unusual. Burney, S. W., Graves. R. C. and Fritdell, C. H. Umlorio Inrrrnationotis 25:69-75, 1970. Other Rra.tora: U. S. Public Health Service and Atomic Energy Com- miuion. From the ('ancer Research Institute and the Department of Surgery, New Fngland lkaconeu Ilospital, Botton. UNUSUAL METASTASIS OF A NUMAN COLONIC TUMOUR XI:NO(;RAFT IN THE HAMSTER BRAIN (iW-77 is a human carcinoid tumor of the transverse colon that has been successfully propagated in unconditioned golden hamsters for almost three years. When transplanted in the hamster check pouch, subcutaneously or intramuscularly, no morphological evidence of inetastasis Mas seen. However, after intracerebral implantation of the GW-77 tumor, tumor cell emboli and uthentic metastatic nodules were found in over 50°f% of the 30 treated hamsten. Transplantation of a 20% homogenatc of lu.igs from ten of these hamsters having 20-day-old brain transplants to check pouches of other animals has resulted in viable GW-77 tumors in almost all cases. This extracerebral retention and proliferation of GW-77 human cokmic tumor cells transplanted to the hamster brain is the first example reported of inetastasis o/ a acnogeneie tumor still exhibiting properties of its species of origin. CoWrnbot. D. M. Nature 226( 5245 ) :550, 1970. Frosn the Dcpartment of Pa(ho(ogy, University of Pittsburgh S.:hool of Medicine, Pittsburgh. IDENTITY AND NATURE OF ISOLATED LYMPIIOID TUMORS (SO-CALLED NODAL IIYPERPLASIA. IIAMARTOMA. ANI) ANGIOMATOUS EiAMARTOMA) AS REVEALEI) BY FfISTOLOGIC, ELECTRON MICROSCOPIC. AND IIE:`TE:ROTRANSPLANTATION STIJDIFS Two cases of iaolated lymphold tumors, one in an 11 -year-old girt and one in a 42-year-(ld man, are presented. While both wes exhibited histo- pathologic features of both neoplastic and non-neoplastic lesions, both tumors als) cuntaincd giant cells rnorphobgically indistinguishable from Stcrnbcrg-Recd cells characteristic of Flodgkin's disease. Virus-like par- ticles resembling those depicted as occurring in some murinc as well as human Icukcnrias and malignant lymphomas were also noted in the second paticnt's lesion. Similar particles were also observed in cells comprising "primary" growths and mctastases noted following hetcrotransplantalion of aliquots uf this tumor to the check pouch of unconditioned hamsters. This information strongly suggests that some lymphoid tumors may possess  malignant biological potential, being in this regard analogous to the situa- tion experienced with the nodal ksion apparently induced by antiepileptic drugs. Fisher, E. R., Sieracki, J. C. and Coldenbrra, D. M. Cancer 25(6):12R6-1300,1970. Other Rrar.torr U. S. Public Health Service. Fn+m the 1)cpartments of Pathology. University of Pittsburgh SchrKil of Medicine and the Veterans Administration Ilospital, Pittsburgh. TRANSPLANTATION TECNNIpUE FOR ACCELERATION OE: CARCINOGENESIS BY BENZJa/ANTHRACENE OR 3,4,9,10-DIBENZPYRENE JBENZO(RST)PENTAPEIENE/ Transplantation of combined carcirwgen-injection sites from four C57BL/6 J male mice into one secondary host significantly accelerated tumor growth in the secondary recipient. In this study, acceleration ot chemical carcinogenesis was obsetved after transplantation of injection sites with a small dose ( 25rg) of the strong carcinogen benzo( rst )pcntaphcne (DBP) and with a large dose (500 pg) of the weak carcinogen benzoia)- anlhraccne ( BA ). When BA was kft in tltu. two tumors developed among 48 mice 52 weeks following the original injeetion, whereas significant tumor incidences occurred within 24 weeks after the original injection when site tra! 'sfers had been made g, 12. 16, or 24 weeks after the administration of carcinogen. Site transfers made eifht weeks after the original injection yicldcd 67% tumors 24 weeks after injection. Following site transfers made 12 weeks after the first injection, there were 80% tumors 12 weeks later. More delayed site transfen gave lower tumor yields. With UBP, the first tumor appeared 12 weeks after single injeetion, whereas, following trans- plantaticxt af injection site six weeks later, the first tumor appearcd nine weeks after the original injection. IlomburRer. F. and Treger, A. Journaf of the Nurional Cancer Insrlrurr 44:357-360. 1970. Otlhrr Rrn..tor.: U. S. Public Fieallh Service and Virginia an(I 1) K I ud- wig houndation. From the Bio-Rescarch Institute, Cambridge. Mass. 20 21

FATE OF SU[1CUTANf=OUS1.Y INJECTED F1f3NT_O(RST)- PI-•.NTAPHFNE IN C57E3L/6 MICE Bcnzo(rst)pentaphene is an aromatic polycyclic hydrocarbon with high carcinogenic potential. Early studies on this compound indicated that when injected subcutaneously it remains at the injcction site and is not metabolized. flowever, experiments repotted here, run with "('-labeled benzo(rst)pentapherx, demonstrate that 95% o( the carcinogen is removed from the injection site. This removal is accomplished in two stages: first, removal of significant quantities which can be detected at other body sites and which is associated with the trauma of the injection, and secn,xily, a chronic renxoval, nearly compkte in ten weeks. No relationship was found between the rate of tumor formation and the amount of carcinogen remain- ing at the injection site. Kelley, T. F. (llomhurttr, F.) ): ProcredinRs of rhr Society for Esprrimtnrol Biology and Mrdic inr 133 (4 1402-1414, 1970. Other Rror.tor: l). S Public Hcalth Service. From the Bio-Research Institute, Cambridge, Mass. INIIIBITORY E:FFE~(T OF L-ASCORBATE ON TUMOR FORMATION IN URINARY BL-ADDERS IMPLANI ED WITEI 3-HYDROXYANTI IRANILIC ACID A 2 X 2 factorial experiment designed to test the effect of elevated urinary kvels of ascorbate on the carcinogenicity of 3-hydroxyanthranilic acid (3-HOA) waa carried out in Swiss albino mice. Pellets of 3-11OA, a known producer of uroepithelial tumors in mice, were inserted into the bladders of 121 mice. Blank cholestero( pellets were placed in 91 controls. A total of SI exposed nd 33 control mice were then fed L-ascorbate (250 mg/100 ml) in their drinking water ad libiturn. The probability of survival was checked and found to be the same in sll four of the working groups of mice. However, when all surviving mice were killed at IheTand o/`orty weeks, t)robse~rveryd In the diRerc the R o~rpsrrc tumots (pre gnan~-~ ~n vealed that ascorbic acid inhibited the anticipated carcinogenic etfcct of 3-IEOA. Pipkin, 0. E, Sch/eprf, l. U., Nishimura, R. and Shultr., G. N. rroceedings of the Society for Etptrlmtntol Biology and Medicine 131(2): 522-524, 1969. Other 6re.torr National Cancer Institute. From the Department of Surgery, Tulane University School of Medicinc, New Orleans. THf•. ROLE OF ASCORBIC ACID IN THE PREVENTION OF BLADDER TLIMOR I-ORMATION Pellcts containing 3-hydroxyanthranilic acid (3-I1OA ), one of the tryp- tophan metabolites, were implanted into the bladders of Swiss albino mice. Mice implanted with 3-LIOA had a significantly higher incidence of bladder tumors. Oral administration of large amounts of ascorbic acid which resulted in high urinary levels of ascorbate prevented this carcinogenic efiect, pre- sumably because of the competitive affinity for oxygen which prevented the oxidation of 3-l1OA. Because of this observation, it would appear that 3-HOA, in itself, is not a carcinogen, but rather that the oxidation of this compound is of importance in carcinogenesis induced by this orthoamino- phenol. On the basis of these results, recommendation for oral administra- tirxr of ascorbic acid as a possible preventive measure of spontaneous bladder turmrr fr+rmation and recurrence in man appears to be warranted; this suRgcstion is further supported by the evidence of lack of toxicity af the dosage required to maintain an adequate urinary level. Schlegel, !. U., Pipkin, G. E., Nishimura, R. and Shultz, G. N. Tron.ractions o/ the .I rrKricon Atsociation oJ Genito-Urinory Surgeuni 61:85-89. 1969. Other grantor: U. S. Public Health Service. From the Department of Surgery, Tulane University School of Medicine. New Orleans. NONENZYMATIC FORMATION OF CINNABARINIC ACID IN URINE OF PATIENTS WITH TUMORS OF TIIE URINARY BLADDER This study explores the identity of compounds formed by oxidation of 3-hydroxyanthranilic acid (3-HOA) in urrne, and checka for the pres- ence of these oxidative compounds in the urine of tumor patients. To accomplish this, identical amounts of 3-HOn, which is a urinary metabolite of dietary tryptophan in man, were added to urine samples collected from 12 subjects with tumors of the urinary bladder and from a group of normal subjccts (five heavy smokers, three smokers, and 14 nonsmokers). Ekrth groups of such urine samples were incubated overnight at 37"C in air. By use of chromatography and ultraviolet tpectroaeop)r, an in vino oxidative product of urinary 3-11OA was isolated, aemiquanUtated, and identified as cinnaharinie acid. This acid formed oxidatively from 3-II()A in urine samples from both I roups; however, quantltatively, more was formed in urine samples from the group of lumor p.tienta. Furtht:rmore, oral admin- islration of l; ascorbie acid to both groups of sub)eets in quantities sufficient to cause spillage of ascorb.te, an antfoxidant, Inlo the urine prevented the in vitro oxidation of urinary 3-EIOA and the formation of cinnabarinic acid in all urine samplcs. This instability of urinary 3-HOA could thus result in formation in vivo (if oxidative products such as cinnabarinic acid which could play a role in the etiology of carcinoma of the urinary bladder. 23 22

Nishimura, R., Pipkin, G. E., Duke. G. A. and Schlegel, !. fl. Invtru'4arivr f/roloRy 7(3):206-214, 1969. Otlhrr Rra,.tor: National Cancer Institute. From the Department of Surgery, Tulane University School of Medicine, New Orleans. TIlE AETIOLOGY OF BLADDER TUMORS The chemiluminescence o( urine from a number of nonsmoken, smok- ers, nd bladder-tumor patients was evaluated in this experimental attempt to assess the role rr[ redox environment in the aeliology of bladder tumors. Previous studies have indicated that redox environrnent might be important in determining whcther potential carcinogens would be capable of c><erting their earcinogcnic potential. Using the Dupont Luminescence BicNncter for measurement, chemilumineseence In urine was determined by placing l/ a(1 ml of urine in a vial and injecting 0.02 ml of 30% hydrogen pcroxidc. Examinin~ 43 nonsmoken, 36 smnken, and six bfadder-tumor patients it was found that there was a significant difference between the chcmilumi- nescence elicited by urine from nonsmoken on the one hand and smokers and bladder-lumor patients on the other. This difference was significant with a p value of lcss lhan (1.05. Since most of the bfaddcr-tumor patients were smokers, it is difficult to evaluate whether what was determined was a sig- nificant difference between smokers and nonsmokers, or between bladder- tumor patients and eontrols. The administration of ascorbic acid leading to significant concentrations in the urine showed as in previous studies a sup- pression of chemiluminesccrxe, thus indicating that thc presence of an anti-oxidant in the urine will prevent chemiluminescence. Schlt`rf, !.fl., Pipkin, G. E. and Shultz, G. N. Brirish Journal of flroloty 41(6) : 718-723, 1969. Ot11er grantorf Nationd Cancer Institute. From the Department of Surgery, Tulane University School of Medicine, New Orleans. Slll FATTORI INTRINSECI DELLA CANCEROGENESI POLMONARE DEL TOPO: EFFETTI DEL "COMPLETE FREUND'S ADIUVANT" Two groups e-4 40-dar-old virgin male and female BAI.B/c mice were injected subcutaneously with urethane at a dose of I mg/g of body weight. One week txfore and one after the injection of the carcinngen, or.e group of mice was also treated intraperitcxreally with 0.1 nil Complete I-rrund's Adjuvant (CFA ). Mice treated with CFA and urethane dcvchtfxd 17.1 lung tumors per m<wse at an average age of 414 days. Control mice stKrwed ten lung tumors per mouse t an average age of 435 days. Sex dependent variatioxts of the number of lun6 tumors were observed only in the group of mice treated with CFA and urethane. Analysis of incidence and of average number ol lung tumMKs per mouse in rclation to the sizc of tumors showed that larger tumon were seen mainly in the CFA treated mice. This paper includes a discussion of the mechanism through which CFA enhances urethane lung tumorigenesis in BALB/c mice. Ribaeehi. R. (Stveri, L.) I-ov. Anor. Por. Perugia 29( 2): 81-91, 1969. From the Division of Cancer Research, University of Perugia, Italy. 111. Cardiooa.calnr System BRONCFIOPl1LMONARY AND CARDIAC EFFECTS OF I IYDR(X'ORTISONE In an attempt to gain an insight into the therapeutic actions of hydro- cortisone as regards several heart disordcrs, experiments were designed to ascertain (a) the direct cardiopulmonary effects of hydrocortisone and (b) the interaction between hydrocortisone and isoproterenol. Canine heart- lung preparations and canine preparations with right-heart bypass were used for these investigations. In both preparations hydroeortisone accelerated the heart rate and stimulated contractility. There was also relaxation of bronchial snxx.th muscles and vasodilatatron of the pulmonary blood ves- scls. The cardiac stimulat(xy effects of isoproterenol were not potentiated but appeared to be reduced by hydrocorlisone. Oskoui, M. and Aviado, D. M. Archives Inrernorianoler de Plrarmocodynamie et de Thfropie 179(2): 314-325, 1969. From the Ekpartment of Pharmacology. University of Pennsylvania Schrx,l of Medicine, Philadelphia. EFFECT OF NICOTINE ON CONTRACTILITY OF TIIE INTACT EIEART The effects of nicotine on the instantaneous force-velocity of the intact left ventricle in closed-chest dogs were studied before and after the induc- tion of /3-adrenerRic blockade with propranolol. Nicotine was administered by intravenous infusion. Velocity of shortening was measured in the 22 lest dogs by means (if n intracardial strain-gauge catheter assembly. Nicotine, ahme, aurmcnted myocardial contractile atate as indicated by an increase in both Ihe force and velocity of shortening. When P-adrenergic bhxkadc prccedcd nicotine. Ix)wevcr, the rise in left ventricular systolic pressure was proportiunatcly greater but velocity of ahortenin¢ showed a reciprocal decline. Lcft ventricular end-diastolic pressure rose srgnificanlly; the increase in pressure rise was less marked. These findings suggest that pnopranulr,l impaired the rarepinephrine-like effects nf nicotine on the myoKardium while its peripheral vasopressor action became enhanced. Puri, P. S., Alamy, I). and Ring, R. 1. Cardiology DiResr 5: I9-25, 1970. 24 25

Other Rranror.: U. S. Public Health Service. Michigan Ilcirt A~cnciation, American Medical Association Education and Research Found:rt (in, and Detroit General Ftc.spital Research Corporation. From the Department of Medicine, Wayne State University School of Medi- cinc, Detroit. DIRECT ANE) RFFLEX EFFECTS OF IEYPOTHERMIA, IIYPOTENSION AND HYPOXIA ON THE HEART This book chapter deals with the effects of three lows - low tempera- ture, low blood pressure, and low oxygen content - on the working of the heart. Hypothermia, which is widely used in cardiac sur8ery, has b:ncfscial effects on the arrested heart. The lowered temperature reduces coronary blood flow and mrocardial oxygen consumplion, and usually causcs a fall in heart rate, cardiac output, and arterial pressure. Of course, such lk rcduc- tion in oxygen consumption must have generalized metabolic cf(ccts upon the heart and body tissues; many studies have been carried out in this area. Discussion in the section on hypotension is restricted to hemorrhagic shock. The roEe of the heart in initiating and sustaining the hypotensive state has been investigated widely. Although most of the dala point to the neart as being primaril~ responsible for irreversibility in hemorrhagic shock, some studies have dcmonstraled that the onset of myocardial failure c><curs at such a late stage that other causes could be implicated. In any case, the development of mrocardial failure is an ominous sign and usually heralds death. In the section on hrpoxia, the effects of myocardial infarction on myocardial metabolism and function, as produced by ligation of branches of the coronary artery, are rcportcd specdically. In addition to considcra- tion of the immediate and delayed myocardial responses to coronary artery occlusion, the stimulation of reparative processes following experimental myocardial infarcation is discussed. Robin, E., Gudhjarnason, S. and Bina. R. l. In Oaks, W. W. and Moyer. l. H. (eds.): 19th llahnrmann Svmposium, New York: Grune! Stratton Inc., 1970, pp 251-267. Otber rs.ror.r U. S. Public Health Service, American Medical Asuxia- tion Education and Research Foundation, and Detroit General Hospital Research Corporation. From Wayne State llnivenity School of Medicine, Detroit. THF. EFFECr OF NICOTINE ON EFFECTIVE AND TCYI'AL CORONARY BLOOD FLOW IN THE ANES71iES1-LED CEASED-CHFST DOG The use of rubidium" as a diRusible Indicator, kogethcr with a double coincidence counting systuem. Provides a techniyue to study the effect of nicotine on the total nd effective coronary flow in the closcd chrst anirnal and in man. Intravenous administration of nicotine ( I(X) Ng/kg in one minutc) in 12 healthy, closed-chest, anesthesized dogs caused incrcases in Icft ventricular wurk, in myocardial oxygen consumption, and in both elfec- tivc ( nutritional ) and toaal coronary flow. The increase in effective capillary flow to the uiyocardium after nicotine administration was suflicicnt tu mcct mycxardial oxygen dcmands. Effective capillary flow appcared to be pri- marily regulated by myrxardial oxygen consumption. The proportional in- crease in myocardial oxygen consumption and effective capillary flow indi- catcs that the eRcctive capllary flow to the myocardiurn is cluscly relatcd tu myocardial oxygen supply. Leb, G., Derntl, F., Robin, E. and Bing, R. l. The Journal of Pharmacology and Experimental Therapeutics 173(1 ): 138-1'4, 1970. Otiierr Rrar.tor.: U. S. Public Health Service and Michigan Heart Asscs cia/ion. From the Department o( Medicine. University of Southern California, liuntinston Memorial Ifospital, Pasadena, Cal., and Department of Fxpcri- mental Medicine, Wayne State University School of Medicine, Detroit. A ROLE OF TIlE CENTRAL NERVOUS SYSTEM IN THE CARDIOVASCULAR ACTIONS OF NICOTINE In the present series of experiments, blood pressure responses to nico- tine were measured in 39 adult mongrel dogs following general anesthesia, spinal ancsthesia, spinal transection, or decerebration. Results showed that all of these procedures reduced both the depressor and pressor responscs to nicotinc, thereby reinforcing the concept that an intact central nervous system is necessary for the o imal cardiovascular effects of nicotine. In addition to nicotine, the 8anionic stimulant dimethylphenylpipcrazinium (DMPP), cpinephrirx, norepmephrine, and isoProterenol were given intra- venously for comparative purposes. The finding that the cardiovascular effects of DMPP are reduced by pentobarbital in the same manner as nico- tine would suggest that peripheral reflex (chemoreceptor) or ganglionic facilitation, due to an active central autonomic dischar8e, is more likely than a direct action of both of these substances on the brain itself. (DMPP would not be expected to penetrate the bEood-brain barrier as readily as nicotine. ) Although further research in this area is obviously indicated, the evidence now vailable clearly indicates that the central nervous system has an important role in the overall cardiovascular actions of small drnes of nicotine in doEs, and is prominently involved in the overall pharma- cology or Ihis most interesting drug. 1)omino. E. F. ArchiveJ Intrrnarionalrt de Pharmocodynamle rt de Thlropir 179(1 ): 167-179, 1969. From thc Department of PharmacoloRy, University or MichiRan, Ann Arbor. 26 27

TIIF F.FFECT OF NICOTINE ON DIETARY ATFfEROGFKESFS IN RABBITS In this series of dietary experiments, four groups of ten New 7ealand rabbits each were fed either a stock diet; a stock diet plus nicotine injcc- lions; a cholesterolcontaining diet, or a cholesterol diet plus niartinc injcc- tions. Those rabbits on a cholesterol diet plus nicotine injections denxm- strated wider areas of involvement of the internal surface in the aorta than rabbits on a cholesterol diet alone. In both stock-fcd ^nd cholesterol-fcd animals, nicotine produced an increase in aortic triglrcerides and a decrease in the free cholesterol content. An increase inphospholipids, particuiarly in lecithin and cephalin, was observed In the eholesterol-fed rabbits treated with nicotine. Aortic acid mucopolrsaech^ride composition did not exhibit any significant changes following nicotine treatment. Concomitantly, it was shown in in virrn dialysis ei<periments that heparin and nico(jne fcrm a relatively stable complex, in a molar ratio of aMwt 1:2(1; nicotint also inhibits the hydrolysis of "C-Iabekd triolein in a homogenale frorn abhit aortic tissue. l hese data, indicating an apparent complex formation bc'wcen heparin ^nd nicotine, suggest that the basis for some of the biological t ficcts of nicotine may be related to an in vivo interaction with heparin. Stcfanovich. V., Gcwe, /., Kajiyama, G. ^nd Iwanaga, Y. Experimental and Mofrcvlor PorholoRy 11( 1):71-81, 1969. Other Rranto-t U. S. Public Nealth Service. From the Department of Pathology, University Hospital, and Boston Uni- versity Medical School, Boston. TIIE ESTIMATION OF BLOOD PLATELET SURVIVAL: 1. GENERAL PRINCIPLES OF TNE STUDY OF CELL SURV'VAL Estimation of plstckt survival is a matter of some importance today since the economy of the platelet has become recognized as sonkthing largely separable from the behavior of the coagulation system. Moreover, since many of the probkms concerned in the measurement of platelet sur- vival are common to lhox of ineasurenxnt for any migrating ccll, basic ideas and principks tested here could be adapted to other cell populr.tions. Since migrating cells cannot be individually Identified, inferences about their pattern of survival must be based on the collective behavior of a defined group of such cells. A precise nonxnclature for the aspects of such cells and their behavior is necessary. Accurate estimates of mean survival of cells depend on the use of a model, which can only be constructed by considering pertinent factort in the Internal ^nd external economy of the cell. But dermxtstration that a factor is indeed pertinent depends in large part on observing change in rne^n survival. This circularity may be avoided by studying those properties of such survival curves which are uninfluenced by the form of the drstnbuticxt of cell survival. Since these properties ^re logical necessities, there Is no need to verify them experimcntally. Murphy, E. A. and Frands, M. E. Thromhosh tt Diorhttit Hoemorrhoglcn 22(2):281-295, 1969. 28 From the Departments of Medicine and BioslaliStics, The Johns llopkins University SchcH,l of Mcdicinc, Baltimore. SERUM-FREE-FATfY-ACIDS AND THEIR RELATION TO COMPLICATIONS AFTER ACUTE MYOCARDIAL INFARCTION In an attempt to learn whether the concentrations of serum-frcc-fatty- acids (F.F.A.) noted at the onset of acute myocardial infarction (M.1.) are predictive for the development of complications or death, admission F.F.A. levels were measured in 78 M.I. patients and plotted against the patients' clinical courses. Serum F.F.A. kvels were also determined when- ever possible on fasting specimens drawn one day after admission, on the fifth day, three weeks after admission, and at the time of any complication. Results showed that there was no relationship between the initial levels of serum F.F.A. and the devclopnsent of arrhythmias, cardiogenic shock, or late deaths. Congestive heart-failure, persistent chest pain, and embolic accidenls, likewise, could not be predicted by the initial serum F.F.A. Ifowever, the serum F.F.A. tended to be elevated at the time that compli- cations developed throughout tle hospital course. While this temporal ele- vation was noted for most conplicalrons, it was not necessarily seen in t(xne patients who exhibited poot peripheral perfusion ("shock syn- dronse"). Thus it would seem that the elevation of serum F.F.A. ^t the time of complications may he related to increased catecholamines in the most savereiv ill patients, but the data do not support any independent adverse eRects of the increased serum F.F.A. Rutcnberg, I1. L., Pamintuan,l. C. and Solo#, L. A. The Lcncer 2:559-564, 1969. Other Pr^ntorr U. S. Public Health Service. From the Division of Cardiology, Temple University Hcalth Sciences Ccn- ter, Philadelphia. INCIDENCE OF SIGNIFICANT CORONARY ARTERY DISEASE IN RHEUMATIC VALVULAR HEART DISEASE Between 1963 and 1968 Ihere were 77 necropsiea performed at Tem- ple University Ilealth. Sciences Center in individuals who died afler surgical treatment for rheumatic valvular heart disea^e. Of these 77 palients, ten (13% ) were found to have clinically significant (g^de 3) coronary artery disease. This disorder occurred at all ^ges but was more common after age 40. It was commoner in aortic v^lvutar disease either alone ( 17.7% ) or combined with milral valvular disea^e (21.1%) than in isol^ted mitral valvular disease (8.6% ). This difference might be due to the older ^ge of death of the patients who had aortie lesions. Beeause clinically significant coronary ^rtcry disease complicating v^Ivular heart disease is ditTicult to recognize on clinical grounds and because it might adversely affect prog- 29

nosis, coronary cinearteringraphy and Icft ventricular angiography are suR- gested in the overall evaluation of patients for valvular heart surgery. Such studics should he made particularly in those above age 40 and in those with x-ray evidence of aortic calcification and with atherosclerosis detected dur- ing retrograde cathetcrixalion of the femoral artery. Coleman. E. 11. and SoloO. L. A. American Journal of Careiofoay 25 ( 4):401-404, 1970. Other grantor: U. S. Public Health Service. From the 1>ivision of CGrdiofogy, Temple University Health Sciences Cen- ter, Philadclphia. ON TffE AS.S(X'LATION OF CK7ARETTE SMOKIN(; WITFI CORONARY ANf) AORTIC ATHEROSCLEROSIS The association of cigarette smoking and atherosclerotic lesions in the coronary arteries and in the abdominal aorta was investigated in 747 autop- sied men, 20-64 yean of age. This paper, an interim report, presents results from approximately half of a projected study of 1.500 cases. In this study, aortic and coronary lesions were evaluated visually in coded specimens and objectively by analysis of radiographs. Using schedules that had been tested for validity and reliability on pairs of living persons, interviewers obtained estimates of cigarette smoking habits of the deceased men from surviving relatives. The data were analyzed with reference to total sample .nd also to subsamplcs grouped according to the presence or absence of diseases thought to be associated with smoking (emphysema, lung cancer, etc.) or with coronary heart disease (myocardial infarction, hypertension, diatxtes, rtOroke, etc.). Atherosckrotie involvement of aorta and coronary arterics was greatest in heavy smoken and least in ransmoken. Occupational physical activity and educational level achieved did not account for cbserved differences in extent (t( lesions. These preliminary studies suggest that smok- ing or an associated factor affects the development of mural athcrerszIcrosis, and that the apparent relationship of smoking to CHD is not limitcJ to the events surrounding the terminal occlusive episode. These suggestive tindings, if confirmed with larger numbers of cases, indicate the need for experi- ments in animals to determine whether cigarette smoking accelerates arterial lesions. StronR, /. P., Richarda, M. L., McGitl, H. C., lr., Eggcn, 1). A. nd McMurray, M. T. Journal of Athtroacfrrosfs Rextrrch 10:303-317, 1969. OtCrer grar.tor.r Louisiana ffeart Association and the National fleart Institute. From the Departments of Patand Biometrr, Louisiana State l)ni- versity ScFKx,l e~f Mediei*ne, New Orlcans, and "f fic Uni%crsity of 'lcxas Medical School at San Antonio, San Antonio, T'ex. SINUS ARRIfYTIfMIA IN DOGS AFTER CARJIAC T RANSPLANTA"ITON ERcrent reinnervation of the heart has been reporteo to occur within three to five months of transplantation. If such reinnervation is sufticicnt to give rise to a normal physiological phenomenon such as sinus arrhythmia, thc dcmonstrati„n cif this arrhythmia in a transplanted heart could prove a useful and simplc indication of cardiac reinnervation. With this in mind, the recurrence of sinus arrhythmia after cardiac transplantation was studied in 17 dogs previously subjected to cardiac autotransplantation and in two dogs after homotransplantation. Sinus arrhythmia was demonstratcd in 13 animals between 2'/: and 20 months after cardiac autotransplantation and in one dog 140 days after cardiac homotranspfantalion. Sinus arrhythmia recurred in these animals after parasympathetic reinnervation of the heart. These results show that sinus arrhythmia occurs in most animals with car- diac autotransplantaticxt after parasympathetic rcinncrvation of the heart. The recurrence of sinus arrhythmia after cardiac transplantation signifies the occurrence of parasympathetic rcinnervation of the heart; absence of sinus arrhythmia, howevcr, does not exclude the presence of such reinncr- vation. Thamts, M. [)., Kontos, 11. A. and Lower, R. R. (Student Fotlowship , Reeipient ) American Journal o/ Cardiology 24:54-58. 1969. Other grs.torr National Institutes of Health. From the Departments of Medicine and Suraery, Medical College of Vir- ginia, Richmond. DEVELOPMENTAL PATTERNS IN HYPERTENSIVE CARDIOVASCULAR DISEASE: FACT OR FICTION? Of 1,130 whitc mak medical students registered between 1947 and 1960 in a tong-term study of the rson of hypertension and coronary disease, 16 subjects had deve clinkal hr~ertension by 1968, while 89 others had exhibited transitory ypertension. When the prevalence of hyper- tension in the older gradualin classes was compared with that in the younger classes, it was found t~at the proportion of subjecta with clinical hypertension had tripled while the proportion with transitory hypertension had not quite duubted, suggesting a movement of some of the transitory group into the clinical group over time. No clear-cut differences were found between the clinical and transitory groups in respect to age at discovery of elevated blood pressure levefs, or to rtatin6 blood pressures recorded while in medical school. A study of the subjeeta' histories showed that in 62.5% of the subjects with clinical hypertension both Qarents evidenced hyper- tension and/or coronary diaease, as compared with 21.9% of the parents of the control group. The prevalence of disorders among both parents of subjects with transitory hypertension was intermediate (36.0% ). Hyper- tension alone was more frequent among the parents of Ihe clinical hyper- tension group than among the parents of the transitory hrpertension Rroup, while parcntal hypertension was more frequent in butb of these groups 30 31

than it was in two control groups. No definite crrnclusirms rcR:rrdinF the existence of develnpmental patterns could be reached on thc basis c.f this preliminary expk+ration. Thomas, C. R. Buffrtin o/ the New 1'orA Arodrmy of Medirinr 45(9):R31-850. 1969. Orher grantor: Maryland Heart Association. From The Johns Hopkins Univenity School of Medicine, Baltimore. DECREASED THROMBUS FORMATION IN RATS AfTER CHRONIC NICOTINE ADMINISTRATION A total of 70 fcmak Sprague-Dawky rats was used in this study of the effects of chronically administered nicotine upon in vivo thrombus sus- ccptibility. The ratt were divided into five grrwrs of 14 rats{x r Rroup; four groups received nicotine alkafoid In the drinking water ((157, I 14, 2.28, or 4.56 mg/k6/day) for 18 weeks. The fifth group was untreated All rats were tested for thrombus formation. A mean concentration of 90 6:! 10.9 N1H units/ml thrombin productd platelct thrombi within the ten-minute exposurepc riod in untreated rats. Groups treated with nicotine in doses of 0.57, 1.14, 2.28, or 4 56 required: 97.4 ± 8.5, 129.7 :! 16.0, 130.4 -± 13 4, and 158.1 ± 21.0 NIH units/ml respectively. Animals treated with the largest dcne of nicotine required a significantly higher concentration of thrombin to produce thrombi than did untreated rats or rats treated with the lowest doses (p < 0 0 1 ). Instead of an increased tendency to Ihrom- bosis, as anticipated from studies of smoking in man and frc.ni in vitro studies, chrnnically-administered nicotine increased the amount of throm- bin required to prcxluce thrombi. Wentrf, D. G. and Richards, M. H. European lournal o/ Pharmacology 10( 1): 143-144, 1970. From the f)epartment of Pharmacology and Toxicology, Univcnity of Kansas School of Pharmacy, Lawrence. IV. Respiratory Syt+tem Nose and Mouth EXPERIMENTA[1.Y INDUCED CHANGES IN NASAL MUCOUS SECRETORY SYSTEMS AND TNEIR EFFE(_ON VIRUS INFECTION IN CHICKENS: 1. EFFECT ON MUCOSAI. MORPHOLOGY AND FUNCTION Physiokogical chanles were Induced in domestic chickens by eeposure to drugs, systemic dchydration, temperature manipulation, vitamin /t depri- vation, (~ermfree environment, and cold. These different stresses had dif- ferent dfects on the ciliary and mueous systems. Cilia were directlr affected when paralyzed by cocaine and, of oourse, when cksquamated b) hcxyl- caine. Mucus quantity and quality as judged morphologically by histo- chemical staining were alfected in a diffetent way by each uf the stress methods. There was no evidence that any of the area-specific (lacrimal, olfactory, etc. ) systems was selectively affected quantitatively by any test method: if there was hyper- or hyposccretion or reduction in acinar size, it obtained generally This was usually true also of mucus quality; the single exception being that gcrmfree rearing induced intensive staining of the flask-shaped mixed acini, yet drastic depletion of the paraolfactory periodic acid-Schrff complex. With a few exceptions, there was no clear evidence that the normal balance between the Akian blue and pcriodic acid-Schiff components in the mixed alcini was altered either. Howevcr, there was distinct loss of the normal zoning of these components after cxp<nurc to intense cold, after repeated cocaine injectiorts, and after both pdocarpine stimulation and rehydration of severely dehydrated chicks. These results show clearly that respective areas of the mucosal blanket serve local func- tions to some cxtcnt, and it is known that innervation, sccrctory Iyfxs, and lymphoid resprxrses are fairly kxalited. The spectrum of effects pnxluced by altered physiology emphasizes how little is known about factors which control synthesis of mucous or serous secretions in the nose. Ban6, B. G. and Bona, F. B. lournal of E[prrimenral Medicine 130(1) :103-120, 1969. Otlher grantor: National Science Foundation. From the Department of Pathobio{ogy. The Johns Hopkins University School of Hygiene and Public Health, Baltimore. EXPERIMENTALLY INDUCED CHANGES IN NASAL MUCOUS SECRETORY SYSTEMS AND THEIR EFFECT ON VIRUS INFECTION IN CHICKENS: 11. EFFECTS ON ADSORPTION OF NEWCASTLE DISEASE VIRUS In the studies reported here, the actions of several pharmacological agents which affect the adsorption of Newcastle disease virus to the intact nasal mucosa of chicks are examined and interpreted. When chickens three weeks old were inoculated intranatally with a meso6enic (mcxkratcly viru- lent) strain of Newcastle disease virus, they developed necrotic lesions of the mucous acini, predominantly of the middle turbinates. Paral~sis of ciliary action by cocaine increased the number of infccted cells in the tur- binates about 10-fold at one, three, and five hours after viral exposure. Pilocarpine injection before virus inoculation caused a large increase in the amount of infected cells one hour after virus administration, but was followed by a sharp drop in infected cells by three or Ave hours. Pihrcar- pine given after the virus decreased the number of infected cells and changed the relationship of infected cells to adherent virus. Exposure of chicks to sustained or severe cold caused a similar but kss marked effect. The drop in infected cells was restored to control values if chicks were returnei to brooder temperatures. The marked drup of Infected cells pro- dueed by pilocarpine and cold in living ehicks, and in cultures e,t chicken 32 33

trachea (previous study), is consonant with the idea that virus has been adsorbed on mucus granulcs in the mucous cells of the lurbinates and then has hfen reescrcted. as unincory+orated virus, into the moving mucous sheet. Bang, F. R. and Foard, M. A. lnurnal oJ E.rperimental Medicine 1)0(l ): 121-140, 1969. From the Department of Pathobiology. The Johns Hopkins University School of Ilygiene and Public Health. Baltimore. REPLACEMENT OF VIRUS-DESTROYED EPITFIELIUM BY KERATINIZED SQUAMOUS CELLS IN VITAMIN A-DE?RIVED CHICKENS Intranasal inoculation of chickens with Newcastle disease virus ( NDV ) produced lesions in mucous cells in the inner surface of the middle turbinatc where thc mucous membrane is shallowest. This same quite extcnsivc mucrnal area showed urliest signs of incipient keratinizing mctaplasi in vitamin A-deprived (VAD) chickens; in NDV-infectcd VAD chickens, mucociliated cells in this region were rapidly destroyed and replaced by kcratiniring squamous cells. In normally-fed birds, desquamated epit(xlial cells were replaced by mucocitiated cells. These experiments raised several questions in relation to upper resPiratcx~ tract infection in vitamin A-defi- cicnt populalions, questions dealing with diRerential absorptions of virus, relative susceptibilities to virvs, and cellular effects of repeated insult on mucosal sites of normal and VAD populations. A means of studying these combined factors seems to be offered in this whole-animal model. Bang. B. G. nd Bona, F. B. Proceedings of rhr Society for E.tprrimenral Biology and Medicine 132( 1): 50-54, 1969. OtAcr `rwtorr National Science Foundation. From the Department of Patltobiology, Tfic Johns Flopkins University School of Nygictx and Public Health, Bdt"imore. TOBACCO SMOKE TOXICITY: LOSS OF HUMAN ORAL LEUKOCYTE FUNCTION AND FLUID-CELL METABOLISM The human moutb, which serves as a natural "srnokin machine" and trap for tobacco smoke, has been used as an in vivo open ~ioassay system for tracing undesirabk tubstanccs present in tobacco smoke. Employing a standardized method of sampling the oral nvity, oral fluid-cell harvests before and after smoklnj were obtained from 45 male and 41 female smok- en and mxmnokers. Control readings showed that such oral fluid-ccll harveats usually contain significant numbers of peripheral kukocytes, d)ughed epithelial cells, granular masses or casts, numerous mic roorgan- isms, and other bits of protoplasm. Results of these tests denr3nstrated that exposure of the mouth to whole tobacco smoke and its retairxd re- siduum (or to the partkk-frce gas phase and its retained residuum), after the subject had srpoked one cigarette, provided encwgh toxic material to inhibit completely the function of the in tiru exposed oral Icukocytcs. Exposure to whole tobacco smoke and its rctained residuum also induced 507o inhibition, or more, of the aerobic oxidative metabolism and anaero- bic glucolysis of the in tilu exposed oral fluid-cell components. In in vitro experiments, it was found that two important compounds in the gas phase of tobacco smoke, acrolein and cyanide at concentrations lower than that contained in a single puff of smoke, inhibited the function of oral Icukocytes and the metabolism of the oral components. Another series of experiments demonstrated that the functiorr of oral leukocytes remained unimpaired under conditions that selectively excluded the toxic substances contained in the gas phase, but which permitted significant amrwnls of the particle phase to enter the mouth. These results would indicate that the volatile gaseous phase of tobacco smoke (not the "tars" or nicotine) contains most of the undesirable substances toxic to the human oral kukocyte. F.irhel. R and Shahrik, FI. A. Science 166: 1424-142A, 1969. From (he Science Resources Foundation, Watertown, Mass. Bronchi and Lungs FIORMONES ANL) PULMONARY EFFECTS OF TOBAC CO. 11. PROGESTERONE This report deals with the influence of progesterone on the broncho- spasm induced by cigarette smoke and nicotine. Administered subcutane- ously, daily for seven daysM progesterone altered the pulmonary response of the anesthetized rat. There was a reduction or blockade of broncho- ccxrstrictor responses to the following procedures: inhalation of cigarette smoke and intravenous injection of nicotine, acetykholine and histamine. On the other hand, bronchodilator responses to cigarette smoke and iso- proterenol hydrochloride were not influenced by progesterone. "ilre fact that progesterone blocked moat bronchoconstrictor responses to a number of procedures was totally unexpected. Accordingly, it would appear that the relation of these observations to an antiemphysematous action of Pro- gesterone and the relation of the presence of progesterone to the lower inct- dcnce of pulmonary disease in females require further investigation. Shore, S. R. and Aviodo, D. M. Archivts of Environmental fltollh 19:59-69, 1969. From the Department of Pharmacology. University of Pennsylvania School of Medicine, Philadelphia. CARDIOPULMONARY EFFECTS OF NOREPINEPIIRINE AND PROPRANOLOI. Identification of a local action of propranolol on the bronchial srmx)th 34 35

muscle independent of a CNS or catecholamine-mediatcd blockade of adren- ergic receptors was sought in seven canine heart-lung prepuations. In these experiments, norepinephrine was administered in the following dosc%: 0.l?4, OOR, (1.20, 040 r.g/kR min. The most frequent cRects were: (a) fall in pulmonary resistance; (b) fall in pulmonary compliance; (c) incrcase in pulmonary vascular resistance and pulmonary arterial prtssure; (d ) i all in coronary sinus blood flow; (e) increase in myocardial contractility; and (f) tachycardia. Propranolof (0.25 mg/kg) blocked norepincphrine rflccts (c) and (f) and reduced the intensity of (b). The local vascular actiim of norepinephrine which is not blocked by propranolol is responsibk for (d), (c), and even (a). The fdl in pulmonary resistance (a) induc:d by norepinephrine is exptainod by a local vaaooorutriction of bronchial blood vessels. Propranobl akine caused an increase in pulmonary resistance. This increase inpu Imonary resistance is explained by a local action, either local spasm of tix bronchial muscle or vasodilation of blood vessels, in thc bronchial mucosa. Oskoui. M. and .1 vlodo, D. M. Europeon lournal of Pha.rrrwofoay 5(4):321-327, 1969. From the Dcpartment c.f Pharmarniogy. University of Pennsylvania School of Mcdicinc, Philadelphia. CIGARETTE SMOKE AND PULMONARY EMPFIYSF.MA: INFLUENC'E OF BRONCIIODILATORS AND BI(X;F,NIC AMINES IN EXPERIMENTAL INDUCTION IN RATS Experiments reported here were undertaken to examine whether ciga- rette smoke alone can induce pulmonary emphysema. A tota) of 133 male albino rats o( Mcndcl•(Hbome strain were used for the five investigations. Two groups of rats (oue exposed, one control) were used to study the pulmonary eRects of daily expow re to cigarette smoke. After ten weeks of exposure, there were no differences in functional residual caPacity. pul- monary resistance, pulmonary compfiance, and respiratory minute volume. An explanatirxr was aought as to why cigarette smoke alone did not induce pulmonary emphyserna, whereas  combination of tracheal ligation and cndotracheal injection o( papaln did. Two differences between the cxperi- mental procedures were considered: (1) airway resistance and (2) content of biogenic amines. Experiments designed to duplicate the biological con- diticxu o/ smoking in ligated and papain-injected rats showed that admin- istration of brorrchodilators, ekvation of lung aerotonin Icvel, and depleticxt of histamine level did not Influence the development of emphysema. These experiments in rats, therdore, failed to support the widespread belief that cigarette smoke can Induce experimental pulmorury emphysema. Avlodo, 0. M., Sadavon6vivad, C. and Cari11o, L. R. Archivcs of Environnrrntd Hr.lth 20(4):4E3-IE7, 1970. From the Department of Pfiarmaar{oEy. University o( Pennsylvania School of Mcdicinc, Philadelphia. CIIRONIC BRONCHtTIS ('hronic bronchitis is one of the foremost disabling diseases in the Unitcd States. The currently accepted definition of this disease is based on thc clinical symptom of chronic productive cough on most days for at least thrce successive months of the year over a two-)rcar period. While the exact cause of bronchitis is not known, many contributory factors have been isolated and identified. Pathologically there is hypertrophy and hyper- plasia of the mucus-sccreting broncial glands relative to the bronchial wall thickness and of the goblet celfs of the bronchial ep thelium. Thcre are difiuse inflammatory changes of the bronchial epithelium, some of which may interfere with mucociliary function. In this paper, the etiolo6Y, symp- tomatolody, d.-.tection, clinical sludy, treatment, and course of chronic bronchitis are presented. In general, based on clinical impresaions, it is suspected that the earlier chronic bronchitis is recogniicd, the more favor- able will be the outcome. The intelli6ent use of diagnostic criteria, with particular emphasis on mild cough and sputum production, may result in a substantial improvement in the early detection of this disease. Ch.>Qo.rh, S., Weiss, E. B. and Segal, M. S. In Conn, If. F. nd Conn, R. B., Jr. (eds.): Currcnl Dio;notis 2. Phila- delphia: W. B. Saundcrs, 1968, pp 1S1-1S4. From Tufts University School of Medicine, Boston. CftRONIC PULMONARY EMPHYSEMA Emphysema, a disease affecting the acinus, destroys the alveoli, thus forming abnormally large air spaces, and causes a decrease in the amount of alveolar elastic tissue and in the number and size of the capillary bed. The distribution of such alveolar destruction may be centrilobular, pan- lobular, or paraseptal; panlobular emphysema is oQ more serious conse- qucnce than either centrifobilar or paraseptal. Clinically, the major com- plaint is dyspnea, and this must be associated with increased airway resist- ance and hyperinflation of the lungs with actual destruction of alveolar wall structure. In this book chapter, the course, identifrcation, and handling of emphysema are presented. Special attention is paid to thcph ysical exami- nation, laboratory study, and physiology of refevance to the disease, i.e., mcchanics of breathing, lung voiume, gas exchange, arterial blood gases and pH, ventilation, and gas distribution. Although factors intensifying air- ways obstruction have been shown to be important clinicallr, the cause and patho~ nesis of chronic pulmonary emphysema are not known. Chronic bronchitis, Qarticularly that occurrina with heavy cigarette smoking, appears to be associated with emphysema in susceptible individuals. Once the full clinical spectrum dcvclops, it is often difficult to separate these two disease entities, even though emphysema is the dominant component. Weiss, E. B., Clrodosh, S. and Se6al, M. S. In Conn, Ft. F. and Conn, R. B., Jr. (eds. ): Current Dioanosis 2, Phila- delphia: W. B. Saunikrs, 196g, pp 154-15f3. From Tufts Univcrsity Schixil of Medicine. Boston. 36 37

i EXAMINATION OF SPUTUM CELLS Many diagnostic measures are used routinely by physicians to differ- entiate chronic bronchitis (CB), chronic bronchial asthma (CBA), and chronic asthmatic bronchitis (CAB). Sputum cytologic examination is another valuable laboratory procedure that should be added to this diag- nostic armamentarium. It is a simple and informative procedure, requiring onlr a modest investment of ~ractice in the identi6cation of tl•e various Icukocytes and mucosal epithelial cells that occur in sputum to e,iable one to reasonably differentiate alkrgic from nonallergic inflammation:;, and the chronic "obstructive" brorsclwpulmonary diseases from one another. The microscopic examination of afresh, wettpu tum preparation car often be of diagnostic help in differentiating CB. CBA, and CAB. Rcqu'rinR only a few minutes, it should be a standard laboratory procedure in lhe initial and subsequent evaluation of patients with these three types of rcxtdition. lhe validity of other sputum tests (such as gram nd acid•fast rtains and cultures) can be improved by the demonstration that the matc-ial being evaluated does, In fact, arise from the brorschopulmorsary system. Chodosh, S. New Entfand lovrnal of Mrdlcint 2E2:E54-a57, 1970. From the Lung Station (Tufts), Boston City Hospital, Boston. A COMPARISON OF ALVEOLAR MACROPHAGES ANI) PULMONARY SURFACTANT(7) OBTAINED FROM TlfE LUNGS OF HUMAN SMOKERS AND NONSMOKERS BY ENDOBRONCHIAL LAVAGE Alveolar macrc.phages and material thought to be pulmonary surfactanl were obtained from eight healthy human smokers and eight nonsmokers by cndobrohchial lavage. Centrifugation of lavage fluid produced a sediment consisting of two layers, a lower compact brown layer containing cells and an upper fioocuknt white layer. The brown layers from the smokers were greater in volume than those from the nonsmokers. Macrophages consti- tuted about 93 % of the cells from the smokers and about 6396 of the cells f(om the nonsmokers. Tlsese data sugi;W that more free macrophages occur in the lungs of smokers than nonamokers. In addition, many of the macro- r agra obtained from the smokers were filled with cytoplasmic inclusions. n contrast to the volumes of the brown layen, the volumes of white layers from the smokers were smaller than those from the nonsmokers. In one case, the white layer obtained from a norsamokcr was esamincd in a Wil- hclmy balance and ptoved to be surface-active. These observations seem to indicate that surface-active material (pulmonary surfactant) may be reduced in lavage fluids from smokers. Pratt, S. A., Finky, T. N., Smith, M. I1. and Ladman. A. 1. A naroanical Record 163 ( 4):497-507, 1969. Otber Rrantort National Institutes of Health. Frnm the I?cpartments of Anatomy and Medicine, The University of New Mexico School of Medicine, Albuquerque. 38 . GENETIC ANf) ENVIRONMcNTAL DETERMINANTS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE This epidemiological examination prc sents a systematic, objective study of the prevalence of obstructive pulmonary disease and its relation- ship to alpha,-antitrypsin deficiency among relatives of patients with chronic obstructive pulmonary disease as compared with a control group. Results showed that the prevalence of abnormalities of pulmonary function among 156 relatives of 61 patien:s with chronic obstructive pulmonary discase was significantly higher th:n the prevalence in a control group of their spouses. No relationship cauld be demonstrated between this increased familial prevalence of chronic pulmonar~ disease nd alpha,-antitrypsin deficiency. This provides further evidence lhat at least some chronic obsaruc- tive pulmonary disease may be genetically determined and that this genetic dctermination may be independent of alpha,-antitrypain deficiency. Although it was not the primary purpose of this project to study the effect of smoking on pulmonary function, it is apparent from the data that smoking is very significantly associated with abnormalities In pulmonary function. The greater prevalence of abnormalities in smokers compared to nonsmokers was significant at the 196 level. It is concluded, therefore, that heredity and smoking probably contribute about equally to the likelihood of devel- oping chronic obstructive pulmonary disease. Larson, R. K.. Barman, M. L., Kueppen, F. and Fudenberg, I1. H. AnnaCs of Inrtrnal Medicint 72:627-632, 1970. Other Rrantor: American Medical Association Education and Research Foundation. From the Fresno (Cal.) General Hospital. nd the Department of Mcdi- cine. University of Califomia San Francisco Medical Ccnter, San Francisco. t A CRITICAL REAPPRAISAL OF BRONCHIECTASIS The pathogenesis, evaluation, classification, and treatment of bronchi- ectasis are presented in this clinical reevaluation of the syndrome. Specific historical, physical, and general laboratory data including sputum bacteri- ology were gathered on 130 patients who reported with bronchial symp- lomsm Detailed clinical and radiographic correlatkxa were made. Of the 130 patients. 81 had brorschiectasis documented by bronchosraphic findings and cinefiuorobronchosraphic criteria. The 81 patients presented three dis- tinct clinical patterns: (1) asymptomatic patients who experienced a sud- den hcmoPtysis; (2) patients with chronic cough, sputum, hcmoplysis, and recurrent mfection; and (3) patients with poorly controlled asthma whose bronchospasm is provoked and aggravated by regional bronchiectasis. On the basis of this study, bronchkctasis, which has been found to be the most common cause of chronic cough and sputum in adolescents and all adult age 6roups, comes through as a very important medical entity dcserving of individual diagnosis, treatment, and investigation. Lowrnzl. G. A. Medical Times 98( 5): E9-95, 1970. 39

OtAer grantor: U. S. Public Health Service From the Department of Mcdicine, Saint Vincent Ffospital, Worcester, Mass. "IIYAI-INE MEMBRANE DISEASE" IN NEWBORN INFANTS: MACROSCOPIC. RADIOGRAPHIC. AND LIGIIT ANf) ELECTRON MICROSCOPIC STUDIES This study reports a variety of observations - gross, light, opticnl, morphometric, electron microscopic, and by vascular injection of the lungs - in more than 80 babies with hyaline membrane disease. In reviewing the pathology of this disease, particular emphasis is placed on the ultrastruc- turc of devetopin~ and neonatal lun~f as compared to adult lungs. A sharp distinction is made between the air-blood barrier, the interalveolar septum, and the alveolar wall. Ilyaline membranes are still the most reliable cri- terion for the diagnrcnis of hralihe membrane disease: thcse membranes are the result of increased ~lama transudation, epithelial necrcnis, and inhaled amniotie fluid. In this dixase, pulmonary lymphatics are enlarged and distended. Postmortem vascular injection experiments show a t.lling defect involving the small muscular pulmonary arteries and the pulmonary rterioles. Lametlar bodies, considered to be related to the secretion of pulmonary surfactant, are present in the type 11 alveolar epithelial r.clls. Tlrere are multiple, apparently related mechanisms involved in the p:,tho- geneais and outcome of the idiopathic respiratory distress syndrome, and it is not as yet certain which is primary. Important factors seem to be high pulmonary vascular rnistatxe; impaired or deficient surfactant activity; increased alveolar wall permeability and transudation; and inhaled amniotic fluid. Lavwrrynt, !. M. Humun Pamholoay 1(2):175-204, 1970. Other Rrawtors: National Heart Institute, World Health Organization, and the Belgian "Fondi voor WetenachappeGjk Onderzoek." From the Department o( Pathology, University of Leuven School of Medi- cine, LCuven, Belgium. PULMONARY CHANGES IN 7,000 MICE FOLLOWING PROLONGED EXPOSURE TO AMBIENT AND FILTERED LOS ANGELES, AIR Three inbred strains of mioe - lung tumor svaoeptible A and A/1 strains and lung tumor resistant C57 blacks-were used to study the i.xi- denee nd appearance of lung tumors and pneumonitis in over 7,000 mice, following prolonged exposure to ambient as eompared with filtered LcM Angeles air. Mice in the ambient air ooloria showed no diQererxe in .sis- tolo6ic appearance and no Mcrease in incidence of lung tumors in the three strains; on the rnntrary, more lung adknomaa In A/1 mice were noted in the filtered air 6rewp. Acute broochopneumonla and intentitial pneumonitis were qualitatively similar but quantitatively more common in ambient air . C57 black mice. This quantitative difference was significant at P-<0.01. In the C57 black mice squamous metaplasia and extensive bronchiolar- alvcolar cell hyperplasia have been infrequent findings, always in associa- tion with severe interstitial pncumonitis. However, these features have been observed in 19 ambient air mice and only one filtered air mouse. These findings suggest that prolonged exposure to ambient Los Angeles air is associated in several strains of mice with an increased susceptibility to pul- monary infection but not to increased pulmonary neoplasia. Gardner, M. B., Loosli, C. G., Hanes, B., Blackmore, W. and Teebken, D. Archives of Environmental Hralth 20:310-317, 1970. Other 6rantor.: U. S. Public Health Service and the Hastings Foundation Fund. From the Departments of Patholosy and Vivaria. University of Southern California School ot Medicine, Los Angeles. SERUM ELASTASE IN111B1:'OR DEFICIENCY AND a,-ANTITRPYSIN DEFICIEKCY IN PATIENTS WITH OBSTRUCTIVE EMPHYSEMA , Antitrypsin activity and elastase inhibition were meuured in 20 normal, healthy adults, nine subjects with chronic obstructive lung disease, and six subjects with a,-antitrypsin deficiency. Results showed no statistical differ- ence in elastase inhibition or trypsin inhibition between the normal controls and the subjects with chronic obstructive lung disease. However, there was a definite decrease in clastase inhibition in all persons with a,-antitrypsin deficiency. Moreover, five of these six patients exhibited severe clinical and physiological emphysema of the type identified by Benjamin Burrows as emphysematous. ' These results, in extending thp defect of inhibition by serum to a second, biologically active protedytie enzyme, reinforce the concept that a form of early onset emphysema exists where tissue destruc- tion predominates and which may be secondary to an intrinsic biochemical defect which results in primary parenchymal destruction. Turino, G. M., Senior, R. M., Garg, B. D., Keller, S., Levi, M. M. and Mandl, I Science 165:709-711, 1969. Other Lrentor: U. S. Public Health Serviice. From the Department of Medicine, Columbia University College of Phy- sicians and Surgeons, ind Francis Delaficid Hospital, New York. ALVEOLAR MACROPIIAGES: CELL-FREE PROTEIN SYNTHESIS A cell-tree s~stem derived from alveolar maerophaaes has been shown t i ric ate radioactive kucine into protein. In this investigation, alveolar acr ages were harvested from New Zealand rabbits Pretreated with I beat-kdled Mycobtwrerenm bovis, and subcellular fractionation, incubation, protein isolation, and radioactive assay procedures were carried out. Results 41 40

indicated that optinial incorporation of radioactivity into protein d.pended on the presence of microsnmes, adcnrrsine 5'-triphosphate (A 1 f') and an A'f P•gencrating system, pl1 5 enzymes. Ruanosinc S'-triphosphatc ((;"TP), and magnesium. Suppkmental amino acids were not required. In the com- plete system, incorporaticxt of radioactivity into protein was linear with time for 20 minutes and reached a plateau at about 30 minutes In the absence of the p11 5 enzyme fraction or of magnesium, protein synthesis decreased approximately 50%. Noted requirements for protein synthesis by an alveolar macrophage cell-free system were similar to the rcquire- mcnts of other tissue types. The information presented here should facilitate the study of factors affecting protein synthesis in alveolar macrophages at various steps in the biosynthetie process. Mastaro. 1). American Review of Respiratory Disease 100:249-211, 1969. Other grar.tort American Thorack Society. From the Pulmonary Division. Veterans Administration -(ieorge Wash- ington University Medical Center. Washington. D. C. PROTEIN SYNTFfESIS AND SECRETION BY LUNG Work reported here shows that lung tissue can synthesize protein rapidly in vivo and in vitro, and that in vitro a small percentage of this newly formed protein is actively r+ecreted. The data from these experiments with rats (in vivo) and rabbits (m vitn?) indicate that the lung rapidly incnr- porated radioactivity from leucine into protein both in vivo and in vitro; the kinetics of incorporation were compatible with a precursor-product relationship between acid-soluble radioactivity in either blood or suspend- ing medium, acid-soiubfe radioactivity in lung, and acid-insoluble radio- activity in lung. The in vivo distribution of acid-insoluble radioactiv:ty sug- gested a precursor-product relationship between radioactive protein of the microaxnal fraction and a heavier particulate fraction sedimenting at 15.000 g. Some of this newly synthesized protein was secreted beyond the cell in an energy-deFxndent fashion: Cyanide inhibited the rekase of radio- active protein, as did chilling. Epinephrine, on the other hand, stimulated the secretion. In a related experinxnt, it was demonstrated that a cell-free system from lung can synthesize protcin. This system required an energy source, micrc•somal protein, pfl S fraction matcrial, guanosinc triphosphate, magnesium ion, glutathione, and supplemental amino acids for maximal protein synthesis. Marsaro, 1)., Weiss, II. and Simon, M. R. American Review of Respiratory Disea.se 101( 2): 19g-206, 1970. Other grnntor: American 7lroracie Society. From the Pulmonary f)iviurxt, Veterans Administration - George Wash- ington University Medical Center, Washington, f). C. \ / AI.VEOLAR MACROPFIAGES: DEPRESSION OF PROTEIN SYNI I1fSIS DURING Pf1AGOCY"I OSIS Incorporation of radioactivity from kucine-"C into acid-insoluble material is decreased when alveolar macrophages are incubated in the presence of a sucpcnsion of polystyrene beads. Thus, in some way the bcads produce a depressing effect on protein synthesis. The time course of protein synthesis and bead uptake suggests that the decrease in protein synthesis occurs during the phase of phagocytosis devoted primarily to the intracellular handling of the engulfed beads. Accumulation of acid-soluble radioactivity is thc same in phagocytizing and non-phagocytizing cells; all the detectable acid-soluble radioactivity had the same R, as nonradioactive leucine. A I110-fold increase in the amount of leucine added to the reaction mixture caused no alteration in the difference between the amount of acid- insoluble radioactivity recovered frorrt phagocytizina and resting cells. Addi- tion of beads to cell-free extracts of alveolar rnaerophages did not alter prolcin synthesis. Depression of phagocytosis by EDTA in the presence of txads resulted in a return of protein synthesis toward values achieved by nonphagocytizing alveolar macrophagq. EDTA alone had no effect on protein synthesis. Ma.rcaro, D., Kellcker. K.. Massaro. G. and Yeager, Ii.,1r. American Journal o/ Physiology 21R(6):1533-1539, 1970. Other Rrantor: American Thoracic Society. From the Pulmonary 1)ivision, Veterans Administration - George Wash- ington University Medical Center. Washington, D. C. THE DISTRIBUTION OF ACETYLCFfOLINESTERASf: ANf) CATECNOLAMINE-CONTAINING NERVES IN TIIE RAT LUNG This investigation was undertaken to demonstrate the dual innerva- tion of the rat lung (adrenergic vs. cholinergic). To this end, the distribu- ticxt of catecholamine- and acetylcholinesterase-containing nerve fibers was studied employing specific histochemical techniques. Silver impregnation and methylene blue staining were used to allow comparison with the results of previiws workers. Catecholamine-ccxttaining nerve fibers were found associated with the nerve plexus about bronchial arteries and werc carried to the bronchial wall and the pulmonary vessel wall along branches of the artery. Acetylcholirxsteraserontaining fibers followed along the bronchi and hronchioles and were found in the adventitia, mucosa, and submucosa. Results of this study demonstrate the relation between nerve fibcrs con- taining norepinephrinc and the bronchial vascular bed, while the pulmonary vein and the bronchi(ile muscle and glands are associated with chodmester- ase-containing nerve plexuses. El-Bcrmani. A-W.. McNary, W. F. and Bradley, D. F. The Anatomical Record 167 ( 2): 203-212, 1970. From the Departmcnt of Anatomy, Boston University Sch«)I uf Medicine. Bostt n. 42 43

TIfE PREOPERATIVE MANAGEMENT OF PATIENTS WIlli IfRONC111AL ASTIfMA Patients with bronchial asthma must be carefully managed th -ough- out the surgical period in order to reduce operative and postoperative com- plications. For example, in major abdominal or thoracic surgery, putntonary problems are a common eause of morbidity and mortality. While only 3°6 of patients with normal preoperative pulmonary funclion will develop atel- ectasis or prxumonia following major surgery. 70% of patients with chronic obstructive lung disease with altered pulmonarr function will encounter such ditTicutties. Operative and postoperative difficulties in paticnlt with asthma can be reduced with careful preoperative medical therapy. This book chapter deals with the faetors considered imprxlant in the prrnpera- live approach, namely; (1) Definition of the clinical disease; (2) Physio- logical evatuatirm; (3) Risk (aclors - facton promoting bronchrnpasm or respiratory insufficieney; (4) Therapeutic eonsitkralie.ns; and (S) Pre- anesthetie nd anesthetie technques, hazarda. It is strongly ernphasired here that definition of disease, evaluation of functional capacity and pul- monary reserve, and therapeutic considerations are necessary in the inten- sive preo(xrative management of asthma patients that is a prerequisite to any significant surgical procedure. Faling. 1.. 1, Weiss, E 8, Chodosh. C. and Segol, M. S. In Oaks, W. W. and Moyer. 1. 11. (eds): 19rh Hahnemann SymMr.rium, New York : Grvne & Stratton Ine., 1970, pp 108-1 19. From Tufts University School of Medicine and the Lung Station (Tufts). Boston City Nospital, Boston. pH-DEPENDENT CIIANGES IN SURFACE A(TIVITY OI~ LUNG EXTRACTS The work reported here emphasirn the importance of pH changes in alterin~ surlace activity as measured by the surface film balance. Tissue extracts frcwn the lungs of normal dogs and rabbits were used to test the effects o/ abnormalities in ionic environment. Specirrxns of these lungs were extracted in various concentrations of NaCI, KOli, KCt, and NaOli. Extracts in KON had a higher minimal surface tension than saline extracts. Most KCI extracts were normal. A total of 12 lungs was extracted with NaOII, and an additional seven saline extracts were alkalinized with 10% N.OH solution. Of these, 16 showed a marked rise in minimal surface tcn- sion. In the three that did not, the contour of the tension-area curve changed markedly with more gradual slope and narrower hysteresis loop. Minimal surface tension was consistently raised with addition of K,CO, and N.IICO, as well. Similar abnormalities wete produced by lowering plt with 0.1 N IICi. The pH of 26 lung extracts was afso altered with phosphate buffer solution. Minimal surface tension changes were not so extreme, but there was a slight positive correlation of PFI with minimal surface tension. The F 11 of saline extract of normal lung tnsues and of the lung itself was slightly ower than normal blood pN. This study, in demonstrating an influence of I ( pH changes on surface activit~ of normal lung extract, raises the possibility of a functional role of pf1 in Ihe lung. Sutnick, A. I.. Cronlund, M. M. and SoloQ, L. A. ProcetdinRt of the Society for Experimental Biology and Medicine 133(2): 506-512, 1970. Other Rrantora: U. S. Public Health Service, Heart Association of South- eastern Pennsylvania, Pennsylvania Tuberculosis and Health Society, and the Commonwealth of Pennsylvania. From the Institute for Cancer Research, Fox Chase, and Temple University Medical Center, Philadelphia. TIIE ROLE OF SIIRFACTANT IN POSTOPERATIVE A7liLECTASIS ANI) IIYPOPERFUSION STATIS Pulmonary surtactant, the lipoprotein film which lines the walls of Ihe alveofi, lowers interfacial tension in the alveoli as they become snraller and acts to prevent a decrease in compliance, atekctasis, or even com lete collapse of the lung. If pulmonary surfactant is lost or destroyed, the force gencrated by the changes in the size of the alveoli without changes in sur- /ace tension can be fully expressed, and atekctasis may readily (ccur. This book chapter explores the role of surfactant - or loss of it - in post- operative atelectasis and hypoperfusion states. It is concluded here that the loss of surfactanl appears to be a factor in both postioperative atelectasis and hypoperfusion states. The relative importance of this factor and its rok in the pathogenesis of these disorders are the subject of current inves- ligation. Sutnick, A. I. and SoW, L. A. In Oaks, W. W. and Moyer, 1. H. (eds.): 19th Hahnemann Symposium. New York: Grune & Stratton Ine., 1970, pp 12-24. Other 6rs.tor.: U. S. Public Health St;rvice, Pennsylvania Tuberculosis and Health Society, and Commonwealth of Pennsylvania. From the Institute for Cancer Research, Fox Chase, and Temple University School of Medicine, Philadelphia. V. Neurophy,iology EFFECTS OF CIIRONIC ADMINISTRATION OF NICOTINE ON STORAGE AND SYNTIIESIS OF NORADRENALINE IN RAT BRAIN Groups of rats were given nirntine (0.5 mg/kg) subcutaneously four times a day, five days a wcek, for six weeks. This chronic administration of nicotine did not affcct the growth rate and water intake in rats. In these u 45

animals food intake was normal for the first five weeks, but rns siRnifi- cantly increased during the sisth week of treatment. Nicotine vdministra- tion increascd the blood pressure of rats from 120 mm Ilg to 151 mm 11g. At thc end of the exposure period, measurements were made o' the effect of chronic administration of nicotine on the concentrations cf hiogcnic amines in the rat brain; on the initial accumulation of 'll-norad7enaline in tfx brain of rats; and on noradrenaline turnover rate. 'l he con :entrations of endogenous noradrenaline, dopamine. S-hydroxytryptamine, und acetyl- choline in thc brain remained unaltered. However, chronic trea ment with nicotine increased the turnover rate of noradrenalinc. Initial ac( umulation of 'H-noradrenaline was also significantly increased. It is concluded from these studies that changes in the lurnover of cerebral noradrenalinc caused by chronic administration rather than changes in the concentration of nor- adrenaline may he an important factor in nicotine-induced behavioral changes. Bhaaar, R. Rritijh lournol of Pharmacolo`y 3g( I):g6-92, 1970. Frcxn the Ikpartmcnt of Physiolog)I. St. Louis University School of Medi- cine. St. Louis. EhFf:(.TS OF NICOTINE ON FIXED-INTERVAL BEHAVIOR AND THf:IR MODIf-ICATION BY CIfOLINERGIC ANTAGONISTS The demonstration of a differential effect of nicotine on hipJr and low response rates within the same animal consitutes a powerful test of nico- tinc's possible amphctaminc-like, rate-dependent actions. In worrt reported here, nicotine effects were studied on operant responding maintained in seven test rats by a fixed-interval gg-second schedule of water reinforce- ment. Nicotine was administered immediately prior to the experimental session in doses of 0.05 to 0.4 mg/kg subcutaneously. The drug produced an initial cezsaticxt of responding, the duration of which was dase-related. After the initial dePression, local rates of fixed-interval responding were a,/tered during nicotine sessrons. Base-line rates below 20 responses/minute were variably aRecud; whereas, rates above 30 rcsponses/minute were reliably depressed. The degree of rate depression was dose-related. The actions of nicotine, 0.4 mg/kg, were compared to those of d-amphetamine, 0.4 mg/kg. At the oomp.rison dose, nicotine produced more depression of high rates than did d-amphetamine; whereas d-amphetamine was more effective in elevating low ntes than was nkotine. Cholinergic antagonists were used to demonstrate the specificity of the response to nicotine. It was concluded that drug-induced initial depression and response rate depression were due to a nkotinic cholinergic action. Stitzcr, M., Morrison, 1. and Domino, E. F. The lournal of Pharmacoio4y and Experimental Therapeutics 171(2): 166-177, 1970. From the Department of Pharmacology, University of Michigan, Ann Arbvr- INFLUENCE OF ACUTE AND CNRONIC NICOTINE AUMINISI RATION ON EEG REACTIVITY IN RABBITS: I. NUCLEOSIDIiS AND NUCLEOTIDES Small sedative effects of adenosine and adenosine monophosphate are transfcxmed, following p:olonged chronic nicotine treatment, into clear-cut stimulant actions. Adenosine, 50 mg/kg administered intraperitoneally, produced a 17 ,^o increase in integrated brain wave amplitudes, indicative of a mild sedative effect, since this was manifested by "EEG synchroniza- tion." Following an acute dose of nicotine (200 pg/kg) this effect was abolished. When adenrxix was administered to animals treated chronically with nicotine (20t1 pg/kg s.c. five times daily), a definite reversal of the oirection of the change was seen. This, in turn, corresponded to "EEG desynchroni:atkxm," thus arousal. The slight excitatory effect of adenosine triphosphate became, foflowing chronic nkotine, definitely enhanced. Not only are these changes expressed in the overall means of the integrated EEG amplitudes; they appear also in the levels of variability which are elevated when sedation prevails, while they are decreased when the efkct is reversed. Bhattacharya, 1. C., GOILJ!lin, L. and Pfeiffer, C. C. Research Communications in Chemical Pathology and Pharmacology 1( I): 99-107, 1970. From the Neuropharmacology Section, New Jersey Neuropsychiatric Insti- tute, Princeton. INFLUENCE OF ACUTE AND CHRONIC NICOTINE ADMINISTRATION ON EEG REACTIVITY TO DRUGS IN RABBITS: 2. PSYCHOACTIVE AGENTS In this study, rabbits with and without chronic nicotine treatment were used to ascertain whether prolonged intake of nicotine would affect reac- tivity to dcsipramine, deano(, chlordiazepoxide (Librium), and S-hydroxy- tryptophane, four widel used psychoactive agents. Chronic nicotine treat- ment (200 Mg/kg s.c. frve times daily for two weeks) produced a change in the EEG effects of two of Ihe psychoactive drugs. It reduced the seda- tive action of chfordiaupoxide and transformed the mild stimulant effect of desipramine into a sedative one; the same treatment did not affect the EEG changes produced by deanol and S-hydroxytryptophane. 7he first two drugs exert their effects, at least in part, at the level of the limbk sys- tem, while the other two have been found to affect the reticular formation. The fact that nicotinc interacts with desipramine and chkrrdiarepo.ide could be interpreted as a further indication of the preferential site of action of the alkaloid at the level of the limbic system. Bhattacharya. I. C.. Gold.srrln, L. and PfeiRer, C. C. Research Communicarlons in Chemical Pathology and PharmacofoRy 1( 1): 109-114, 1970 From the Ncuropharmacology Scction, New Jersey Ncuropsychiatric Insti tute, Princctun. 46 1 47

INFLUENCE OF ACUT'E AND CHRONIC NICOTINE AI)MINISTRAIION ON INTRA- ANF) INTER-STRUCTURAL RF.I.ATIONSHIPS OF TIfE ELECTRICAL ACTIVITY IN TIIF: RABBIT BRAIN Chronic dministr.tion of nicotine (200 mg/kg injected subcutane- ously five times a day) was performed on male albino rabbits and the changes produced in the cortex, the reticular formation, the hiPpoczmpus, the amygdala, nd the hypothalamus were evaluated for a period ol three weeks. Not only were measurements performed within the structurrs, but mutual relationships were studied also to determine whether the overall integrative nxchanisms of the brain were modified under such cexeitions. Statistical analysis of the distribution of amplitude levels per successive epochs of two seconds revealed a ehan~e Tbe characteristic unimodal distributions were replaced at cortkal and hippocampa( levels by bimodal distributiotn. The extent of mutual involvement between atructures was estimated by the ratio of the variances between Urvctures. Chronic n cotine administration produced a Rrsdual inereaae for the pairs cortex/hipFocam- Qus and cortc>t/amyRdala. These results are discussed in terms of a rccently introduced hypothesis of a two-system arousal in the brain. Bhattacharys, 1. C. and Goldstrrn, L. NrurophmmocofnRy, Osford/t.ondon: Pergamon Presa, 1970, pp ID)-1 18. From the Neuropharmreoio6y Section. New Jersey Neuropsychiatric Insti- tute. Princeton. EFFECTS OF NICOTINE ON SEVERAL SCHEDULES OF BEHAVIOR IN RATS The effect o( nicotine on a number of unlearned and learned behavior patterns was investigated in Ibino rats of both sexes. Nicotine over a dose range of 0.05-0.4 mg/kg had a stimulatory effect on spontaneous motor activity and on responses to fised-interval schedules with positive tfood) and negative (shock) reinforcements. Under fixed-ratio schedules with food or water reinfcxcernents, nicotine stimulated the response rate at 0.1 mg/kg dose, but decreased it at higher doses. This depression mar be relitcd to the high rate of responding compared to those under other sched- ula. The patterns of response did not show any significant difference whether or not these schedules were a part of multiple schedules and sepa- rated by time-out periods. Nicotine also enhanced the time-out responses. Under some of these schedules effects of amphetamine were also studied for comparison; in these schedules the overail, effects of nicotine appeared to resemble those of amphetamine. Prodhon, S. N. Archives Intrrrrorlonafrs dr Pharn.ocodymmmle rt de Thlroprr 183( 1):127- 138, 1970. Other grentorl U. S. Public Health Service. From the Ikpartment of Pharmaoofogy, Howard University ('ollcgc of Medicine, Washington, D. C. COMPARATIVE EFFECTS OF NICOTINE AND AMPIII:TAMINE ON TIMING BFHAVIOR IN RATS In this neuropharmacologkal study, eight male rats were trained to press a bar for reinforcement wilh food pellets in DRL (differential re- inforcement at low rates) schedule. After training, the required interval between consecutive responses was fixed at 40 seconds. Nicotine hydrogen tartrate at four dose levels (0.05, 0.1, 0.2, and 0.3 mg/kg) and ampheta- mine at three dose levels (0.2, 0.4, and 0.8 mg/kg) were tested for their effects on the timing behavior of these trained rats. Both the drugs caused an increase in the numbtr ofrespotrtes and a decrease in reinforcement, and thus disrupted the timing behavior. No consistent delayed effect was observed with these doses. In the case of each of these drugs, a rough dose- effect relaticxt could be demonstrated, and the inter-resPonse time distribu- tinns were found to be ahi:ted to the shorter class intervals, consistent increase occurring in the in.ermediate interval group. Prodhon, S. N, and I>trtta, S. iV. Nruro pharmoc,ology 9 (1) :9-16, 1970. OtAer 6re.tort U. S. Public Health Service. From the Department of Pharmacology, Howard University College of Medkine, Washington, D. C. NICOTINE INFUSION INTO THE FOURTH VIrNTRICLE OF UNRESTRAINED CATS: CHANGES IN EEG AND BEHAVIOR Previous studies have shown that nicotine injection into the 4th ven- trkle of immobilized cats elicits marked changes in the EEG and in the activity of the peripheral autonomic system. In the experiments reported here, nicotine was infused into the •th ventricle of unrestrained, free- moving cats in order to further rnderstand the effects which nicotine trcal- ment of the brain exerts upon the behavior of the cat and also to correlate nicotine-induced changes in behavior with ehan~a of the EEG. The infu- sion usually led to behavioral rousal iwith EEU desynchronization. in- ereased motor activity, hyperpnea, tnewing. IiCkin¢, swallowing, and signs of autonomic stimulation, such as: retchin6, vomitrng, salivation, urination, defecation, and panting. These changes were followed by immobility with EEG hypenynclrrony exceeding the synchronization occurring prior to nicotine administration. Protracted dcsynchronizalion of the EEG, without subsequent hypenynchrony, occurred in those cats exhibiting vigrxous, prolonged autonomic or respiratory symptoms. Thus, after an initial phase of arousal, nicotine administration into the 4th ventricle usually leads to protracted sedation. Stadnicki. S. W. and Schorppl, U. Archivrs lnrrrnationa/rs de Phortnecodynamlr tl dr Thfraplr 183(2): 277-298, 1970. From the Mason Research Institute, Worcester, Mass. 48 49

TRYPTAI.DEIIYDFS (INDOLEACETALDEHYDES) IN SF.ROTONf;RG1C SI.Ef:P OF NEWLY HATCHF.D CNIC:KS To explore the role of tryptaldehydes in the sleep mechanism. the behavior of newly hatched chicks was monitored after intraperitnneal injcc- lions of ten drugs with and without monoamine oxidase inhibitor ( MAOI ) pretreatment. Tryptaldehyde, 5-hydroxytryptaldehyde, tryptophot, and 5-hydroxylrypk.pfwl (metabolites of tryptamine and scrotonin catalyzed by monoamine oxidase ) were as effective as the amines in inducing sl"p. The MAOI pargyline induced drowsinesa and reduced (but did not block) the sleep-promoting effect of 5-hydroxytryplophan, tryplamine, and to a les- ser exlent, that of serotonin and tryptaldehyde. Nocitine induced typical sleep-like behavior followed by hyperactivity; both effects were reduced by parsyline pretreatment. These results suggest that tryptaldchydes are biologically active and may be partly responsible kx the behaviora7 effects of their amine precursors. It is speculated that the behavioral cflects of MAOI may be partly due to inhibition of the synthesis of dcaininalcd dcrivativcs of biogenic amincs, and that tryptaldehydes may be draminatcd products of Iryptaminet postulated by others to trigger REM skep. Sabelli, 11. C. and Giardina. W. 1. (Grantee: l. E. P. Tornan) Arzneimitrrl-Fo.schung 20( I ) :74-50, 1970. Other Rrar.tor: U. S. Public Ifealth Service. From the Department of Pharmacology. The Chicago Medical School, Chicago. VI. Tissue and Organ Culture CYTOPATFIOLO(;Y OF ADENOVIRUSES TYPES 7 AND 12 IN Hl1MAN RESPIRATORY EPITIiEL1UM This study rcprexnts a preliminary inqmry into thc growth proper- tih nd cytopathdo~r o( adenoviruses in the ciliated epitheiiurr of the respiratory tract. Organ cultures of fetal and adult human trachea sup- ported the growth of adenoviruses types 7 and 12 for periods as long as 1.000 hours in vitro. Each of the two viruses induced characteristic cyto- pathic changes in the differentiated epithelium of the respiratory mucosa. Adenovirus type 7 cytopathok>ty initially was local but progesscd to in- volve all of the epithelium. In contrast, the alterations induced by adeno- virus type 12 remained localized throughout the period of cultivation. Cytopathic effects usually developed 100 hours or more after the appear- ance of virus in the medrum; the extent of these changes correlated poorly with the quantity of virus recoved from the cultures. Comparative studies illustrated that the growth proQerties of adenoviruses in the resp+ratory epithelium and in monolayer cell cultures diffcr. Organ cultures provide a unique tool for investigating the Infectious process in intact, fully differen- tiated tissues. CraiKhrad, l. F.. Laboratory Invrsrigorion 22(6):553-557, 1970. From the Department of Pathology. University of Vermont College of Medicine, Burlington. INFLUENCE OF VITAMIN A AND 3,7-DIMETIIYL-2,6- OCTADIENAL (CITRAL) ON TNE EFFECT OF BENZO(A)- PYRENE ON IiAMSTER TRACHEA IN ORGAN CUL7URE In studies with suckling hamster trachea in organ eulture, benzo(a)- pyrene (BaP) produced cellular pkcxnorphie or aquamous mctaplastic cpithelia and shrinking of cartilage matrix. Citral alone did not produce squamous metaplasia but i: produced three clearly squamous states within eight days when used in combination with BaP. DNA synthesis preparatory to cell division, indicated by autoradiographie evidence of incorpexation of tritialed thymidine in nucler, was increased in some ptecxnorphic and nxla- plastic states produced by BaP alone or by BaP plus eitral, but citral did not produce significant eflects on proliferative activity. Vitamin A. 10 or 20 i.u./ml, produced shrinLage of cartilage matrix but sustained well-dit7er- entiated columnar epithelia with normal low degrees of rrplicalive activity during 15 days of cultivation. When vitamin A was added to media con- taining BaP, columnar differentiation of epilhelia was preserved. Prolifera- tion induced by RaP was a'.so inhibited by vitamin A in some instances and more effectively by 20 than by 10 i.u. Dissolution of cartilage matrix was greater in the prescnce of BaP and vitamin A. These observations indicate that both vitamin A and BaP act directly on the respiratory epithelium in a competitive fashion and on cartilage with an additive effect. On the basis of these experiments it appears that the organ culture method is applicable to the study of the mechanisms of action of vitamin A and a carcinogenic polycyclic hydrocarbon on tracheobronchiat tissues. Croclter, T. T. and Sanders, 1.. L. Cancer Research 30:1312-131a, 1970. OtAer ~rentora U. S. Public flealth Service and American Medical Asso- ciation Education and Research Foundation. From the Canecr Research Institute and Department of Medicine, l)niver- sity of California San Francisco Medical Center, San Francisco. IIfSTOLOGICAI. REEVALUATION OF EVERTED GUT TECIINIOl1E FOR STUDYING INTESTINAL ABSORPTION Since evidence of a nonpasaive process of absorption has been seen In past in vivo investigations of intestinal abraorption of drugs, in vitro tech- niques are now being investigated as a possible way of getting data for nH.re adequate characterization of this nonpassive ss. One of the cri- teria for adequate characterization of the process Iransfer of compounds across the intestinal epithelium is that viability of biological integrity of the barrier must be verified under the conditions of the study. This criterion was not satisfied in previously reported studies when Ihc everted intestinal 50 5t

sac was used as the esF+erimental procedure. Now, histological studies indi- cate that everted intestinal sacs of the rat progressively lose structural intcg- rity Immediately after eversion, but before incubation, sacs of rat intcstine are morphologically unchanged. Changes are apparent five minutes after incubation at 37"C in oxYBenated bufier; at 30 minutes 50-75% of the normal epithelium has disappeared; at one hour there is total disruption of the epithelial border. Tissue damage is slower at 23^C or in tissues of animals sacrificed under anesthesia. Studies with everted sacs of golden hamster intestine indicated that this tissue maintains its intesrity. at 23"C, longer than those from the rat and between 30-60 minutes shows only moderate k+ss rd detail at villi tips. Apin, the rate of disinacKration is greater at 37°C. Levine, R. F., McNary, W. F., KornButh, P. J. and LeBlanc, R. Furopran lournal o f Pharnsacolory 9: 211-219, 1970. Other 8ra.tort U. S. Public 1Etalth Service. From the Ekpartments of Pharmacology and Anatcrmy, Boston Ilniversity Medical Center, Boston. V1I. PhorntucoloRy PFiARMACOL(X;ICAL SIGNIFICANCE OF BIOGENIC AMINES IN THE LUNGS: 5-IIYDROXYTRYPTAMINE A technique has been developed for the analysis of 5-hydrosytrypta- mine (5-EIT), histamine, noradrenaline, and dopamine in a single sample of lung. Using this spectroflucxonxtric techniquc, all four amines were analyzed in samples of lungs in which the bronchopulmonary responses had been investigated previou.ly. In the studies reported here, prime atten- tion was paid to the concentration of 5-F1T in the lun8s of rats and guinea pip. Several procedures were soen to influence this concentration. The content in the lungs of both speciea was increased by injection of either 5-IfiT or 5-hydroxytryptophan. In the rat, p{hlorophenylalanine did not influence the 5-EIT content of the lung even after repeated administration for up to two weeks. Reaerpine consistently qused a fall in the 5-liT con- tent of the lung. Il appean, therefore, that the content of 5-FIT in the lung is readily influenced by ptocedures that increase its uptake nd rekase but is rather resistant to procedures thal influerwe the pathways of sinthesis and de¢tadation. As to amine locaticxt, it is suggested that the 5 F1T con- t.ined in the lung tissue is stored mainly In the platelets and in the mast cells. SadavonRvivad, C. (Grantee: D. M. Arlado) British Journal of Pharmacology 38:353-365, 1970. From the Department of Pharmacolo8y. University of Pennsylvania School of Medicine, Philadelphia. PFIARMACOL(X;ICAL SIGNIFICANCE OF BIOGENIC AMINES IN TIiE I.UNGS: HISTAMINE The availability of a technique for analysis of four biogenic amines offers an opportunity to investi8.ate the histamine content of Ihe lung for several specics, and to reinvestigate the anaphylactic phenomenon in the guinea-pig and rabbit. Ilistamine content was measured for eight species; comparison of thcsc results indicates that the eight species can be divided into three groups: (a) the mouse lun8, which contains the lowest amount of histamine, 0.70 pg/g; (b) the rat, guinea pi8, and rabbit lun8s, with a histamine concentration ranging from 4 to 7 r8/6; and (c) the cat, do6, 6oat, and human lunss, with  histamine concentration of from 10 to 35 rR/6• In two species of the hi8h-kvel group (cat and dog) the amount of histamine that elicits an increase in pulmonary resistance is one-fifth to one-tenth of the dose that elicits an increase in species of group b (rat and rabbit). There is an inverse relationship between the content of histamine and the dose of histamine that produces  25% increase in pulmonary resistance. Anaphylasis increases the histamine content of the lung of the rabbit but not of the lung of the guinea pig, In both specics, anap hylasis is accompanied by an elevation of the concentration of 5-111' in the lun8, indicating the trapping of piatekts in the lung. Aviado, D. M. and Sadavonavivad, C. British lournal of Pharmacology 38:366-373, 1970. From the Department of Pharmacology. University of Pennsylvania School o( Medicine, Philadelphia. PNARMACOLOGICAL SIGNIFICANCE OF BIOGENIC AMINES IN THE LUNGS: NORADRENALINE AND 1?OPAMINE Concentrations of noradrenaline and dopamine in the lung were meas- ured in the cat, rabbit, doa, 8oat, and human. The bronchomotor effects nd content of both catecholamirres were correlated in the lungs of the four animal species; the effects of reserpine and tyramine on these parameten were measured also. In the cat, do6, rabbit, and 8oat, tyramine produced 2a fall in pulmonary resistanoe, which was reduced by the administration of either reserpine or cocaine. Although an infusion of noradrenaline in- creased the content of this amine in the lun6 of the cat, previously depicted by reserpine, the bronchodilator property of tytamine was not restored. The infusion of isoprenaline did not restore Are response to tyramine. The role of either catecholamine in mediatin8 the bronchomotor response to tyramine could not be asccrtained. The concentration of dopamine was as high as 6.4 rR/6 in the goat lung and less than 0.5 r.a/; in the lungs of the other species. 1)irpamine, injected intravenously into the cat, do8, rabbit, and goat, produced a ali8ht rise in pulmonary resistance. This increase was blocked by tolazoline, indiutin8 that the response was mediated by a-adrenoceptors in the bronchial passages. Aviodo, D. M. and Sadavon8vivad, C. Britisl+lournal of Pharmacology 38:374-385, 1970. 53 52

From the Department of Pharmacology. University of Pennsylvania School of Medicine, Philadelphia. FACTORS INVOLVED IN MAINTENANCE OF CARDIAC CATFCIIOLAMINF. CONTENT: RELATIVE IMPORTAN( li OF SYNTHESIS AND RE-UPTAKE Work reported here was undertaken to determine ( I) the capacity of re-uptake, and the extent to which adrenergic transmitter synthesis can he stimulated during increased impulse aetivity, and (2) the relative impor- tance of re-uptake and synthesis in maintenance of cardiac catecholamine Icvels. Endogenous catecholamines in rats exposed to cold remair.ed un- altered or reduced slightly dependin upon the strain of rats used. In con- trast, labelled noradrenalinc declineTrapidly, but the decline was irhihited when animals were pretn:ated with mono.mine oxidase inhibitors. Increased sympathetic nervous activity aa.ociated with cold resulted in a four fold increase in fate of synthesis of noradrenaline. Reduction in erxkogcn(ws and labelled catecholamine levels assoeiated with cold was exaggerated by pre- treatment with cocaine, imipramine, or phenoxybcn2amine - drugs known to inhibit the uptake of nrxadrenaline into the nerve terminal. It is con- cluded that, under nnrmal conditicxn, the re-uptake mechanism may not play a significant role in the maintenance of normal cardiac eatecholamine levels and that such levels are maintained by synthesis alone. Bhagat. B. and Friedman, E. Britishlournal of Pharmacology 37:2a.33, 1969. From the Dcpartment of Pharmacology, New York Medical College, New York City. UPTAKE OF ('II)NORADRF.NALINE IN TIfE RAT HEART DURING INCREASED SYMPATHF:TIC NERVOUS ACTIVITY ASSOCIATED WITEI COLD Male albino rats were exposed to cold for five hours in an attempt to stimulate sympathetic nervous activity. At the end of this time, lhe rats were injected with 6.5 wc/100 g('H/noradrenaline and returned to the cold for an additional hour. Some animals received subcutaneous injections of angiotensin, desi4xamine, or cocaine ten minutes after ('1ljnoradrenaline in~cction. All animals were killed and their hearts analyzed for ('Eltnor- adrenaline. The results indicate that there was no significant increase in accumulation of ('}1)noradrenaline injected durina increased sympathetic nervous activity associated with cold, compared with that of controls. Ilow- ever, under similar conditions, there was a 20-30% release of ('f 1(nor- adrenaline when endogenous noradrenaline stores were labelled one hour bcfore the experinxnt. It is, therefore, suggested that retention of ('II(nor- adrenaline is increased during incteased sympathetic activity to meet the need for replacement of eatecholamines in the nerve endings. In another series of espcriments, nkotine, a pnglionic stimulant, was used to stimu- late srmpathetic activity. Results of these studies indicate that nicotine caused a significant increase in retenticxm of ('H(noradrenaline. Elvwcver, nicotine has a dual action; initially it stimulates and later blocks the gan- glion cell. Since ganglionic blockade results in increased retenticm of in- iected noradrenaline, results with nicotine may not be due to increase in sympathetic nervous activity, and therefore cannot be considered as con- clusive. Friedman. F. and Bhaqat. B. lournal of Pharmary and Pharmocology 20:963-965. 1968. From the Department of Pharmacology, New York Medical College, New York City, and the Department of Physiology, St. Louis University School of Medicine, St. Louis. INFLUENCE OF VARIOUS DRUGS ON ACCUMULATION OF 'ff-NI('O77NE: IN ISOI.ATEI) RAT ATRIA Studies described here were undertaken to test the hypothesis that nicotine must enter the sympathetic fiber In order to act. Rat tria were incubated with '11-nicotine, and various drugs were tested to determine their effects on accumulation of 'EI-nicotine; a series of experiments was also run in nesthetized cats. In the study of 'H-nieo(ine binding it was found that isolated atria take up and bind'll-nicotine from the surrounding fluid. This uptake was dose and time dependent. With increasing the con- centration of 'If-nicotine and incubation Qeriod, aeasmulation of 'H-nico- tine was enhanced. Accumulation of 'H-mcotine was maximum at pEt 7.4. Addition of atrupine, nicotine, hexamethonium, and chlorisondamine to the organ bath, or pretreatment of animals with guanethedine or reserpine, did not affect the accumulation of nicotine. The binding appeared to be at nonspecific sites and not, at (east, at sites where noradrenaline is stored, since 1) nerve stimulation, injection of nicotine or acetylcholine did not ffect the spontaneous release o('H-nicotine in the efffuent of the perfused cat spleen and 2) acetzlcholine, DMPP, nicotine, or tyramine in moderate dases (aikd to release H-nicotine from isolated rat >,tria. It seems that the uptake of labelled nicotine is a physical process of diffusion and is not related to any particular storage meehanism. Bhaaar, B. European lournaf of Pharmacology 10(1) :11-18, 1970. From the Department of Physiology, St. Louis University Medical School, St. Louis. POTENTIATION OF VENOCONSTRICTION BY a,d-BIS - (DIME:fE1YLAMMONIUMACETALDEHYDE DIETEfYLACETAL)- p,0-DIACETYt.ElIP11ENYE. DIBROMIDE, DMAE Constriction of the cephalie vein of the dog was employed to study the influence of DMAE on nerve impulse transmission and on certain agents known to induce venoconstricticxs. In these esperinxnts, ven(KOn- slriclor responses to norepinephrine, epinephrine, xetylcholine, and ucl- 54 55

latc ganPJion stimulation, and blockade of venoconstriction by atropine sulfate were tested akme and in the presence of DMAE. In ccrta.n cases thc dh+gs were prctreated with the gang)ionic blocking agcnt, hcx:imctho- nium Results showed that DMAE potcntiated the venoconstrictor responses to norepinephrinc, epinephrine, acetykhotine and stellate ganglior•. slimu- lati~m. FurthcrrrNne, hexamcthonium interfered with the potentiatin; action of I)MAE: With cpinephrine in the presence of hexamethonium, fnr cxam- ple. OMAE showed no significant potentiation. Althcwgh DMAfF poten- tiated the cffects of acctykholine, administration of atropine sulfate 5locked or abolished the acetylcholine-induced venoconstriction. The data piesentcd in this paper indicate that DMAE potentiates catecholamines by acting at the vascular level. Also, the results of the experiment with acetyl•:hnline. DMAE, and atropine indicate that the venous response to accty choline results from the libcration of a catccholamine. Wong. S.. Grrns, E. (i. and f,ant, l. P. Archivet lnlnnarionaler Pharmocodynam/t cr de 77rfrapic 17R( I):177- 1 R4, 1969 From the [kpartment of Pharmacology, University of Iowa ('ollcge of Mcdicine, Iowa City. FFFF(.TS OF a,d BIS-([)IMETHYI.AMMONIUMACETALI)E:FIYDE UIEfllYLA('fi I AL) p.lt-1)IAC'E'-.TYLBIPIIE:NYL BROMIf)Ei (UMAE) ON N[:UROMl1SCULAR 'IRANSMISSION The effcc/s of DMAE at the neuromuscular junction were studied in rabbit sciatic ncrvc-gastrocnemius muscle preparations. f)MAf~, which blocked ncurnmuscular transmission, exhibited mixed propcrtics including nondepolarizing blocking activity during the early phase of neuromuscular blockade and hcmicholinium-like blocking effect on acetylcholine synthesis during the late Phase of blockade. During the early phase of blockade, the effect of DMAE was augmented by choline; during the late phase, however, the DMAE blockade was reversed by choline but not by decamethonium nor by d-tubocurarine. Neostigmine antagonized the effect of DMAE when the (iose of DMAE was low but no( when the dose was high. These results indicate that DMAE might be slowly converted into hemicholinium in the body to block the acetykholine synthesis during the late phase. The median effective doses of DMAE were fairly ekne to those of hemicholinium, which might also indicate the conversion of DMAE to hcmicholinium. DMAE appears not to he a depolarizing agent. Howevcr, the nondepolarizing blockade of DMAE was not a curare-like effect because there was no parallel shift of the dose-respcx~se curves of acetylcholine on frog rectus abdominus musck by DMAE. Chiou, C. Y. nd Lr»+g, !. P. The JournaJ of Pharmoeology and Experimental Therapeutics 167(2): 344-350, 1969. From the [kpartnxnt of Pharmacology. University of Iowa COlegc of Medicine, Iowa City. BIOASSAY OF EN[XX;ENOUS ACETYLCNOLINE RELEASF[) BY ACETYLCEfOLINE RELEASERS This report describes a rapid, sensitive, and accurate method for the direct assay of endogenous acctykholine (ACh) in the presence of releas- ing agcnts, thc recommended procedure being based upon the combination of a cooling technique and a superfusion technique. Using superfused guinea pig ileum, dose-response curves were plotted for ACh and nicotine before and after the coolir,g treatment. The cooled ileum was about two times more sensitive to ACh than the normal tissue, but was inactive to nicotine. Therefore, this supcrfused cooled ikum preparation can be used to nssay released endogenws ACh present in mixtures of tissue extracts and releasing agents, or ir. incubation mixtures of synaptic vesicles and such releasing agents as nicotine, carbachol, choline, and Ietramethylam- mcx+ium. Qrinu, C. Y. and Long, l. P. lournal of Pha.maceuri.-al Sciences 5S(9):116E-1169, 1969. From the Department of ?'harmacology. University of Iowa College of Medicine. Iowa City. ACETYLCI-IOLINE-RELEASING EFFECTS OF SOME NICOTINIC AGENTS ON CIIICK BIVENTER CERVICIS NERVE MUSCLE PREPARATION The mechanism of action of 13 nicotinic agents was studied on the baby chick biventer cervicis nerve muscle preparation. Dose-response curves were determined by injecting drugs in two-foW logarithmically increasing doses, and the percentage response of drugs was calculated from the maxi- mum response of acetykholine (ACh) as 100% piotted against the log dose of drugs injected. The dose-response curves of the nicotinic agents were redetermined after triethykholine treatment or after ncuromuscular blockade. Since the effects of various nicotinic agents were blocked by these methods but the dose-responsive curve of ACh was not altered, it appears that the nicotinic agents tested are presumably acting primarily at the nerve terminals rather than at the receptor sites on the tFunctional membrane. After the effects of the nicotinic agents were com etely blocked by triethyl- choline alone, the muscle was still responsive to nerve stimulation. This suggests that the blockade effect may be at the membrane site of the nerve terminal since ACh is still available in the stoiage site for release after tri- ethylcholine blockade. In the same preparation, the responses to most of the nicotinic agents were markedly enhanced and prolonged by the presence of phyxxiti6mine. Since the nicotinic agents tested are not susceptible to the enzymatic hydrolysis of cho[inesterascs, the potentiation of their nicotinic effects is probably due to the ACfi released by these nicotinic agents from the nerve terminals. Chiou, C. Y. nd LonR, l. P. ProcrrdinRs of rhr S.xirry for Experimental Biolory and Mrdirinc 131( 2): 732-737, 1969. 56 57

From the Department of Pharmacology. University of /owa College of Medicine, Iowa City. STl1D1ES OF CIIOLINERGIC INfIIBITION USING THE (3111NEA-PfG 11.FUM Nicotinic agents have been found to act primarily through rrlease of endogenous acctylclK,linc (ACh), whereas muscarinic agents act directly on the ACh receptors. In the work reported here, the mechanisms of nico- tinic nd muscarrnic eRects were studied on guinca-pig ileum treated with 1.2 x 10' M o( triethykholine (TEC), 3.7 x 10 • M o( hexamethonium (C,), or cooling at 2• C for 24 hours. The respnnses induced by nicotinic agents such as nicotine, tetnmethylammonium bromide, and 1,I-dimcthyl- 4-phenylpiperazinium iodide were blocked by c+ooling. C„ and TEC treat- rncnts, whereas those induced by muscarinic agents such as ACh and acetyl-P-mcthyl choline chk+ride were not altered. D+up with mixed activi- ties o/ muscarinic and nicotinic rrsponses were significantly bhv:ked by cooling. C„ and TFC Ireatments but retained more than 40% of n sponses with maximum doses. Tlsese rnults indicate that the nicotinic agerts acted through release of endogenous ACh from the nerve terminals, in contrast to the muscarinic agents which acted through direct effect on the ACh- recepton on the muscle membrane. The nicotinic agents were tal.en into intracellular sites of the nerve endings to release endogenous A('h, which was blocked (probably at the rnembrane site of the nerve terminals) by nicotinic blocking agents, Chiou, ('. Y. and fong, 1. P. Archivet lnrrrnorinnafrt de Pharmocodynamit rr de Thfrapie 182(2): 269-278, 1969. From the Department of Pharmacology. University of Iowa College of Medicine, •Iowa City. EVIDENCE FOR BfOGENIC AMINE RECEPTORS IN TOAD SCIATIC NERVES Isolated sheathed and unsheathed toad sciatic nerves were used to study drug interaction between biogenic amines and conduction blockers such as CNS active agents, 5 Ffi' antagonists, and other autonomic drugs. Applied alone, L-epmephrine, histamine, and other neurotropic drugs increase spike amplitude in the toad sdatia. In the tests reported here, the biogenic amines peotolinium, nicotine, and arecoline anugonired nerve block induced by oocaine, procaine, ch romazine, imipramine, strych- nine. LSD, etc. Fteversa) of conduction bloc (without removal of blocker) showed that the antagonism did not result from interference with penetra- tion. The action of the bingenic amines seems related to interactions with specifk receptors rather than to general ionic effects since (r) they antag- onized both Na-dependent threshold raistn (cocaine) and Na-indcpendent blocken (chlorprornazlne); (b) specific competitive-like antagonisms were observed ( serotonin vs. imipr.mine block; antihistaminics vs. histamirse pro- tection against cocaine). The presence of scattered synaptic-like reccptors on the axonal membrane is discussed. Sabelli, li. C. and Gorosito, M. (Grantee: 1. E. P. Tonran) Intrrnariorral luurnal of Nruropharmacoloay 8(6) :495-513, 1969. Other Rront.rr.: U. S. Public Flealth Service and the Consejo Nacional de Invcstigacioncs Cienlificas y Tecnicas (Argentina). From the University of Litoral, Inslituto de Farmacologia, Rcnario, Argen- tina, and The Chicago Medical School, Chicago. TNE EFFECT OF CATECIIOLAMINES AND NICOTINE ON TIiE TRANSMEMBRANAL POTENTIAI. OF FROG LIV[:R CELLS The resting ppNential oi frog liver cells was tested before and at various intervds after the intramuscular administration of graded dosages of such drugs as Ltpinephrine (E), pargrGne, nicotine, DL-norepinephrine (Nf:), isoproterenol (1), phenylacetaldehyde, and tryptaldehyde. Rcsults showed that E increased the resting potential at 0.1-0.5 mg, and reduced it at larger doses. Ilyperpolarizalion wi h E was demonstrated in unanesthctizcd pithed frogs. Although pargyline (100 mg/kg) 24 or 48 hour pretreatment failed to rRect resting potcntial, it prevented the hyperpolarizing effect of E (e.g., 0.1 mg E rncreased membrane potential 21 % in untreated frogs, and 1% in pargyline frogs) without blocking high dose depolarization. The catecholamine releaser nicotine and NE induced small dcpolarization. While I slightly augmented resting potential, phenylacetaldehyde and tryp- taldchydc had no effect. The depolarizing effect of NE and 1; (high dose) may be attributed to their vasoconstrictor efiect, since ischemia dcp"arizes liver cells. In contrast to NE and 1. E had stronger metabolic eflecls, as well as hyperpolarization action on the liver; the two phenomena may be related. Orozco. A. and Sabelli, H. C. (Grantee: l. E. P, Toman) Efptrenria 26( I ) :48-49, 1970. Other 6rantor: U. S. Public Health Service. From the Department of Pharmacology, The Chicago Medical School. Chicago. OPTIC EVOKED POTENTIAL CHANGES INDUCED BY DEAMINATED METABOLITES OF SEROTONIN: S-I-IYDROXY- TRYPTOPIIOL AND 5-IIYDROXYINDOLE ACETIC A(.'I[) Equal doses of scrotonin (SHT), S-hydroxytryptophol (5HTOl.), and 5-hydroxyindole acetic acid (SFIIAA) were given intraventriculariy to non-anesthetized rabbits, and monopotar recording of the photic evoked potential was carried out. All three agents decreased to the same extent 58 59

the amplitude of the slow negative wave (SNW) immediately aftcr injec- tion, and the depression tasted for more than one hour. t.atcncy to the peak of the SNW was also shortened by all three drugs SHTOIL and 5111AA reduced the amplitudc of the positive fast potential much more than SI IT. La- tency to ttx maxinral positive fast potential was initially shortened by 511701., whereas Slff prnlonged it slightlr; shortening of this latency was not observed with 5111AA. The work reported here definitely shows that 5111AA and S117OL are biologically active at a dose level commonly used to demonstrate similar effects of SNT, and that the effects cxertcd by 511TOL and S111AA upon the photic evoked potential closely resemble the effects of S11T in both direction and magnitude. Sabclli, F1. C. (Grantee: J. E. P. Tonwn) Experentia 26( I): SR-60, 1970. Other Rrantnrr U. S. Public Health Service. From the Department o( Pharmacoiogy, The Chicago Medical Schox,l, ('hitago. WATER STRUC?URE IN ANESTHETIC ACTION: TIME-DEPENDI?NCE D,O EFFE(-'tS ON NERVE The influence of D,O on the axonal effects of anesthctic aRems was studied as an in vitro model for the analysis of the role of water in narcosis. U,O (75-99%) replacements markedly prolonged survival of frng sciatic nerve; on (axrg exposure (R days) threshold was somewhat reduccd, spike amplitude relatively increased, and Aypcrexcitatrlity during rapid stimula- tion or following supramaximal stimutation was relatively augmented. In contrast, short D,O exposures (10-30 minutes) only depressed frequency hyperexcitability. Results suggested early direct solvent effects attritrrtable to the greater icc-likenesa of D,O relative to FLO, fo(lowed by slower charlges rcsulting from deuteration of tissue constituents. Time-dcprndcnt differences were also demonstrated by atudies on conduction blocking time by drags. Conductinn block by ether or ethanol was antagonized by con- current application of D O(but not by prior 24-hour exposure to D:O) suggesting that increased structural order In water antagonized narcosis. Concurrent aliplicaticm of D,O also antagonized conduction block by nico- tine and ouabain but had (itUe effect on block by cocaine, procainc, and lidocaine. Sabclli, FI. C. and Priest, W. C. (Grantee: J. E. P. Toman) .I rtntimltrrl-Fo..tt-hunR 20(1) : g0-EE, 1970. Other Sras.tor: U. S. Pubtk Health Servke. From the Department of F'harmaooEogy, The Chicago Medical School, Chicago. INF-LtIFNCE OF AhRENALECTOMY ON TI-IE SYN fI/FSIS OF NOREPINEPIILtINE IN TIiE RAT NEART Bilateral adrenalcctomy was performed on male Spraguc-Dawlcy rats and the influence of this procedure on the synthesis of nurcpincphrine ( NE ) in the rat heart was determined by thrce independent methods six to nine days aftcr the operation. Two of the methods of measurement involved estimating turnovcr rates whereas the third method involved measuring the amount of C"-NE formed in the heart after the i.v. administration of C"-tyrosine. Results obtained from all three methods showed a significant increase in the synthesis rate of NE in hearts from adrenalectomized rats over that obtained in normal or sham-operated animals. Elydrocortisone, dcsox qcorticostcrone acetate, and hexamethonium all prevented the accel- crated synthcsis rate. Adrenakctomy did not alter the uptake of H'-NE in the isolated perfuscd heart but did result in a si~niBcant increase in niyocardial mornumine oxidase activity. It is su~ested uhat the increase in synthesis rate of NE and in moncumme oxidase activity is the result of  reflcxly mediated increase in sympathetic nerve activity secondary to a decrease in blood pressure from adrenalectomy. Wesr/all, T. C. and Osada, i1. The Journal of 1'harmacoloay and E rlxrimental Therapeutics 167 ( 2): 300-30R, 1969. From the Department of Pharmacology. University of Virginia School of Medicine, Charlottesville. INFl.l1ENCE OF ADRENALECTOMY ON TIIE RECOVFRY OF NOREPINEPIiRINE LEVELS FOLLOWING GUANETIIIDINE AND ME"fARAMINOL The possible contribution of the adrenal medulla to the maintenance of norepinephrine (NE) in adrenergic nerve terminals~was studied by com- paring the recovery of myocardial and renal NE kvcls in adrenalectomized rats after depiction with two drugs, guanethidine and metaraminol. Results of ahese experiments showed that the recovery of myocardial or renal NE levels after doses of the two drugs which produce greater than 90% deplc- tion of the transmitter was similar in both adrenalectomized and sham operated animals. It is concluded that the ability of guancthidine to block the normal accumulation of NE in the heart for as long as 72 hours after its administration is partial explanation for the similarity in the recovery of myocardial NE; in adrenalectomized and sham operated rats. This ex- planation, however, is ncK tenable following wxtaraminol since this drug prevented the accumulation of 11'-NE for only a short period of tirnc. Osada. If. and Wrrr/oll, T. C. Archives /nrtrnalionalrt Pharmacodynumir rf de Thrrulrie 190( 1): 162- 172, 1969. From the Department of F'harmacology. University of Virginia School of Medicine, Charluucsville. 60 61

FFFF(T OF ALPIIA-METIIYL TYROSINE ON CONTFNT ANI) SUItCELI-ULAR DISTRIBUTION OF: NOREPINF:PIIRINE IN RAT I(I;ART ANI) BRAIN The importance o( the release of norepinephrine (NFi) from particu- Iatc and soluble fractions of the rat heart and brain was asscsscd by measuring the lime course of depletion following inhibition of synthesis. Alpha-methyl lyrosinc (a-MPT) was the drug administered lo inhihil the customary action of tyrosine hydrosylase. The results presented show that NE present in the solubk cytoplasmic fraction of homogenized organs is depleted more rapidly than the mrresponding particle bound fracl'on fol- lowing treatment with a-MPT. This preferential depletion of NE in the soluble fractions of heart and brain was very pnxx.unccd at two hours after drug treatment. Since depletion of NE levels following tyrosinc hydroxy- lase inhibitirxr with a-MPT is dependent upon intact nerve stimulalion, it has been suggested that this method provides a rcliable mcans of rnonikx- ing sympathetic nerve activity. wrsr/aff, T. C. Life Sciencei 9( 1):339-34g, 1970. From the Department of PharmacoMgy, University of Virginia School of Medicine. Charlottesville. INFLUENCE OF CHRONIC NICOTINE ADMINISTRATION ON BLOOD PRFSSURF ANf) HfiART NOREPINEPIIRINE TURNOVER In this study of the effects of chronic nicotine administration on the sympathetic nervous system, male Spraguc-Dawley rats were given nico- tine ( I mg/kg twice daily ) and measurements were made of thc turnover of heart norepincphrine and of the systcrlic blood pressure. Results show that there was no significant difference in amine turnover aftcr nicotine was injected daily for one, seven, or 14 days. Nowever, after 47 days of nico- tine administration there was a significant increase in myocardial norepine- phrine turnover when compared to saline-injected controls. There was no alteration in the endogenous levels of norepinephrine in the heart at any time after nicotine trcatment, but the rate constant of norcpinephrine loss went from a control of 0.073 hr' to 0.103 hr' after 47 days nicotine result- ing in an increase in the turnover rate of from 0.047 to 0.07 Ng/g/hr. Chronic administration of nicotine for eight weeks showed a significant increase in systolic bktodpresaure going from a control of 120 14) 132 mm Ilg. It is concluded that this alteration in rwrepinephrine turnovcr reflects a marked disturbance in adrenergic sseurotransmittcr homeoslasis arwl raises the question of a possible conrsccticxt between the rise in systolic blood pressure and accekrated rartpinephrine turnover. werr/arf, T. C. European lournaf of PharmocofnRy 10(1) :19-24, 1970. From the Department a( Pharmacology. University of Virginia Sc xx,l of Mcdicine, Charkottcsville. Vl1l. Metabolic Studies TFfE ABILITY OF FfUMAN SERUM TO AGGLUTINATE SIfEEP ERYTIiR(X'Y'fI:S AND THE EFFECT OF TOBACCO MOSAIC VIRUS: COMPARISON BETWEEN SMOKERS AND NONSMOKERS In an attempt to devise a test suitable for determining differences in man related to exposure to cigarette smoke, serum of smokers and non- smokers was examined for the presence of tobacco mosaic virus (TMV) antibodies and their ability to agglutinate sheep erythrocytes. Although TMV has been detected in I1 brands of cigarettes and two brands of cigars by a hemagglutination test, antibodies specific for TMV were not dctecled in the serum of either smokers or nonsmokers. Howevcr, a diRer- ence was observed between smokers and rsonsmokers in the ability of their serum to agglutinate sheep erylhrocytes. The serum of nearly all of the nonsmokers agglutinated sheep erythrocyles (titers ?reater than 1:12!!), whereas the serum of most of the smokers did not (titers less than 1:64). Studies are now in progress to determine the effect of long periods of non- smoking on the ability of serum to agglutinate sheep erythrocytes. There is another possibility that is also being considered; namely, that hemagglu- tination titers greater than 1:64 for smokers and less than 1:64 for non- smokers are connected with other factors such as recent respiratory diseases, e.g., influenza. Flctchcr, R. D., Sumney, 0. L.. Langkamp, H. 11. and Platl, 1). (American !)enral Astotiarinn Councif on Dental Retearch) American Review of Respiratory Disease 100:92-94, 1969. Other grantor: National Institutes of Ifealth. From the Department of Microbiology. University of Pittsburgh School of Dental Mcdicinc, Pittsburgh. TRYPTOPIIAN METABOLISM IN PATIENTS WITff BLADDER CANCER: GEOGRAPHICAL DIFFERENCES The basal excretion levels of a number of urinary tryptophan mctabo- liles were compared in five study groups (Wisconsin controls, Wisconsin bladder cancer palicnts. Boston controls, Boston bladder cancer patients, and industrial bladder cancer patients). Similarly, post-tryptophan loading levels were compared between these groups. Abnormal levels of urinary Iryptophan metabolitcs, after a loading doae of tryptophan, were nwre frequent in the bladder cancer cues from Wisconsin than in those from the Boston area. In the post-loading metabolic picture, the Boston patients nd the industrial cases had, on the average, very similar urinary mctabo- lile Icvels, and these Ievels were consistently different from those found In the Wisconsin group. Melabolites shown to be elevated in the Wisc-r.nsin prlicnts were generally those found to cause bladder cancer in micc when rmplantcd into ttx bladder. T he mctabolic differences noted did not scenr to be due to variations in vitamin B, nutrition or other factors known to 62 63

aRcct tryptophan metabolism. They may indicate othcr etiologic factors in thc more urbanized Bnslon environment. Brown, R. R.. Price, 1. M.. Fricdell, G. 11. and Burney. S. W. loarnal of the Narional Cancer !nslirutr 43(1):295-30I, 1969. Oth.r Rrnntor.: National Cancer Institute, American Cancer S!xicty, U. S. Public Ilealth Scrvicc, and the Elsa U. Pardce Foundation. From the Division of Clinical Onco{ogy, University of Wisconsin Medical School, Madison, and the Cancer Research Institute, New England Deacon- ess Hospital, Boston. LACK OF EFFECT OF SMOKING ON TIIE EXCRETION OF TRYPTOPIIAN Mf;TABOLITES BY MAN A total of 12 healthy adults who smoked regularly was'sclccted for tryptophan studics to be done whik smoking, after having strrppcd for one and three wecks, and after resumption of smoking for one week. In every instance, urinary excretion of tryptophan and Aiacin metabolites was meas- urcd before nd after oral loads of 2.0 g L-tryptophan. The rnctabolitcs mcasured were kynurenine, hydroxykynurenine, acetylkynurcnine, kynurenic acid, xanthurcnic acid, o-aminohippuric acid, anthranilic acid glucuronide. N'-melhylnicolinamide, and N-methyl-2-pyridone-5-carboxamide. Also measured were 4-pyridoxic acid and creatinine as respective indices of nutrition and reliability of ecdleclir.ns and nieotine as an index of smoking. Nicotine values indicated that the subjects had faithfully stopped smoking during the non-smoking period. With the exception of an inconsistent change in acetylkynurenine e>tcretion, no significant changes were observed in the excrclicm of any of the mctabolites measured. Additional studies comparing 17 regular male snxAers with 13 male nonsmokers failed to show any differences in urinary excretion of these metabolites. These results, while not refuting the statistical ssocialion between smoking and bladder eancer, suggest that this association is not mediated by altered urinary excretion levels of tryptnphan or niacin metabolites. Brown, R. R., Price, 1. M.. Burney, S. W. and Friedell, G. If. CancerRrtearch 30(3):611-614, 1970. Other grw.tor.r National Cancer Institute, American Cancer Society, U. S. Public Heallh Service, and the Elsa U. Pardee Foundation. From the Division of Clinical Oncology, Univenity of Wisconsin Medical School, Madison, and the Cancer Research Institute, New England Ikacon- css f fospital, Boston. STUDIES OF OPT IMAL CONDITIONS FOR TIIE MEASURE- MENT OF CIRCULATING ENDOGENOUS LIPt)PROTT3IN 1-IPASE ACIIVITY Aliquots of platekt-rkh plasma and platelet-prxu plasma were obtained from the blood of fasting healthy human voluntecrs by graded centrifuRa- tions. These plasma specimens were then mixed with coconut oil crnulsion, bovine albumin, and normal saline, and the resultant frcc fatly acids were determined at zcru time and after 15 and 30 minutes of incubation. In cxperinrcnts comparing fatty acid-poor and regular albumin, a similar sys- tem was uscd, except that platelet-rich plasma was used throughout and the two sets of tubes contained fatty acid-poor and regular albumin respcc- tively. In 63 of the 86 plasma experiments there was a significantly greater release of free fatty acids when platelet-rich plasma was incubated with coconut oil than whcn platckt-poor plasma was used. With the albumin esperimcnts, 19 of 20 trials showed that fatty acid-poor albumin enhanced the lipolysis of coconut oil. Therefore, endogenous lipoprotein lipasc activ- ity was shown to be associated with the presence of platekts and the composition of albumin. Since it is reasonable to assume that the use of fatly acid-poor albumin reflects the physiological situation in vivo as there is a very rapid turnover time of circulating frce falty acids, it would appear that fatly acid prKrr albumin and platclet-rich plasma should be used when endogcnous plasnu lilK,pwtcin lipasc activity is being studied in virr.,. EnRrlbera, ll. lournal of Arlrrro.rclcroiit Research 10(3):353-35E, 1969. Other 6rantor: California Arteriosckrosis Research Foundation. From the Cedars-Sinai Medical Center, Los Angeles. I IX. Chemistry and Biochemistry FACTORS INFLUENCING TNE ABSORPTION SPECTRUM OF VERTEBRATE NEMOGLOBIN IN SOLUTION The spectrum o( methenaglobin at acid pH is a sensitive test for minor modification of hemoglobin. Speetrophotometric changes may be produced by a variety of treatments and agents, a common fcature being possible "perturbation" of the protein structure. lfowevcr, differences in Preparation, handling, and treatment of hemoglobin specimens may result in experimentally induced speelrophntometric abnormalities. In this meth- odology study, an analysis of eomrrKm methods of collection and prepa- ration of solutions of hemoglobin showed that a number of techniques and materials produced a modifxd material, eharacterized by a relative increase in absorbance at 570 nm in the acidic melhettaglobin form. T hc urxksir- able conditions include, most im antly, dialysis against distilled water, exposure to a IarFe excess of oag trgent, oxidation of an inadequately dialyzed hemoglobin stock solution, failure to semove excess o.idant, c.po- sure even briefly to a p1t below 6.0, and freezing of methanoRlobin sulu- tions. The effect of 4 M urea on the spectrunr of inethenKigkobin indicates that a comrrK.n feature of these agents is protein "perlurbalion " Utiliring the results of this .tudy, a recommended standard procedure for the prcpa- ralion of hemoglobin samplcs is presented. 64 65

Comrron, R. F. and Gcorge, P. Riuchimica rt Riophy.rica Acra 194:16-24, 1969. Other Rra,.tor: U. S. Public Nealth Service. From the Department of Chemistry. University of Pennsylvania. Philadel- phia. and the New England Institute, Ridgefield, Conn. DETERMINATION OF IRON IN NEME COMPOUNDS: Ill. EXTENSION AND MODIFICATION OF THE ME:THOD A method for the estimation of Iron in a sample by wet digestion and analysis as the colored ferrous 1,10-phenanthroline complex was developed originally for use in the study of human hemoglobin. Other materials con- tain iron, however, and this method has been used to study the hemc con- tent of plasma and the iron content of such materials as eytochronres, tis- sue e><tracts and secretions, and sperm whak myoglohin. The current paper presents a modificatic.n of the originalpr ocedure which has been dcvcloped for use with such varied materials, and with samples in which volume may be excessive or in which resistance to digestion is greater than expected for the original assay. A comparison is given of the original method for henx.- globin iron and the present modification. The agreement is exeellent, with no degradation in quantitatinn. Further analyses are reported on hemo- globins from various uources, as well as application to a glandular sccretion. Camcron, B F. Analyrical Binchrmirtry 35(2):S1S-S17, 1970. From the Ikpartmcnt of Internal Mcdicine, University of Miami School of Mcdicine, Miami, F la. ELECTRON SPIN RESONANCE AND OPTICAL STUDIES OF TNE INTERACTION BETWEEN NO, AND UNSATURATED LIPID COMPONENTS Electron spin resonance (ESR) and optical spectroscopy were used to stody the interaction of NO, with an unsaturated fatty acid, its ester, two phospholipids, and two unsaturated aliphatic hydrocarbons chosen on the basis of location and configuration of the double bond site. Solutions of all of thcu compounds were shown by ESR to give rise to stable free radicals upon reaction with sofutions of NO,. In addition to the stable free radicals, it was established that the reaction o( dinxthoxyethane (DME) solutions of the unsaturated fatty acid, okie acid, and a DME solution of NO, gave rise to a transient free radical which decayed to yield one of the stable free radicals. The chemical naturrs of both the transient free radicals and stable free radinls produced In these reactions are discussed. Estcfan, R. M., Gause, E. M. and Rowlandr, !. R. Fnvirnnmcnrof Rruarrh 3:62-7g, 1970. From the Department of Physical nd Biological Sciences, Southwest Rc- scarch Institutc, San Antonio, Tex. PRELIMINARY STUDIES ON TNE FREE PROLINE CONTENT OF IteLa CELLS EXPOSEE) IN VITRO TO A METNANOL- SOLUBLE FRA("iION OF PARTICULATE MATTER FROM CIGARETTE SMOKE HeLa cells were exposed in vitro to two different samples of methanol- soluble particulate matter. One of these samples was obtained from 100 mm filter cigarettes of a popular brand; the other was gotten from the smoke of an equal number of non-filter regular kngth of three different brands. In both cascs, the amount of free cellular proline present in the treated cultures, as compared to the free proline present in control cultures, was f,nrnd to have increased t all smoke particulate treatment levels studied. Smith, C. W., Nau, C. A. and Wrndrr, S. H. ToAacco Scirncr X 111:107- I Og, 1969. Other grantor: National ('enter for Urban and Industrial IFealth. From the Department of Environmental Flealth, University of Oklahoma Medical Center, Oklahoma City, and Chemistry Department, University of Oklahoma, Norman. I X. Reeiew, TFiE EFFECTS OF URBAN AIR POLLUTION ON NEALTH This well-documented review of the investigative fabric relating air pollution and human health provides a provocative examination of one field of environmental medicine. The data discussed here lead to the inescapable conclusion that community air pollution is capable of producing scrious health effects. Included in this paper are descriptions of the relationship between pollutant emission, atmospheric ekansin¢ prviceases, and ambient air pollutant concentrations. Toxicologic studies involving the administra- tion of sulfur dioxide, nitrogen dioxide, carbon monoxide, and particulate suspensions to both animals and man are reviewed and demonstrate that aingk pollutants cannot explain the irritant potential of the urban atmos- phere. A number of important epidemiologie studies are presented which emphasize the relationship between human illness and atmospheric pollu- tion. Synthesis of both toxicologic and epidemiologic studies leads to the conclusion that the noxious nature of the environment is due to a compli- cated "mix" of pollutant and meteorologic factors. Ayres, S. M. and Buehler, M. E. Clinical PharmacofoRy ond Therayeutk: 11( 3): 337-371, 1970. Other Rrantor.: U. S. Public Health Scrvke and the New York Tubercu- losis and Nealth Association. From the fkpartment of Medicine, St. Vincent's Ilospital and Medical Center of New York, New York City. 66 67

PATF1OGfiNFSIS OF ESSENTIAL HYPERTFNSION AS VIFWFD IN RECENT PSYCHOPFIYSIOLOGIC STUDIFS Nervous mechanisms are important in essential hypertension, but cxaclly how these neural inftuerxes are manifested is not known at the present time. In this review paper, several hypMhcses of ncurogcnic origin of hypertension are discussed. The mechanisms considered are: 1. The blood pressure regulatory function of the carotid sinus and aortic depressor nerves are such that alleration of systemic arterial pressure regulation by the resetting of the baroreceptor mechanisnn might result in essential hyper- Iension; 2. llypertension might be a cardiovascular neurosis, in accord with Pavlov's general view that the cerebral cortex controls the activity of all internal organr, so that elevation of arterial prtssure results from Ihe par- ticipaticxt of the cardiovascular system in the conditional refka; 3. Similarly, hypertension might result fromt+ptrant conditioning of visceral rrsfmnses; 4. Psychosocial stimuli might indiroe hypcrtension; 5. llypcrtcnsitrn might bc related to the "eflect of perwn" described by Gantt, which would har- monize with Freudian theory. Thot+ws, C. H. Current Medical Dlrrn 36(6):472,474 176&481, 1969. Other grar.tor: Maryland Heart Association. From Tfie Johro Flopkins University School of Medicine. Baltimore. 68 Recipients of Active Grants Following is a list of all recipients of currently active grants (as of )uly I, 1970) that have been approved by the Scientific Advisory Board. Project titles are alxi included. A number of projects have been completed since initial grants were made in late 1954 and the recipients of these are listed in a later section. CRAKTEE AND IN4TITlT1ON DOMINGO M. AVIADO. M.D, rro- )rswr of r/brn.ecoforl. University of Pennsylvania Sctxxrl of Medicine. Pbil- adelphn. STEPIIFN M. AYRfS, M.D., Dlrrrro., Crdioprfn.on.r~ laf.orarory, St. Vin- ccnt's Nospital, New York City. OSCAR 1. RALCHUM, Pw.D., Hotlwts lroJrasor of Mrficiwr. Uni.enity of Southern California School of Medi- cine, Lo. Anaeks. FREDERIK S. BANG. M.D., ho/rt.ar awd CA.Mw.an. DrrrM.rnt of radYO- •lofaa~. The loMs Hoollr Univenily Schod of Hytsiese and PuNic Healtl4 e.Mimore. BENJAMIN dELL, M.D_ Dlrreror of the Normative Agiwt Strfy, VA Ort• p.tient Clinic, Boston. (Initiated t.nder C. L. Rose) SAMUEL SELLET, M.D., DLvrto.. Df- riiion of Crdioloty, Philadelp\ia Gen• ecal Hospitaf. Philadelphia. PROJECI' TITLE EJfecis of nieotine and cigarette smoking on ne.rollenic wrecl.nisms in the lung Tolerana of lonp to tobacco smoke with .pecial refercnce 10 Pulmonary emphy- .emo and vascular occlusive ksions Ilrvwc6sw..w1.r eRecu of cigarette smote Measuremewt of .Iveol.r-.rteri.l nitrogen difference by gas cA.om.topaphy The diRusinR capacity of the alveolar membrane In pulmonary emphysema Relation of ak pollution to development of ebrowie tau[monary disease The effects of measured small amounts of carbosylgemoaloAin on cardiorespra- tory fundion in man Effect of tobacco smoking and community air pollution on human myocardial mN. ism Determinants of the course of empby .emrbronchili. IMeraction o( viruse+.ith mucoaa of the respiratory troct, and .n analysis of the tRecH of environmental vanauons on the function of the mucocitiary system Social predictors af lonae.ity TDe effect of nicotine on ra.diac 4rita- tion in rM presenot of reserpine. and the effect of nicotine on coron.ry htood pow I. dop with ooronary inwrflkiency Efteds of .iooli.e on the morphology of eoronul .rterlea and aort.; nbrindytk elfeds of wkotir on human and ad- rnal rla.wa: aBeds of cea.tion of tKnotina ow .errrrn ebkuerol levels of cA.owk rw.oters: !he eRcN@ of cigarette nnota on free fattr acid k.el* of sub leee. with .ryoe.rdral,infarcrions The effect of sicotine on various paranm• eters of eardiov.scular function 69

(;RANTEF. AND INSTITVTION 1OHN A. BEVAN, M D., lro/rnu+r of Iharn.r.rufoey. t)niverady of Caldornia School of Medicine. I os Angeks. B(1DHDEV BIIAOAT, M D.. IroJrrsor of fhyrioln[y. St. I ouis University School of MedKine, St Louis. RICHARD 1. BINO, M D., IroJrawr of M.lklw.. University of Southern C.U- fornia School of Medicine, Los Angeles. Rrsrrch Asrociarr, C.lifornia Institute of Technok.gy: hirrcrnr o/ Cr/roloty awd Inrrar.rwal Mrdrerwr, HYn1inR/on Memorial 11o.pnal, Pasadcna. ('al. PROJE(T TITI.E Facilitation of vasoconuricti on by nicn- tine and related agents The mechanism of nicotine-induced re- kase of catccbolamines Effect of ciprette srnokinR .nd nicotine on tbe disposition of calecM.laminei in esperimentd coronary artery insuffi- cicncr The effect of satoking on the coronary blood fbw and certain phases of myo- cardial metabolism in patients with arteriorCknNK or bypertenuve carduw vascular disease Srudin in cellular physiology of heart wrascl. Mearurement of coronarr bl.rrt /Sow by mearo of radioactive albumin Tbe effect of smoking on coronary blood Row in patients with anerioselerotic beart disease and the effect of nicotint on storage of amines in heart muscle Measuremenl of coronary blood fiow with a syslem using coincidence counting; tbe effect of nicoline and change in t. t t l cs ra e on car iac mc a o isrn an b rt d d CRANTEE AND INSTITLJTION BRUCE F. CAMFR()N, M D., Pa D., How,erd IhrRhrr Inrruprr, University of Miami Schotd of MedKinc, Miami. WII 1.IAM ALVIN CARTER. M D., Aur.ranr lr.rfnror u/ Mrdrernr and MrcrnhrofoRy, lhe lohns Hopl,un Uni- venity School of Medicine. Battimore. IACK CHAI.ON, M D, Aitisrenr Iro/ri- snr of Anrvhror>InRy. Albert Einsltin ('ollege of Medicine. New York City. SANFORr) C1IOIXX/1, M 1) , Aulrunt Professor of M.duwnr, Tufls Ilniversity Scboof of Medreinc, Bouon (Iniliatcd under Mauricc Srgal. M.U ) NAITER M. CHUPRA. PsrD., Iro(n- inr of Chrnr4tuf, North Carolina A4ri- cultural and Technical State Univeruty, Greensboro. IOHN F. CRAIOIIFAD, M.D.. AuocLrr lrnfruw of rarhohrr). Univcrsiq of Vermont Medical Sch,xsl, Burlington. i related subjects Epitbelial cell transformation and urci- StudKs on cardiac metabolism with spt- nana induction by C type RNA viruses ciat refcrence to myccardral a wsu T. TIMOTHY CROCKER, MD, rro- Biologic adisity of tobacco smoke con- The Infiuence of nicotine on lipid compo /r».w of Medicine. University of Cali- dentales on respiratory mucou of ro- Jtion of vascvlar wall of the coronary fornia School of Medicine. San Fran- dents, canines and pimates in or~n vencls; its effect on distribution of co.- Clfco. cvlture• a eistototic and autoradio- onary flow Raphic study hM D. Rro/ra- WALTER M. BOOKER Studies on the possible scnsititation of the he.esNion or revenal of abnormal states . Dr~r rnvnl of fh.rnsa- Jor aw/ Hral vascvlar mecfsanism to catcchdamines of respiratory epilhetium produocd by . Howard University Washing- cororr following nicotine administration cipretle smoke condensate and benno- . . ton, D. C. Furtlser swdies on the cardiovas:vlar ef- (a)pyrene (ects of nicotine CARFOLL E. CROSS. M.D. Aaduanr Effects of dprette smoke on tbe pulmo- rrolrssor of Inrrrn.i Mrticine, Univer- nary lympboretieular system dEOFFREY L. BRINKMAN. M.D. Ar- Tlr effect of cigarette smoking on the sity of California Scbool of Medicine, .ociwr Iro/rs.or of Mrfinnr, Wayne ultra microacopie structure of the broo- Davis. State Uni.ersity Scfod of Medicine, tlid mocoaa EDWARD F. DOMINO. M.D., rro/rr EReets of tobacco .noke and nicotine on Devoit. aar of lhrrnacofoty. University of the eentral nervous system BARBARA B. BROWN, nr D. ChkJ, Nicotine and smoking effects on ekctro- Michigan. Ann Arbor. E.prrln.rwr.l Psychiatry. Vetenna d-A encepbalopun correlates of bebavior, BERTRAM EICHEL BS. D.DS., Di- Metabolic felerrelationaN e between t ministration Hoapital. Sepulvedti Cal. emotional resporniveneu nd visual rector. /nullWr of Sro+naroiotiod Rr- p o- baooo arnoke and tlsa IWman mouth perception iw cats lrrrh, Science Resourees Foundation, Metabolic nw/ eyto9AysloloRical<bemical E.ap/orNion of the diRerences ie EEO Walertown, Mass. interrelatlonsNpa between tobacco pttern-subiedive Mate correlates In rrnoker and nonrnoker•subjccrs smoke and ,be Ctuman mouth RAYMOND R. BROWN. Hr D. h./rr FRai of smoking on tryptophan wxtabo- .or of Clinkd Owrofoty, Ual.+rdrr d Il.n 1N a+an Wiscodn Medical Scbool. Madi.oa CARLTON K. ERICKSON. M D. A.- •luanr rro/ruoe of /hrnsarolo/ y awI Toskoloty. Tbe llniversity of Kansas School of Pharmacy. Lawrence. PROJE(T TITLG SpectropAotonselric assiy of carbon mon oaidc and nitric osidc hemoglobin Oncogeny and the antivirat action of in- terleron Relationship of an.oking, steroids and menslrual cyck to pulmonary cytomor- pholotr and mucopolysaccharides Changes in cytology of the tracheobron- chial tree Chronic bronchitis entities llm dellradation of DDT. lDl: and Dicl- drin in tbe cigarette mainstream nd sidestrearn aewkes Biology and eytop.thie effects of respira- tory and oncogenic viruses in ortan cultures of human respiratory tract tissue Mechanism of Ie.rninR facilitation by nicotine 70 ~ 71

CRANTF.E AND IN4TITVf1ON PROJE(T TITLE GRANTF,F. AND INSTITlT1ON PROJECT TITLE IIFNRY I FSBFR. Pst D, Rrrrnrh hn. Studiet on immunosupprevive eRecl% of FRFDDY LIOMBIIRGFR, M D, PrrsL Studies on carcinogenesis nd the bio- mun..kryrh/. Mason Research Institute. whole unote and pt v.p„r phase in. drnr and Drrecan, Bio-Research Insti. assay of carcinogenic agents Worcester. Mau. bal ation tute. Inc., Cambridge. Mass. Comparative uudies of effects of various tobacco rnoke condensates on skins of WAI.TER B FSSMAN. Pw D., Prn/rr- Studies of nicotine action upon memory mice s.M of Psfrholatrv, r.3iijKns College of consolidation Systemk eRects of three tobacco smoke tbe City of New York. Flushing. oondensates Biological effects of cili vette smoke TLIF.ODORE N. FINL.FY. M D, Dirre• See I-adman, A 1. . ror of Pulmonary Resrarch liAor.tory, SHIRLFY L. KAUFFMAN. M D.. .Nio- To investip le 16e patbogenesis of ure- Mount Zion /lospital, San Fr.ncisco. crarr Prolrtun ol Perho/otr Down- thane-Induced lung adenomas in mice; (Formerly at The University of New sute Medical Cenler, State Univeruty speci/1uUy the identi/kation of the cefle Meaioo School of Medicine. AlbuQuer- of New York, Brooklyn. which give rise to the adenornaS and we) the fine structural clianties in these cclls during eeopla.ia Cll1.BF.RT H FRIFDPI L- M D_ CAir/ Tbe pathogenesis of human bl.dder cancer Cueiwotsen-indueed alterations in the cell of PaAof..jft, St. Vincent Llospilal, cycle of tlse Type 2 dveolar epuhcbal Worcester, Mass. cell AARON 1. LADMAN. Pss D., ProJrsaor FRec1 of ciprNte smokinR on lipids and MURRAY B. OARDNFR. M.D., Auo- An epidemiological research proliram on .nd CAairns.n, Drpwrmrnr of An.ro- morphology of alveolar lining material ci.rr Prolrrsor of P.rhology. Uni.ersil ~ the etidogr of human cancer rn), The University of New Mesico and macropbages of Southern California School of Med Sclmool of Medicine. Albuquerque. (Ini- cine. I os Angeks. tiated under Theodore N. Finky, M.D.) OFOROP. 0 OI?Y. M D_ Dirrcror. The culture of human lung tinue and PAUL S. LARSON. Pu.D, N..e Proles- Preparation for publication of a book on Finney-No.rlf Cancer RIHNfh LiA- the eRects of known and possibk car- aor of rharrwaco)..ry, Medical College tbe biologic aspects of tobacco and or.rorr: Arrarrarr Prolru.+r of Srr- cinoffenic agents upon such tusue of Virginia, Richmond. ,mokins . The lobns Hopkins UniverWr Characteristics of namal cell Frowth in The possible effect of tobacco smole and U ol of Medreine, Baltimore. (de- culture in relalion to inva.uve carci- nicotine on .scorbic acid metabolism oeased ) norna, especially in the lung Subsidy for publication of a supplement to the monopaph, "Tobacco" DAVID M OOI DFNBERG, Sc.D., M D., Atwclatr Prolruor of Parhol- ory, Temple University Llealth Sci- ences Center. Phdadelpbia. LFONIDE GOLDSTEIN. D.Sc, Rr- sr.rch ScknriH, Srrer of Resr.eA ln NrrroloFZ and Psychiatry. New ler- ay NeuropsJclwatrk Inditule, Prince- ton. IOSEPrt 1. GUARNP.RI, PN D., Dlrec- HN, PMInWnIr) Arro,lofof) I.IAOr/- tor). Drprrnrrnr of Mrdicinr, Saint Vincent Hosptal, Worcester. Mass. Ilnitiated under GuMave A. Laurrn><J, M D.) NORMAN W. HEIMSTRA, PM.D.. As- sociarr Prolrssor of P"cholotf; Diwc- ror. Orlrrr Brh..Mr Llor.rorf. Uni- versity of Sewlh Dakota. Vermillion. Heterolransplanlation uudies with human lung cancer A study of bioekelrk differences between nicotine-habituated and nIM IJhrluated orttanisms by use of high energy pbos- pbate compounds The effect of cigarette smoke on Ihe Im- muno"ical and rrsNaboiic function of alveolar macrophases FReds of smoking on suH.lned perlorm- ance in a simulated driving ,rst An Inveqiptron of the relationship be- tween smoking deprivation .rd uress P.Reets of srnokinj on peripheral visual Acvily RelationshiP between sprntaner/us amok- ins and induced snood chance 72 GUSTAVE A. LAURENZI, M.D. CAieJ of Medicine. Saint Vincent Hospitd, Worcesler, Mass. (Now at Newton- Welksky Hospital, Newton, Mau.) IOSEPII M. I.AUWFRYNS, M.D.. Pw.D_ Pru/ruo. Ordsnarirr in Mk.oicoPic Anatomy; Ch.urnran. Eiprriwrrnr.l Lbora/or) of CarhoPrlnson.rZ and C:rnital Patholoty, University of Leu- ven, Leuven. Belgium. CECII E LFl1CHfF.NBEROF.R, PN.D., Head. DrP.rrnrrnr of CytorArnrl»rZ, Swiss Institute /o. Fsperimental Can- cer Research, I susanne, Swdterlarsd. See Ouarneri, l. l. The IrenpAaties of the lung; their role in Ruid transFort and ckarance of air- borne p..trculate matter A eorrela/ed hirological, cyto/o~icsd and t~1ochemkal•study of the tracbcobrun- esid tree of mice esposed to ciyereue s.rwke TDe iMerselation between influcn.a virus Infectiona, espoaure to cigarette urwke and other factors in the development of pulmonuy and bronchial kswns in mice Comprualive eytoihemical, cytological and hisldogie.l Mudies of early rAects of eilitaretle mroke (wbole, t.s phase. constituents) In mice and /n lissue and 09660 cullures /roan mrct and bumans 73

CRANTEF. AWD INSTITVilON 1. P. LONG. iM D, Prn/rsawr of Pher- r..eroloty, Srate Unrvcrsi/y of low College of Medicrne. Iowa (-ity. CLA,YTON O. LOOSI L Pw D., M D, Hasrints Pro/ras., of A(rlrrine and P.rholoty. University of Southern C.li- tornu School of Medicine. Los Anteka. KENNETH MERRILL LYNCH, M.D. Sc.D. LL D, CAancr)for and Pro/ra- ror F:nsrriras of ParAoloty, Medip) Col- kte o( South Carolina. Charleston. (1• .a.ocialion with Fo.de A. Mclver, M.D.) INES MANDL, Pw D. Aularanr Pro/n- sor of dn.rArn.isr.7. College of Pbysl- cians and Sur Columbia Uni.cr- rNy, New Yor City. 1OHN /t. MANHOI 0. )a, D.M D, Pro- /rsaoe and Drrrcr.w oJ PnAolot y and Ur.l Dr.tnosu, New lersey CotkK of Medicine and Dentiury. Jersey City. DONALD 1 MASSARO, M D. Assorfarr Pro/rsaor of Medicine. (icorte WasA- intton University Scbcx,l of Medicine. Washrntton. D. C. FORDF. A. McIVFR. M D_ Associ.rr Proleuor of Pathology. Mediql Co+- kge of South Carolina. Clarkslon. HANS MEIER. D V.M.. Sw/ Srknrlu, llrc lacksow "boratory, Bar Hubo.. Me. KENNETH M. MOSER. M.D.. Aadrrasr Proltssor of Medicine. Oeorgetown University Medkat School. Wruhint- ton, D. C. EDMOND ANTHONY MURPHY. M.D. Sc.D.. Asaorlarr Pro/rasor of diosarlr rrrl and A(rlNinr, The /ohrM HOpkrM tlniversi(y School of Medieine, ~alti- mde. (Formerly at University of Coio- PRO)F.(T TITI.E Cardiovascular c0ects of nico/ine Further studies concerning sympathomi- metic actions of nicotine l ung tisaue reactions to airborne cbemi- cal and biolotical agents Environrnental factors and pulmonary dis- ease: 1. Asbestos dust; 11 Asheuos and co-carcinotens, vital and chemical The role of bereditary claslase inhibitor deflciency in Ihe elioloty o( pulmonary emphysema FLMolytic Ixeakdown in the rriuloty of pulnlonary emphysema Study of Ibe purported relationship be- Iween snqkint and chantea in human oral tiroc in riro by routine micros- copy, differential slainint, and micro- resFirvmeter metlsods, and further sla- trMrcal esamrnaliorl of two seriH of data Presendy in the principal investi- anor s possession Crnnp.rative racial prevalence of chronic bronchdu Alveolar cells protein and glycoprolein hiosynthesis Protein synthesis and secretion by Ira- cheal mucos. Sre Lyncb, K. M. Orscofcnesis in the rabbit: tenctic sus- ceptibilit~, vertical trantmission of virus and environmental influences EBocta of acvte and chronic citardte smoking upon fiMinolytic activity ard blood coatulalion in man Working ort In detail an appropriate nseans of determining the duration of sur.iral of the human platelet rado Medical Cenler, Denver.) RICLLARD L.. NAEYF M D, Professor Smoking and the putmona.y t.lor~f •es- rT vr m B nnl Ch.irnwn. Drprimrwt of P.rAo!- ..tr, Pennsylvania Sar. llniversdy Col- kte of Medicine. Llersf.ey. 4 sels: a Quantitahve, mrxptsol„tit study m m ri CRANTEE AND INSTITVIIION At.BERT Ft. NIDFN, M D., Prolessor of Medicine: Drrrtn.., Pulmonary Disease Srrtron, Department of Medicine. lem- c University School of Medreine, hiladelphia. ROSE MARIE PANGBORN, B.S., MS.. AasHmnr Food Trrhnolotisr and Lrc- rurrr, Drpornnrnr .,/ f rrod Jr irnrr and Techn,rluty, University of C.li/ornia. Davis. JOHN W. PARKFR- M.D., Auoci.rr Pn.fnsor of Pmholoty. University of Soulhern California 5cbool of Medi- cine. 1 rn Angeles. MARY STf:ARNS PARSHLEY, PsM.D., Auru.nr Pro/ruor of Anatomy /n O6- srrrrru and C. ynrrolotn. ('olkte of Physicians and Surteons, Columbia Uni.ersny, New York City. S. N. PRADHAN. M.D., hM.D_ Pro/rs- sor of Phernrecofoty, Howard Univer- sity Colk(te of Medicine. Washington. D. C. WIL.LIAM REGEI_SON, M.D., Pro/rssw and Chainn.n. Drp.rrnrrnr of Medical (lncoloty, Medical College ol Virtinia, Richmond. WtL.1.IS N. RIESEN. Pn.D., Srnlor sio- chnrJsr, Life Scirncrs Diririon, IIT Research Institute, Chica=o. (Initiated under A. Weinstock, Ph.D.) ROBF.RT C. ROSAN, M.D.. Auorbre Pro/essar of Pathology and Pedlar.ks, SI. Louis University Medical Scbool, St. Louis. CHARLES L. ROSF A.M., Senior Direc- ror, Veterans Administration Outpatient Clinic. Boslon. JOFIN R. ROWt ANDS, Pw.D. Sras Srirnriu, Southwest Research Instilute, San Antonio. Tea. Ul-RICH H. SCHAFPPI, MD. Dkrrroe of Nrr.oOA.r.norolot., Mason Re- search Institute. Worceuer, Mar. PROIECT Tl'R.E Effects of cigarette smoke, drugs and no.- ious furnes on Ihe Icrmmal airways with special reference to rhe terminal bonchroks Interaciioru of gustatory. olfactory, lac- tik, and thermal stimuli mont smok- en and nonsmokers Mechanisms of suppression of cellular im- munity by carunoltemc hydrocarbons Effect of oonsliluenls of toAacco smoke on noenul .nd malignant human res- piratwy epthetium rn vitro F.ffect d/obacco smoke on normal moust lun= liswe Effect of nicoline on behavior Effect of wiooline on behavior and its in- teraction with drugs RES funcl{on. tumor induclion and growth Effects of tobacco amoke on cellular res- piration Bronchopulmonary dyspla,ia see eeu, e. A detailed Investigation of the wature of the re.etion between bioloqical materi- ala and atmospheric coMamrnanls, uan~ ekctron prramagnetic resonanccs nda oy(ical apearo.copk techniques Spectroaoopie investiption of tobacco anqka OonMllsaent" on mammals lnwatlplion of the direcl pimutation of p.rrPmpahetie nerve terminals by nicotin. Nicotine administration to ro.rral are.s of the cat brain: effects upon EF(1 and aulorMnnic ryrlem 75

CRAfKTEE AND INSTITUTION )ORGFN tl SCFII.FGEL, MD, PrrD., Pr.r/rrrnr and Chaonwn. Arv rron of Ur.dnlry. lleparrrnrnr of Su•t rry, Tu- lane University School of Medicine. New Orkans. MAURICE S. SFGAL- M D. Cliwk.f Prr./ruar of M.Arrlnr, Tufts University School of Med.cine: Dirrrto., DeParr- mrnr of lnhalanon Therapy. Roslon Cny Ilospital. Rosron. 1(/CIO SF:VFR1, M 1), D/reeto., lnul- rrrr of M.+6rI Ar..ro.wy and /I/uol- uRf. Drrrrwn o/ Cancer Rrs.weA, tlniverany of Perugia. Perugra. Italy. SH011 SHIRATA, M.D., PH D_ Asao- rrarr Pro/rrt+w of Pharnsacoifo*y. Unl- Ts.ty of /la..n School of Medicine, nolulu. ERIK SKIN1101, M D_ Ch4/, DrPor- n.rwr of NeunrLrty. RispehPers llospi. tal, Copenhagen. lknmark. GENF. M. SMIT11, Phr D.- Aulrranr Pro- /rrsor of hyrholojy, N.rvard Medical School, Massachusetts (:cneral llospi- tal, Iloston LUCILE SMIT11, PH D, Pro/ruor of Dlo- cAensisrry, Dartmouth Medical Schoof, Hanover. N. N. L.OUIS A. Sn1AFF, M D., Pro/rsaor of Clrnk.l Mehcrnr an/CAie/, Diru/on of Crliolory. T emp1e University Health Sciences Center. Philadelphia. SHFI DON C. SOMMERS. M.D. Pro/a- u» of ParAology. Colkge of Pfyskiarta and Surgeons, Columbia University. New York City. DAVID M SPAIN. M D, Dirrcrn+, Dr- fa rmrnr of Parholn*y, The Drookdak lrnpdal Cemer, Rrdrklyn, N. Y. PRO)F.(T TITLE Chan~cs in F-FG anJ hehavr~r induced wnb Ihe prnlracled rntcavenous aJmrn- iaration uf srn.ll Joses of nicotine rn umestraineJ cats The role of uyprophan meuF.M.lites in the etiology of bladder tumor fermatron See Cbodosh, S. An approach to the sludy vf unernalfac- ,oa in lung carcirw.grnrvs m0uence of hormones Rk+od borne carcim.tens in mouse lung tun.orrgenesis Study of sensitivity of vascular tissue lo nicotine The acute effect of smoking upon regional cerebral blood flow in smokers and nunsmokers; the effect of some physio- logical Yimuli upon cerebral blood fiow in smokers and rKrnsmokers 'T'be relations between smoking and per- sonalily The inhibition of cytochrome C osidase by tobacco smokc The effect of tobacco anoking on wr- factant, specific fatly acids, cardiac per- formance and metabolism of adipose I lwe SpeciRc eRects of snroking on myocardial tnechanics, myocardial nxt.holism and on enzymes and formed elements of the blood Hose facton in chronic pulmonary inRam- mation, emphysema and lung cancer Pulmonary p.renchymal alter.tions in an aulopsied "mwmal" Pnpalatron as re- latrd to ae, seR and envnunment.l fKlorr 76 i t CRANTF.E AND INSTITUTION CnRnI INE RI,DIl L THOMAS, M D, Pr../rrrrw l.mrnrur of Mrdrrnnr. The )r.hns Hoplrns On vertrty School of MeJrcine. Halhmore. JAMES E. P TOMAN. PH D, Pro/rssor and CAai•man of Pharnracnlogy- Chi- caRo Medical School. Institute for Medi- cal Research. Chicago. (deceased) 1(-ontinued under Hcctor C. Sabelli, M D.) ROMFO A. VIDONF. M D.. Asroclorr Pro/nsor o/ ParAology, Yak Univer- sily School of Medicine. New Ilaven, Conn. PETER K. VOGT, Prt.D.. Pro/esur of MirroeioloRy, Univer/Ny of Washing- ton School of Medicine. Stauk. IOHN V. WEII., M.D. Aaaltrant Profrs- sor of Mrdrrinr. University of Colo- rado Medical Center. Denver. A. WEINSTOCK. PH D, ReswcA eio- cArmiN, Life Scrrnrra Dfr/abn, IIT Research Institute. Chicago. SIMON H, WFNDER, PH D., Research Prn/ruor of Diorhrnsbrry. University of Oklahoma. Norman. DUANfF O. WF.N7El. PH D., rroJrasor of IA.•mar..lrr~y- School of Pharmacy. Univenily of Kansas. I.awrence. PROIE(T TITLE The significance of different individual Pat- terns of circulatory response to ullia- rerte smoking Studies of genetic differences between smokers and nonsmokers Studies of psrcholoRical differences be- tween smolen and nonsmokers as shown by comparison of figure dr.w- inp Psychological chuacteristics of healthy youn4 adults and Iheir biological im- plicatron; a continuing study in depb, with special reference to the precursors of hypertension and coronary heart dn- ease and to snwking habits A sludy of the precursors of hypertension and cororury dise.se CigarNle smoking pauerns over time: profiks of former smokers compared with continuing smokers and non- vnoken Mechanisms of the psychotropic effects of nicotine The study of actions of nicotine upon cenlral .ynaPses and its co.rclation with the mechamsm of action of behavior- ally active drugs Hislochemislry of epithelial mucins in carcinoma of the lung Avian lunror viruses in mammalian bosts Effecta of cigarette smoking and of chronic air.ray obstruction on hyposic venli- latoty drive in man See Rksen, W. FI. ERect of ciprette smoke and its compo- weMo on free proline in animal tis.ue cultures A study of antihyPertensive activity of nrcolrnN Effects of Intermitlem nicotine admini.- tUalion on blood pressure and myocsr drum 77

THOMAS C. WFSTFALL, Psr.D., As- Action of nicotine on auhcellular di.ui. -su. (ore ProJruor of Phnrrneroloty. Uni- bulion of calecholamines anJ xroronin versity of Vrrginra School of Medicrne, in brain and heart CharlMlesrJlle. Influenee of nicotine and related drugs on the upake, storagc, rrkase nd turno.er of catechalamines in central and peripheral livue DANIEL H WISEMAN, M D, A»Ist.wr Penistent pulmonary dysfunction follow. P.ufrunr'of Prer.r.rrs. Unr.ecsitr of ing spccrfic- lower re%prraio.y di.cases Southern California; CAitdrtw-s DFri- during childhood sron, Loa Angeles County General Ho.- piral, Lof Angeles. Recipients of Completed Projects Following is a list of grantees whose pro}ects have been completed prior to the period covered in this Report. Several o( the grantees are de- ceased. The titles and affiliations listed are those in effect at the time the work was completed. CLARENCE M. AGRESS, M.D., Aaso- ri.rr Clinical ProJessor of Mrdrrnnr. University of Cdifurnia Medical Cen- ter, Los Angeles. ANTt1ONY A. Al BANFSE, Px.D., D1- rrrror, NrrrlNon and Mrtabotlc Rr- se.rrA D/rlrrnw, The Burke RebabilN.- Ilon Center, WArte Ptains, N. Y- ANTHONY P. AMAROSE. Ps1.D. !n- srrrcror, Drp.rnnenr of Obsretrks .nd Gynrr+oloty, The Albany Medie.l Col- kge of Union University, Albany. N.Y. E. T. ANGELAKOS, M.D., Ptt.D.. Pro- rrssor of Physioloty. Boseow University -iebool of Medicine, Boston. D. MURRAY ANOFVINE, M.D, Uni- venity of Wisconsin School of Mcdi- cine, Madison. BRODA A. BARNFS, M.D., Pst.D. Pro- lrssor (.ffili.rr) of PA1siolotr. Colo- r.do State Univenity, Fort Collins. FREDERICK W. BARNPS, )ra. M.D. Associ.tr Pro/rssor of Afrdk/nr. Tre loens Itopkins Univenity School of Medicine, Baltimore. T. C. BARNFS, D.Sc., Rrsr.rcA SclrnNsr, Philadelphia State Hospld, PAiladel- pbia. R. FREDERICK BECKER. Pw.D.. Asso- ciate Professor of Anaowsy and DMrc- ror, L.borarory of Prrirvr.! Sekncr, Duke University Medical Center. Dur- Isam, N. C. RALPH S. BECKER. Pst.D., Pro/essoy of CArmistry, llni.ersity of HourioR Houston. CFSARP. BIAN('IFtORI, M.D., D/.ls/un of Cawrrr Rrsrerch, l)niversity of Perulti., Peruaia, Italy. HYLAN A. BICKERMAN, M.D. Aulst- awr Professor of Mrdrrinr, and ALVAN L. BARACH, M.D., Consub.nr in Afrd- kiwr, Columbia University Colkge of Pbydei.nu asd SurReona; Goldwaler Memorial Hoaptal, New York City. FRED O. BOCK, Pst b, Associate Cancer Rrw.rcA ScknNrr, Iflolog4.f Station. Roswell Park Memori.l Institute. Spring.Rk, N. Y. HERMAN V. BOENIO, Pts.D., Nr.d, CArrn/stur7 and Slocheeriury Drprr- wwwr, Spadlelop ResearcA Center. I.et- inalon, Ky. JAMES F. BONNER, Pw D., Pro/rssor of Sioloty. California Institute of Tec(s- sioloty. Paa.dena. TOM O. BOWERY, tstt D., Prsr/cldr Rrs- Idre [.bor.rory, Chemistry Drprt- mrnr, Nor1A Carolina State College. Rakiaf. IOSEP BROZEK. Psr.D., ProJruw .nd Ch.trns.w, Department ol PsyrAololy. Lehigh University. BetAkhem, Pa. SUE BUCKINOIiAM, M D. Assistant ProJe..er of Prdiurks, Columbia U.1- Ver~ill Cotkar of PAyacians and Sur- geow% New York City. BENJAMIN BURROWS, M.D.. Associate Pro/rssor of A(rdreint. University of Ctikaao, Chicago. H. M. BIIfT, M.D. Chief P.tAologlst, Lo. Asr<ekr County (kneral Itospnal, Lo. Anlleles. RICHARD U. BYERRUM, Pst.D., Pro- /rasor o/ CArwrWr7, Michigan State dni.enity, East Lanrna. SISTER M. EMIt.Y CA11111., Pw.D, Chdrwr.n, ('Aernldry Drparrrernr, Regis College. Wcalon, Mau. 78 79

WILLIAM 11. ('ARNFS, M D, Univer- sity of Uiah ('ollcfc of Medreine. Salt I a1e ('sly. MARCUS N CARROt.L, la, PN.D, Chir/ Dirirlnw of Pha•rnernlnfy, 7he Brookdale /tos{riul Center. Broollyn, N. Y. I FOPOI D R. ('FRFCFL)n, PH D_ Pro- fruor o/ Bru~Arnrurry and Nrrrrtwrn, l)nivernny of Puerto Rrco School of Medicine. San luan WILI.tAM G. CLARK, Pw.D., Director. Psvchopharmecr+f.My ReuarcA L.bora- rory, Veterans Adminis(ralion Horpiul, Sepulveda, C.I. HANS T. CL.ARKF DSc., Pro/nsor of Rrow hrmiur y, Columbia lsniversit y Cof- kfe of Physicians nd Surfeons. New Yorl ('dy JAY D. COFFMAN, M.D. Srcrlon Hrad. PrrrPA.ra/ Yarrr/ar Drp.rrn.rnr, Uni- verarty Hosptal. Boston. DANIFL COIIFN, D V.M, M P H., Ar- srsranr Pro/ru.n of Yrrrriwary t'prdrm- io/ofy and PrFlir IlealrA, University of Pennsylvania School of Veterinary Medicine. Philadelphia. lUL1US H COMROF. la., M.D., Dlrrc- ror, Cardrora.cdar Rrrrarch lerlHrrr, University of California Medical Cen- ler, S.n Francisco DEAN M. CONNORS. M D., Associarr Director. Drpr rrnrM of Laborarory Medirinr. St. Mary's Hospitd, Madison. Wis. PHILIr COOPER. M D. Cllnkvl Pro/rs- • wr of Srtrry awd Directar, Sr~ical Laboratory of CellJar PAyddory, Albert Einsuin College of Medicine; CAk/, Swfinl Srrrkr, VeNeraw Ad- mini.tration Hospital. Rront, N.Y. ROBERT l.. CRAIN. Pn.D. Assistant Pro/essor of Sociology. Uni.ersity of Chicago. C1ksto. CECIL E. CROS$ Rrseor^cA Derarimrnt, S(. losept. Ho.piul, Bwb.nl. Cai. At BERT DAMON. Pf.D, M.D. l..r- rrrrr on Anrhropolo[y; Rr/rarcA Aaao- clarr /n Medical Anrhro/olo*y, Peabody Museum, H.rvrd Uni.cr.Ny, Cam- bridge. M.r R. F. DAWSON. Pit D. P.n/rr.nr of B.,rt any. Columbia Univcndy, New York City. ANDREW S DIBNfR, Pn 1) , f:rrrunvr, hycho-Rrrrarrh, 7he Age Center of New England, Inc , Bouon. RAL.PH l.. DORFMAN. Pit D, Direrror of libo.arorirs, Worcesier Foundation for Esperimental BioloRy, Shrewsbury, Mass. IAMES 1. DYAR. Pw D., Atri,mnr Pro- /rssor of BldoRy, Bcllsrmine ('ollefe, Louisville. Ky. RICHARD H. P-ARl F M D, ClrieJ, Puf- e.owary Frwrriun r.Zoranvy: A„isranr Profrssor of Mrdreinr, (lnivcnrty of Chicago. Chicago. 10HN W. ECKSTEIN. M l), Assistant ProlralJOr of Internal Mrdu inr, State University of Iowa College of Medicine. lowa Cit y. HYMAN ENGF.I.BF.RG, M D, Arrrnd- inf Physician. Cedars of t.ebanon Hos- pi/al, Los Angeles. HANS L. FALK. Psr D, Ad/r.cr Asuori- arr Profrno., Drparrmrnr of Parhnlofy. University of Southern California School of Medicine, Los Angeles. DANA L. FARNSWORTH. M.D., Hrnry R. OUrrr Prolessor of Hyfienr and Dr- rector of f/nirrrsiry Health Services. Harvard University. Cambridge. Mass. FRANK C. FERGUSON, )a., M D., Chain.wn, Drparrmrnt of 1'harmacul- o? y. The Albany Medical College of Union University, Albany, N. Y. WILLIAM 1. FISHBEIN, M D, Chie/ of F.pldtmiolofy. Cbieato Boud of Health. CbrcaRo. RUSSELL S. FISHER, M D, University of Maryland School of Medkine, B.Iti- more. B. L. FREF.DL.ANDER, M D., Director of Cancer Research. Mount 7ion Hos- Pila1 and Medical Center. San Fran- cisco. FREDERIC A. FRENCH. A B, Director of Canrrr Chrm,rthrrapy Research. Mount lion Hotpital and Medical ('en ter, San FranciKo. ao i i JACK FRFUND, M D., A.r,isranr Profn- ,..r of Plrunna,o6rfy, Medical College of VirRinia, Richmond. A R 7 H e1 R F l/ R S T, Pit D, Director, l n,ri- r.rrr u/ ('hrnnral BioloRy, University of San Francisco. San Francisco. THOMAS M. GOCKF, M D., Associate Prolns.n u/ Prrrrnrirr Medicine and Communrry llrahh, New Jersey State College uf Medicine and Dentistry. Jersey City. PAUL GOLDHABER, D.DS.. Auociarr Pro/rssor of Prriodonrolofy, Harvard School of Denr.l Medicine, Boston. IRA (:ORE, M D., Prolnror of PatAol- oRy. Bo.ton Universit School of Medi- cine; Chrr/ of f,a1orarory Sn.kr, Veterans Administration Hospital, West Rosbury, Masa. GERTRUDE Y. GOTTSCHALL, PN.D., Assistant Profrssor of Biochrniisrry, Columbia University College of Physi- cians and Surgcons, New York City. A. CLARK GRIFFIN. PM.D, Head ,f Biochrnrisrry 1)rparrnrrnc, M. D. An- derson Ho+pital ard Tumor Institute. University of Tesas Medical Center. Houston. ARTHUR L. GROSS. M.S., Senior Bio- chemisr, Southwest Research Institute. San Antonio. l ca. MORTON 1. GROSSMAN. PM.D. M.D.. Associate Clinicd Pro ruor of Mrdi- cine, University of Ca ifornia Medical Center. Los Angeles. CARI. C. ORU112IT, Pu.D., M.D. Aaso- cwrr in Physiology awd Phrmardofy. University of Pennsylvania Graduate School of Medicine. Philadelphia. FRANK F.. GU7/1RIE, PM.D., Pro(ruor, and I:RNFSI IIOI)GSON, Pt(.D., A,- sismnr Rraearch Prnlnsor, Drpvlmrnt ol F.'nrwnnL.py, Nrwth Carolina State College. Rakigh. H. B. HAA(;. M D, Professor oJ P/w- n.acolol), Medical College of Virginia. R ichrnond. F. 1. HADDY. MD, PHD, Professor and CAairnraw, Drparrmrnt of Phyriol- oRy. University of O\Lhom Medical Cenler, Uklahuma (tily. IOSF.PN Il. FIAFKENSCHIFL, M D, Medical Drparr,nrnr, Sandoz Pharma- ccuticals, San Francisco. RICHARD 1. IIAVI:L, M D., A„i,ranr Prolessor of Mrd,r,nr, lJniversity of California Medical School. San Fran- cisco. HERBERT R. IIAWTIIORNE, M.D., Chairman. Drp.rrmrnr of Srrtrry, Universitr of Pennsylvania Graduate School o( Medicine. Philadelphia. CLARK W. HEATH, M D.. Pro/esror of Medicine and Director of Health Srrr- krs, Tuft. Uni.ersily, Medford. Mau. PAULINE IIEI2ER, Pw.D. Rr.rarcA .lr- soclatr /n Cyroloty and Cy/ocArml,rry, Saw Francisco InslNute of Medical Scr enoea, San Francisco. LAWRENCE L. HESTER, la, M.D., Pro- /rssor and CAairm.n. Drpatmrwt of Obstrfrks and Gynecology. Medical College of South Carolina. Csarkston. EBBE CURTIS HOFF, PH D., M D, Pro- /rasor and Chairrwan. Dirlslon of Psy- ehlarrir Resroch, Medical Cdlefe of Virginia, RicMnond. RUSSELL L. HOLMAN, M D., I ouisiana Slate University School of Medicine. New Orleans. OLE A. IIOLTERMANN, M.D. Re- srarch Scirnrist, Lobrnd Laborarory, Unl.rrsity of No(re Dame. Notrc Dan.e. I nd. ROBERT W. HULL. PsM L)., Pro/essor ol Bidojkd Sclrncn, Florida St.1e Uni- versity, Ta11.Aasaee. GEORGE JACOBSON. M D.. Prolrssor and Hrad, Drpartmrwr of Radiolofy. University of Southern California School of Medicine. Los Angeks. JERRY HART IACOBSON. M D., Dlrrr- tor, Dlrisiow of Efrcrrophysiulofy, New York Eye and F.r Infirmary, New York CMy. )UI-IUS H.IACOBSON 11, MD. Auo- eLa Pyo%aor of Srr`rr) and Dirrcror of Srrfkaf Research. University of Ver- snoM Colkge of Medicine. Burlington MURRAY E. /ARVIK, Pitl), Auutiarr Profrs.or, oof Phara+a.ol..fr, Albert Fin- srein Colkge of Medicine. Bruna, N. Y. gl

OSWAI.D R JONES. M.D, St. Luke's Flospital, New York City. ANDRFIV A. KANDUTSCH, PHD, Srn// Jrrrnrrer, Roscoe B. )acks.on Mcm- orial Lat.oratcxy, Bar Harhor, Me. ARNOLD R. KAPLAN. Ptl D., Director. l.ehrrorn.) of Mrdiral GenrNcs, Caeve- land Psyc6inric Insrrtute and Hasqit.l, Cleveland. NRATCH KASPARIAN. M D., Ass/se.wr Drrrcro.. Crbnru. rlar (iAorarory: Insrrrrrrr /n Medicrnr, H.bnnnarw Medical College and Hospitd, Psilt delpbia. F.I.I/IU KATT PN D, Assoriarr Pro/rsaar of Sot+oloty, llnivcrsHy o( Chkap, (-h+cago AN('F1. KFYS, h+D. Ohrrror. LA.ra- rory of PAy+lol,qr(al H)Nrnr, 1)ni.er• silr of M.nnesowa School of Public /lralth, Mrnneapolis. 1(XI:P11 B KIRSNFR, M D, Pro/rss.r of M.Jxrnr, llmversiry of Chicago School of Medicine. Ch.cago PETFR 11 KNAPP, M D- RrurrA Pro- 1r++u. of Boston ltm.truty School of Med+crne, Boaon KENNElH P KNl1DItON, MO_ Uwi. versily of Washongton Medical School, Seattle. ALVIN 1. KOSAK. PM D. Aru.ciarr Pro- /rrror of CArmuny, Nrw York Umvcr• sity, New York C'ny. ROBERT A. KUHN. M D, Arroclarr Pro- /rsso., Division of Nrrosrrjrry. New trsey State Co11eAe of Medicine. leney ity. MARVIN Kl1SClINER, M.D, New York University Medical Center, New York City. CHARLES W. lABF.LLP M.D, Ass/sr- onr Pro/r»or of Enrlronmenraf H~- lirnr, Dep.rtmeM of Prevemive Mcdi- eine, Jefferson Medical College. Phil.- delphia. THOMAS C. LAIPPLY. M.D, Pro/rssor ol Pathology. Nortkwes(erw University Medital Sc Clka(to- ROGF.R K. LARSON, M.D, Chief o/ Mrdkinr, Fresno CoyrMy Hoapital, Fre.arw, Cal. AVFRILI- A I IFBOW, /N D, Chmrman, Drparrmrnr of Parhr.rner. Yale llni- versily School of Medicine. New Haven- Conn. FSTEN O. LINDSF.TH, M 1), PN D, St. loseph's Hospilal Research I ahoratory, St. Paul. Minn. ROBERT H. 1.INNF.LI., Pw 1). Asvxiare Prnltssor of Chemurry, lJniversity of Vetmptl, Burlington. HERBERT l.. I OMBARD, M D, M.P H., A/Ninr, Cancer Research Insritute, New England Deaconess Hrapnal, Bo.• ton. DONALD B. I.OURIA. M 1), Assnciarr Pro/rssor of Medicine. ('anell 1/niver• sily Medical ( olker, New York Cny. DAVIL) F MANN, Pro 1). Ae...rrarr Pro /rsior of Pharmarolnry, 1 emp1e llnr versNy School of Pharmacy, philadel- phu. )OHN P. MANOS. M.D, Invrrcr,w in Vrrology and Dertrriolnpr, Medieal College of Sout6 Carolina. (:harleston. CHRISTOPHFR M. MART7N, M D., As- nsranr Prulessnr of Mrd+rinr and urrte• lo.. Dl.isron of ln/rcriors Druasrs. New lersey S/ate College of Medicine. Jersey C:+ty. IIFRRFRT Mcl(FNNIS, 1. , Pw D., Pro- /r.+..r rr/ PlrnrmornlnRf. Medical Col- Ie/te of VuRima, Richmond. VICTOR A. A1cKlJS1(-K, M.D., Prn/rs- aar o/ Mrdu+nr, The )ohnt Hop kins University School of Medicine. Bahi- more. ROSS L. Mcl FAN. M D, Associa/r Pro- Jrrrnr of Mrdnrnr, Fnp+ry Univcrsity School of Medicine. Adanta. - WIL LIAM F. McNARY, 1.., hr D., As- rrwrarr Pru/rs+w of Anaronsy. Boston University School of Medicine. Boston. NF.AI. L. McNIVFN. PN D.. The Wur- n.ter Fuundat...n for FsperimeMal Bi r'hKY. ShrewsM.ry. Mns. 11/1 IA M1 1'/ R, 1'H 1), Ass.wlatr Pru/rr- a... n/ (lrel !'orhuluRy, llnivcrsity of Itl.nors College of Dentistry. Chicago. BF.RNARD 1. MIl.1.FR, M f)., Assistanr Pru/rrww, The Daniel North )nrrirrrr of Anarumr, 1cRersun Medical College. Philadelphia. IAMFS C MILI.F.R, M.D.. Pu D., hu- fr...w of P.yr hr~rry and Pryrh.dnly: Drrrcrrr, Mrnrul HrahA Rrsrr.h In- srirrrr, University of Michigan. Ann Arhor. HUGH MONTGOMERY. M D., Associ- ALBERT B. PAI MFR. PH f) . Ar+hrenr Pru/rssnr. Department nf Pryrhuloty. University of Toledo, TuleJo, (). L'DWARD W. PELIKAN, M D- Chair- nsan, Drp.rcmrnr o/ Pharmarolojy ond Esperimrnul Thtraprnccs, Boston l)ni. versitr School of McJicine, Boston. OTAKAR 1. POI.I.AK, M D, PN D, Etrrrrf.e Dirrcror, Dover Medical Rc search CeMer. Inc. Dover. Del. MORRIS POLLARD. Pw.D., Dirrrror, Lobrnd laboratory. University of Notre Dame, Noire Dame, Ind. C. M. POMERAT. PaD, Director of eiolo~ iraf Research. Pasadena Founda* tion (or Medieal Research. Paudena, Cal. H. R. PRAl1-THOMAS, M D., llranand Professor a/ Parhrrl..ty, Medical ('o) k{e of South Carolina, Charleston. MARTTN S. PROTZFL, B.S.. D D S. Chief. Drprrmrnr of Oral PatAoloty, Newark City Ilospital, Newark, N. l. WALTER REDISCII. M D., Associate Pro/nsor of Cluirol Mrdirinr, New York Universily School of Medicine, and NYU Research Service. Goldwater Memwial Hospital, New York City. HOBART A, RFIMANN, M D.. Pro/rr- CHARLES C McARTTIUR, P„ D, Psy- are Prn/rrr.w of Mrdicine. Universily anr of Medicine. Hahnemann Medical ehdorirr to rhr Un.rrrniry llealrA Serr- krr, Harvard Universrty, (-ambridge, of Pennsylvania School of Medicine. Philadelphia. Colkte and Hospital. Philadelphia. Mw. ROLLAND C. REYNOLDS. M.D. Ar• ' P. O'B. MONTGOMERY. 1.., M.D.. Pro- alsranr Pro/ras..r of ParhrJo>r7, l)niver- ANTS, PH D., Asso- CHARLES B Md ciart Profrssor of Sorls, North Carolrna Stale College School of Asriculture. lrssw of Parhr.luty. Unirersily of Texas Southwestern Medical SeDool, Dal las si/~ d~ Teaas Southwestern Medical School, Dallas. Rakigh. . VICTOR RICHARDS. M D., Chief of GEORGE F. MC>nRF, PN.D., M.D.. D!- Srtrry, Ptesbyterian Medical Center. HENRY C. McQIl.L, 1.., M D., ArrinR Head. Drp.rrrnter of Pa/Aoluty, Loui- recrur, Roswell Park Memorial Insti- Buffalo N. Y. tute San Francisco. uana State University Schrwl of Mcdi- , . R. H. RIODON, M.D, Professor of Pa- eine, New Orleans. HENRY D. McINTOSH. M.1), Pro/rsur+r ' L(URI.FY LEE MOTLF.Y, M.D.. Pro/es- x» rrf Mrdn inr nnJ Dnrrro.. Cardlo- Rrrprrarrny laArxuh.ry, llniversNr of MuloRy. University of Teaas Medical Branch. Galveston. ardrnras- of Medicine and DrrrNor. C l i i k - Soanhern Californi School of h/edi• SYDNEY C. RfTTENBFRG. Pa D, Pro- vers ty r laborarory, Du e L n tr eine Los Angeles. lrrsnr of e.rrrrlulutr, l)ni.crsily of Medinl Center. Durham. N C. , Southern California. 1 os Angeles. WIIIIAM S MIIRRAY, ScD, Srwior FDWARD McKEfy M D, Pro/rssor and /ackson Me• Nuscoe B Q Srirnn.r Sr Asrrxlarr Pro- BENSON B ROF M l) Aetlnt Chairman. Drpartment of Po- . , a Bar Harhor, Me. morial L.huratcwy . , /nror of Swgrry; Chu/, ('ardrac 3rr- rAology, Medical College of Scuth C.r• , f'ry, Univcrdly of Califurnia ticbool of Charleston. olina, CAarksron. L7nNM D M. PA(-F, Pw D, Pro/rssor of Mcdkine, San Francisco. A++oriarr Pro• McKPe M D KELLY T Ph"+iuloRy and Urrrctw, Intnrrtt /ar , . , Medical ('ollete of /raaor of Mrdicinr ('r/lrlar Rr.rarrh, l)nivcrsity of Ne- JOSEPH ll. ROCII?RS. MP. Holy Name , Sowh Cuolina, Charleston hrask., I.inculn of lesus Hoaptal, G.J+Jen, Ala. 82 83

BFN/AMIN A. RUBIN. PN D, Manarer, Diofntiral Prodrerr Derrlopnrent, Wyeth Labor.torier, Pbiladelphia. HENRY 1. RUSSEK. M D., F.A C.P.. Prer/drnt, TTfe Russet Foundation, Inc., Staten Idand, N Y. W. C. RUSSFI.1., M D., University of Te..f Medical Center. Houston. PETER F. SALISBURY, M.D. Pw.D, Head, Inirnrire Trratn.rnr Centcr, SaiM Joseph Ho+pital, Burb.nk, CaI. PAUL SAI TMAN, PH.D.. Aar/Hant Pro- leuw, Drpvn.wnr of I/orArwdmy .wd Nrnltlon, University of Saulher. ('ali- fornia School of MedKlwa, I.o. Antlck.a. ALVIN R. SCHMIDt, PwD_ Director ol CornxNnt. Tufts lJn/vcnily, Mcd- ford, Maa.. ISAAC SCHOUR. D.D3. PM.D., D.3c., Dran, Collete of Drnrlmy. Uni.enity of Illinoir. CAicaRo. CARL C. SELTZER. Pt(.D. Rc.errcA Frlfow /n PAyricd AnMropoloty, Har- v.rd University, C>•rnbridgc, M.r.; Dr- porewnr of NrtriUion, Harvud School of Public fle.lth, Boston. CHARLFS E. SHERWOOD. M D. Ar- rirunt ProJruor of Radroln`y, Univer- aity of Roebcsuer School of Medicine and Denti.rry. Ro>;beste>•. N. Y. DAVID L. SIMON. M D, lnrtrrctor, De- parrrwnr of lnlnn.l Afrdkinr, Cincin- .al Oa+erd Hoyit.l, Cincineai. OEOROE W. SMF1TEM M D. Assocl- .u in PatAoloPy, Nocthc+krn Unr.er- aity Medical Sclwol, C1kMo. ERNEST SONDHFJMFR, PM.D. Arso- c/arc Pro/et"r of elocAerwl4ny. Co1kRe of Forestry. St.te University of New Yort, Syrocvre. T. M. SONNEBORN. PN.D_ Dlnln- `rirhed Ser.k. P.o/.uw of Zoolosy, Indi.na Uni.a+ily, Bloont'wtRtow. SAM SOROF. Pu.D.. Hei.f, Der.nwenr of M.nowrolrcrlar CMnilsrry, TAe 1li- Mitule fo. Cancer Resrvc\, Pfildrl- Psia. AI.FXANDFR SPOCK. MD, Auls/aat Prnfrr>rw of Prdi.erkr, Duke University Medrcal (.:enter, [1,rrf.a N. C. FRFDRICK 1. STARF, M D.. ProJrtjor o/ Nutrition. Harvard Umveniry School of Public Health, Boston. C. HAROILD STFFFFP M D. Director of LDo.oto.irs, Melhodisl Hospilal, Memphis. JACK P. STRONO, M D., Aerociare Pro- /tuor of PorholoRy, 1 ouisian. State Univenity School of Mcdicine, New Orkan,. MARION B. SUI.ZBF.ROFR. M.D, Pro- /rauor and CAainnan. Drpartm.nl of Drrrnatology and Syphololnpy, New York Univcrdsy Bclkvue Medical ('en- Ict, New York (-ity. RENATO TAOIURI, Prr.D , Aa.orlatr Pro/euor of Prychololy, (7raduate School of Business Administration, Harvard Univer.ity, Boston. JEROME F. THOMAS, Pw D..~.olr..ror o/ S.wllary Enriweerin~, Unii,/si,y of CaOirornik Berkeky. /ANETTRAVF.I.L, M D., A:sociata Pro- /earor of Clinical PhacmornloRy, Cor- nell University Medical Collcte, New Yo.t City. LIE SHA TSAI. Prr.D. Research Auoci- arr, Department of Pathofofy. Yde University School of Medicine. New H.ven, Conn. E. D. WARNER. M.D., Pro/.rror of Pe- tAolos St.te University of Iowa Cof- kee ojMedicine, Iow. City. SHIELDS WARREN. M.D_ Director of liAoraro.itr, Cancer Rrarorch Inuirrtr. New England Deaconess Henpital. Bos- lon. BARBARA K. WATSON. PN D.. Aiitrt- ant Qacrrrlologiv, Ma.uchusett. (:en- ec.1 Ho+pital: Rtuarch Asw~cratr, Dr- prtmrwt of Racterlolopy and Immrnnl- ot<y. Harvard Medical Scbool, Boston. JOHN S. WAtK3H, P>. D.. Prolr»or of Chrnrisny, Mauschusetta Institute of Technolo{). Cambridge. RICHARD 1.. WECHSLFR, M,D., Clini- rvl PAyrlofoRUr, Monteflwe 6lcapqUl Institute of Research. Piusburth. 94 i RUSSELL W. WELLER, M.D.. Patholo- tiir, Memorial Hospital of CDesler CouMy, West Cbewee, Pa. FREDERICK E. WHISKIN, M.D. C.M. Dirrctor, Dirltlon of NnltA and Pn- sonafiry Farrlrbrlrn., TLe Age Center of New England. Inc- Boston. ROGER J. WILLIAMS. PH.D. Pro(raaor of Ch.mnt.'; Director. Clayton Forn- dation Siochr.nkal lnultrre, The Urti- vcraty of Te.a.. Austin. 1. EDWIN WOOD, M.D, ln,rrrctor /ow Mcdiclnt, Boaton University School of Medicine, Boston. SUMNER WOOD. la, M.D. Atsbtawr Pro/esor o/ Patholoty. The Johns Ho¢ \in. University School of Mcdiciac, Baltimore. JOHN P. 1YYATT, M.D, Pro/ruor of ParAolory, St. Louis UruvcraMty School of Medicine. St. Louia. as