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Report of the Scientific Director.

Date: 1967
Length: 82 pages
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Referenced Document
List of Abstracts. "Lung Tumours in Animals", by Division of Cancer Research, 660600.
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R&D
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27 Feb 1998
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Little, C.C.
Hoyt, W.T.
Hartnett, T.V.
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List, O.F. Advisors
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Reimann, S.P.
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ANNUAL REPORT o f the SCIENTIFIC DIRECTOR CLARENCE COOK LITTLE, Sc.D. s 0 0 w r 0 ~ J
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SCIENTIFIC ADVISORY BOARD to The Council for Tobacco Research - U.S.A. KENNETH MERRILL LYNCH, M.D., Sc.D., LL.D., Chairman Chancellor and Professor Emeritus of Pathology Medical College of South Carolina, Charleston, South Carolina tHOWARD B. ANDERVONT, Sc.D. Scientific Editor, The Journal of the National Cancer Institute Bethesda, Maryland RICHARD J. BING, M.D. Prof essor and Chairman, Department of Medicine Wayne State University College of Medicine, Detroit, Michigan McKEEN CATTELL, Px.D., M.D. Prof essor Emeritus of Pharmacology Cornell University Medical College, New York, New York LEON O. JACOBSON, M.D. Dean of the Division of Biological Sciences Regenstein Prof essor of Biological Sciences University of Chicago, Illinois CLAYTON G. LOOSLI, Ph.D., M.D. Hastings Prof essor of Medicine and Pathology University of Southern California School of Medicine Los Angeles, California CLARENCE COOK LITTLE, Sc.D., LL.D., LITT.D. Scientific Director, The Council for Tobacco Research - U.S.A. Director Emeritus, Roscoe B. Jackson Memorial Laboratory Bar Harbor, Maine *STANLEY P. REIMANN, M.D., Sc.D. Director Emeritus, The Institute for Cancer Research Philadelphia, Pennsylvania WILLIAM F. RIENHOFF, JR., M.D. Prof essor Emeritus of Surgery Johns Hopkins University School of Medicine, Baltimore, Maryland SHELDON C. SOMMERS, M.D. Prof essor of Pathology Columbia University College of Physicians & Surgeons New York, New York ROBERT C. HOCKETT, Ph.D. Associate Scientific Director J. MORRISON BRADY, M.D. JOHN H. KREISHER, Ph.D. Assoeiate Scientific Director Associate Scientific Director VINCENT F. LISANTI, D.M.D. Scientific Associate tRetired *Deceased
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Stanley P. Reimann, M.D., Sc.D. 1891-1968 Dr. Stanley Philip Reimann, a pathologist and widely-published cancer specialist, died on Wednesday, February 21, 1968. Dr. Reimann had served as a member of the Scientific Advisory Board to The Council for Tobacco Research-U. S. A. since 1954. As- sociated throughout the years with the Uni- versity of Pennsylvania, Graduate School of Medicine; Hahnemann Medical College, and Lankenau Hospital, Dr. Reimann has served as president of the American Association for Cancer Research and the American Society of Clinical Pathology. In 1925, Dr. Reimann founded the Institute for Cancer Research in Fox Chase, Pennsylvania, served as its sci- entific director from 1945-1956 and emeri- tus director. Believing that malignancy was a problem of growth and teaching that the most effective way to find a cure for cancer was to achieve an understanding of the pro- cesses of growth, Dr. Reimann, through his life and writings, exerted a widespread in- fluence on cancer research.
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TABLE OF CONTENTS Introduction . . . . . . . . . . . . . . . . . . . 5 The Progress of Research . . . . . . . . . . . . . . 6 Abstracts of Reports . . . . . . . . . . . . . . . . 15 Psycho-Physiological Studies . . . . . . . . . . . 16 Cardiovascular Studies . . . . . . . . . . . . . 18 Carcinogenesis Studies . . . . . . . . . . . . . 33 Studies at the Cellular Level . . . . . . . . . . . 36 Epidemiology . . . . . . . . . . . . . . . . 39 Pulmonary Physiology . . . . . . . . . . . . . 41 Neurophysiology . . . . . . . . . . . . . . . 46 Chemistry and Biochemistry . . . . . . . . . , , 48 ~ Pharmacology and Psycho-Pharmacology . . . . . . . 52 - Pregnancy Studies . . . . . . . . . . . . 54 Other Studies . . . . . . . . . . . . . . . . 55 Recipients of Grants . . . . . . . . . . . . . . . . 57 N O O r 0 J r 0
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Introduction The Council came into being fourteen years ago (originally as the Tobacco Industry Research Committee) to sponsor financially a wide vari- ety of original independent research studies related to smoking and health. Other agencies, both private and government, undertook also to support research in the same general area. Thus, there began a widespread effort to gain more scientific knowledge of a subject about which little was known. The ramifications of The Council's research program have been and still are, quite extensive. Many scientists who have received and are receiving support from The Council have turned up knowledge and information of value in the ongoing effort to solve the riddles of cancer, heart disease, and other major ailments afflicting mankind. Another benefit to both the general public and the scientific community of The Council's research program is perhaps more obscure but no less im- portant. The fact that reputable, independent scientists at leading research organizations and institutions see the need for more study is a clear indica- tion that the smoking and health situation is not as simple as some people would have us believe. The incidence of the various and sundry diseases attributed by some to cigarette smoking would be a major public health problem even if smoking were not a worldwide custom and had never existed. Many people who have never smoked now die and will continue to die from the same diseases as do those who do smoke. Many people who smoke do not die from the statistically implicated diseases. Whether smoking, as such, is or is not involved in disease or death of certain individuals is still not the solution to the major problem. This solu- tion depends on research which, it is hoped, will lead to the detection of those individuals who, with or without smoking, face in common a greater risk of developing or contracting any of the diseases which have become the major survival threats to mankind. There is increasing and significant evidence that complex, genetically, innate individual differences in susceptibility and non-susceptibility, which affect the rate of aging and the imbalance of various organ and tissue func- tions underlie and profoundly afl'ect the three major public health problems - cancer, cardiovascular disease, and mental health. 5
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The Progress of Research The Council for Tobacco Research is and has been engaged in support- ing studies of those diseases that are currently the greatest causes of illness and of death. Of course, all these diseases occurred, and most were well known, before the use of cigarettes became prevalent, and they continue to occur among nonsmokers. Hence, any hypothetical or even real effect of smoking could, at most, be no more than a contributory or aggravating factor in these dis- eases rather than an "all or nothing" cause of any. Epidemiological studies have been and still are the subject of debate by statisticians with respect to their reliability on technical grounds. Addi- tional research aimed at rectifying some of their deficiencies and clarifying some of the curious contradictions and peculiarities are needed. It is a fact of history, nevertheless, that these epidemiological reports provided the im- petus for abundant research relating in one way or another to "tobacco and health" that has subsequently been undertaken by many scientists. This re- search has been sponsored by government departments and by a number of voluntary health associations and foundations including The Council for Tobacco Research and the American Medical Association Educational and Research Foundation. This was a logical development since a recognized - indeed, the major - role of epidemiological research is to identify areas in which more minute and extended studies of other kinds may be needed in the laboratory or clinic. Within the last half century, notable progress has been made in the control of the infectious diseases with a consequent great rise in life expecta- tion. The average infant born in this country today can expect to live almost half again as long as one born in 1900. This medical triumph has produced a population containing a larger proportion of older persons than any here- tofore encountered in history. With this increase in the older population, disability and death due to chronic or degenerative ailments such as cancer, disorders of the heart and arteries, and chronic respiratory diseases have shown a relative increase. Further progress in improving life expectancy must therefore come largely 6
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from new methods for preventing or deferring the development of such dis- eases, which characteristically have a slow and insidious onset. Experts in these fields point out the complexities that are to be expected in the causation of such diseases. Their origin and development involve various degrees of host susceptibility or of resistance which are deep-seated in the constitutional or genetic nature of each human individual. This "built- in" susceptibility or resistance may then be modified importantly during the life span by such factors as aging, sex, relative activity of the several glands of internal secretion, and the individual characteristics of food absorption, utilization, storage and excretion. Daily life practices such as exercise, hours of sleep, use of coffee, tea, tobacco, alcohol, and the common household drugs, exposures to all kinds of materials and substances on the job, psycho- logical characteristics, and the stresses that assail the psycho-physiological system, may play a role. So may also the numerous bacterial and virus infections, mild or acute, which all persons still experience even though these are much less often crippling or fatal than formerly. Great bodies of data concerning such factors of internal and external environmental origin, have been and are being collected in studies of cancer, cardiovascular diseases, chronic pulmonary diseases and general mortality. In such studies serious fallacies in perspective can result from over- interpretation of one-to-one correlations even though these may be valid mathematically. Because of the lack of multivariate analysis, emphasis on the single factor of smoking in a number of epidemiological situations involv- ing numerous unanalyzed factors may well have masked other possibly im- portant factors and misstated or overstated any possible significance of smoking. The pressing problem is therefore to bring the methods of multivariate analysis to bear for weighting these various factors relatively, in a mathe- matical sense, as contributors to the final evaluation of causation and devel- opment of a disease. The laborious classical method of multiple regression analysis is now being superseded by new computer methods capable of handling a large number of variables simultaneously and rapidly for "clustering tendencies." Such methods need to be applied comprehensively to many large bodies of data that have already been and will be collected in the search for clues to the etiology of degenerative disease by epidemiological methods. The Council is aiding in the development of such computer techniques and their application experimentally to certain bodies of data that have been collected in its sponsored projects. There is also a great need for studies that will show how the many other 7
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habits and practices of life tend to be associated with smoking or nonsmoking. Only as we develop a picture of how smokers and nonsmokers differ in such ways, will it become possible to distinguish between possible effects of smok- ing per se and the effects of other associated habits in the causation or aggra- vation of the various constitutional diseases. In this kind of research also, computer techniques for multivariate analysis should be very helpful and time-saving. Cancer of the Lung In a sense, lung cancer carries a particular emphasis in tobacco and health investigations because of the reputed "strength" of its association with cigarette smoking on monofactorial epidemiological studies. Another reason is the rate at which this disease is reported to have increased in incidence within recent decades. Trends in Incidence It is certain that the rate of increase reported for this disease during recent decades has been exaggerated considerably by the progressively in- creasing skill of clinicians in diagnosis. A number of autopsy studies have shown that whereas lung carcinoma was missed clinically as often as nine times out of ten early in this century, it is presently diagnosed clinically in eighty to ninety percent of cases. Indeed, there are indications now that gen- eral awareness of the disease is leading to overdiagnosis. Even so, in spite of the fact that diagnosis has approached a high level of efficiency, the curves of reported incidence have begun to show signs of approaching a plateau rather than a continuing steep increase. Classification of Lung Tumors _ _ Human lung cancer tissues, still living after surgical removal, are now being observed with respect to their behavior in standardized culture media. Such wide behavioral differences are being seen in a single medium as to suggest that there are many more different types and probably more different causes than previously suspected from the classification of fixed and stained sections on the basis of appearance. - 50004 0744 Cell and Tissue Culture Conference A conference that placed special emphasis upon the histopathological changes induced in cells and tissue cultures by carcinogenic and other agents 8 IL
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in vitro, was held March 6, 1967. In addition to staff and members of the Scientific Advisory Board, the following investigators participated: T. TIMOTHY CROCKER, M.D., Professor of Medicine, Department of Internal Medicine, University of California Medical Center, San Francisco, California. LEILA DIAMOND, Ph.D., The Wistar Institute, Philadelphia, Penn- sylvania. BERLE J. NIELSEN, A.B., Associate Specialist (Oncology), Cancer Research Institute, University of California Medical Center, San Francisco, California. DONALD M. PACE, Ph.D., Director of Cellular Research, Depart- ment of Physiology and Pharmacology, University of the Pacific, Stockton, California. RUSSELL P. SHERWIN, M.D., Hastings Associate Professor of Path- ology, University of Southern California School of Medicine, Los Angeles, California. BARBARA K. WATSON, Ph.D., Assistant Bacteriologist, Massachu- setts General Hospital, Boston, Massachusetts. CHARITY WAYMOUTH, Ph.D., Senior Staff Scientist, The Jackson Laboratory, Bar Harbor, Maine. Cell and tissue culture studies hope for the in vitro production and anal- ysis of such histopathological changes as are observed in the lungs of animals subjected to controlled exposures to various agents. Subsequent direct obser- vations of the proliferative capacities of such tissues when replanted into the host animal may help relate microscopic appearance to tissue behavior. Studies with Cigarette Smoke Condensates Experiments involving the painting of mouse-skins with cigarette smoke condensates (often erroneously called "tars") have been the chief basis for the view of some investigators that cigarette smoke is to be regarded as a contact carcinogen for the human lung. However, the relevance of such ob- servations to the problem of human lung is questionable. First of all, there are great differences between rodents and primates (monkeys and man) in sus- ceptibility to known carcinogens. Secondly, the skin is a very different tissue from the lung and shows very different responses to various irritating agents. Thirdly, condensates of smoke collected by passing smoke through cold traps at very low temperatures, such as -80° centigrade, are not equivalent in either physical or chemical properties to whole smoke. Chemical and physical changes occur in smoke, some rapidly, following its formation in the burning zone and these continue in the condensate after collection. Moreover, such 9
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condensates lack all the gaseous components of smoke and some of the vapors that are not condensed or that evaporate after collection. The physical states of whole smoke and of condensate are obviously quite different. Finally, cer- tain smoke constituents are disproportionately concentrated in the condensate. Whole Smoke Mhalation The controlled inhalation of whole fresh cigarette smoke by experimental animals seems to come much closer to the ideal of bringing the right material, in the right form and right concentration into contact with the right organ, even though the wrong animal must still be employed. Numerous inhalation studies were undertaken by many investigators in the early days following publication of the reports linking cigarette smoking to lung cancer. These added up to an impressive failure insofar as the appear- ance of lung cancers was concerned. Little account of this effort has been described in print, so that the extent of the work is relatively unknown today. The Council has continued to sponsor such studies with effort toward improvement of techniques. These are now approaching the point where a more comprehensive program can be developed. Among the many other factors which need extensive study are: Predisposing factors in lung cancer. Animal models for lung carcinogenesis. ~, Lung clearance phenomena. o ~ r The Cardiovascular Diseases o q Atherosclerosis a There is broad agreement that the process of atherosclerosis tends_ in__ general to predispose to ischemic diseases of the heart and blood vessels. This gradual thickening and degeneration of the vessel walls occurs in all persons but at widely different rates. A nuniber of different kinds of evidence have combined to suggest that nicotine or smoking do not contribute toward any acceleration of this process: (1) the fact that these diseases are not appre- ciably more frequent among pipe and cigar smokers than among nonsmokers, (2) the inconclusive results in animal studies where nicotine was added to an atherogenic diet, (3) the occurrence of angina pectoris no more often in smokers than in nonsmokers, and (4) post nzortem studies showing no sig- nificantly increased prevalence of infarctions of the heart among smokers. One recently reported post morlem study has, on the contrary, found 10
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some relation between thickening of arterial walls and cigarette smoking history. Nevertheless, since so many other habits and practices of life tend to cluster with smoking, it cannot be concluded that the smoking per se was responsible. Further study of these life patterns, or new and better animal studies as well as suitably controlled twin studies, may help to bring a definite solution. Smoking and Hypertension There is little evidence that smoking causes chronic hypertension (i.e., high blood pressure). Although smoking ordinarily causes a small rise in blood pressure of a few minutes duration, many studies show the resting blood pressures of habitual smokers to be lower generally than those of non- smokers. Nicotine and Smoking in Relation to Blood Flow A number of studies have shown that nicotine or smoking tend to in- crease the flow of blood in most of the vascular beds including those of the heart, brain and skeletal muscle. An exception is blood flow in the skin of the extremities. Pharmacology o f Nicotine There is a vast literature on the pharmacology of nicotine and Council projects have added a great deal to it. Though many transient effects have been more fully described and measured in our program, no evidence has emerged of any significant contribution by nicotine, at the levels smokers receive, to causation, aggravation or precipitation of any cardiovascular dis- ease that contributes significantly to mortality. Chronic Pulmonary Diseases Chronic and progressive diseases of the lung, such as bronchitis, asthma and emphysema are attracting increasing attention as causes of disability and death. Clinicians report that such ailments are being seen more frequently and they are appearing more often on death certificates as causes of death. The rise in chronic and progressive pulmonary diseases has been at- tributed in part to the now frequent cure of acute lung infections by anti- biotics so that more people with damaged or susceptible lungs are alive today than formerly. Also, as has been pointed out, the component of older people in the total population is greater than ever before in history. In this age group, and especially in males, these diseases are most frequent. 11
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In this area, the statistics are even more confused and of more dubious accuracy than they are in the case of cancer or cardiovascular diseases, by reason of problems of diagnosis and nomenclature. The term "emphysema" has anatomical definitions and the pathologist uses the term to describe con- ditions that can be recognized under the microscope, classified as to type and estimated in extent. The general practitioner, however, has come to use the term as practically synonymous with a clinical report of difficulty in breathing. There is an abundant testimony that persons diagnosed clinically as having severe "emphysema" often show little or none anatomically, when examined post mortem. Conversely, patients who have had little breathing trouble in life may show extensive anatomical emphysema at autopsy. In view of such variances in definition and diagnosis, statements con- cerning the extent to which "emphysema" has increased over any given period as a cause of death have limited meaning. Conference on Allergic and Immunological Aspects of Smoking A conference on allergic and immunological aspects of tobacco smoking was held on March 3, 1967. In addition to staff and members of the Scien- tific Advisory Board, the following investigators participated: HARRY S. BERNTON, M.D., Attending Allergist, Providence Hos- pital, Washington, D.C. RICHARD S. FARR, M.D., Head, Division of Allergy, Immunology and Rheumatology, Scripps Clinic and Research Foundation, La Jolla, California. PAUL GOLDHABER, D.D.S., Associate Professor of Periodontology, Harvard School of Dental Medicine, Boston, Massachusetts. DAVID W. TALMAGE, M.D., Professor of Microbiology and Asso- ciate Dean, University of Colorado Schnnl of Medicine, Denver, ~ Colorado. 50094 07uR - Nicotine and th.e (..eitr,rat 1`'ervou-s Syst.em There is a recurring question as to whether certain kinds of people ~ especially need or want to smoke under the conditions of modern life because' of a special need for relief of tension. Is there any evidence that such relief is ~ actually provided by smoking? In the past, dependence has had to be placed largely upon the subjec- tive statements of smokers as to why they like or need to smoke. Among the recurring reports are such as these: (1) "It gives me pleasure," (2) "It gives me a pickup and helps me get going," (3) "It helps me relax when I am tense." 12
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Such statements raise the questions whether evidence to check their import could be provided by any experimental method. Some answers may perhaps be furnished by psychological investigations and any promising approaches along such lines should be encouraged. Another approach is through the methods of psycho-pharmacology, a relatively new field of science. By the study of electroencephalograms it has been shown that, both in animals and man, nicotine has a brief stimulatory or "arousal" effect on the brain, especially when this was originally in a state of what might be called repose. When the brain is in the kind of state associated with agitation, nico- tine has an effect on brain waves resembling that of some of the tranquilizers. Thus psychopharmacology is providing some scientific substantiation for the seemingly contradictory subjective testimony of smokers. Nicotine may both arouse the lethargic and calm the agitated. Since direct electrical stimulation of certain parts of the brain produces an effect that is pleasurable, animal studies are being made to determine whether nicotine also stimulates the pleasure centers. Techniques that permit monkeys to inject themselves with nicotine at will, not only show that they find this agreeable, but are shedding light on the effects of environmental conditions on the amounts the animals will take spontaneously. In no case has any of the animals done damage to itself by such unrestricted self-administration. Several studies have also explored the effects of nicotine on the learning process in rats, using various rewards to stimulate the animals to learn their way through a maze, press levers in some pattern or avoid an electric shock by jumping to a wooden pole on signal. Several such experiments show that nicotine stimulates the learning process, more particularly among the animals that are originally relatively slow learners. Oral Cavi-ty Research The oral cavity is subjected to direct contact with smoke derived from pipes, cigars and cigarettes more quickly and in greater concentrations than the lungs. Despite this, the incidence of cancer of the oral cavity has shown no significant increase in amount, or incidence at an earlier age, during the decades in which per capita exposure to cigarette smoke has risen greatly. It is important to find the explanation for this fact. As reported elsewhere, Council studies have shown that the oral tissues of mice are far more resistant to certain carcinogens than are their skins. In mice, liver damage considerably increases the susceptibility of the oral tissues to certain recognized carcinogenic substances, but painting of 13
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cigarette smoke condensates inside the mouths of liver-damaged mice has not been followed by appearance of any tumors. Much more study of the oral cavity is recommended by the fact that it resembles the lung more than does the skin, yet is relatively accessible. Since the saliva, oral structures and especially the oral leucocytes also serve as a first line of defense against external agents entering the body, they merit attention in their own right. The effects of in vivo and in vitro exposure of oral leucocytes to whole smoke and to smoke constituents are being studied in recently inaugurated Council projects. vti 0 0 ~ r 0 14 J O t
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Abstracts of Reports Each recipient of a grant-in-aid from The Council for Tobacco Re- search - U.S.A. is responsible for the initial presentation or publication of the results of his research at scientific meetings or in appropriate scientific journals. Following are abstracts, approved by the authors, of reports on new experimental research acknowledging support from The Council that have appeared in scientific journals since publication of the 1965-66 Report of the Scientific Director. These abstracts have been grouped under the following headings: I. Psycho-Physiological Studies, II. Cardiovascular Studies, III. Carcino- genesis Studies, IV. Studies at the Cellular Level, V. Epidemiology, VI. Pul- monary Physiology, VII. Neurophysiology, VIII. Chemistry and Biochem- istry, IX. Pharmacology and Psycho-Pharmacology, X. Pregnancy Studies, and XI. Other Studies. A number of grantees of The Council for Tobacco Research - U.S.A. participated in The Third Perugia Quadrennial International Conference on Cancer held at the University of Perugia, June 24-29, 1965. "Lung Tumours In Animals," the proceedings of this conference, was published in June, 1966, by the Division of Cancer Research, Perugia, Italy. Grantee contributions to the conference are as follows: "EPIDEMIOLOGIC STUDIES OF LUNG CANCER IN DOGS," by D. Cohen, J. S. Reif and W. H. Rhodes. "THE ROLE OF INFLUENZA VIRUS IN THE DEVELOPMENT OF MALIGNANT TRANSFORMATION IN VITRO AND IN THE RES- PIRATORY TRACT OF MICE, WITH AND WITHOUT EXPOSURE TO CIGARETTE SMOKE," by C. Leuchtenberger and R. Leuchtenberger. "THE RELATIVE EFFECTS OF SOME AIR POLLUTANTS ON THE HUMAN RESPIRATORY EPITHELIUM," by W. H. Carnes and L. E. Moses. "EFFECTS OF INTRAVENOUS CARCINOGEN AND TOBACCO CONDENSATE INJECTIONS UPON THE INCIDENCE OF LUNG TUMORS IN A/He MICE," by F. Homburger and A. Treger. "TUMORS PRODUCED BY METHYLCHOLANTHRENE 1N THE RESPIRATORY TRACT OF THE WHITE PEKIN DUCK," by R. H. Rigdon. 15 ®
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I. Psycho•Physiologicat Studies ! "BIOLOGICAL ASPECTS OF GUSTATION." By Arnold R. Kaplan, PhD, Laboratory of Medical Genetics, Cleveland Psychiatric Institute, Ohio. "Mutation in Population: Proceedings of a Symposium held in Prague in August 9-11, 1965," pp 146-153, Czechoslovak Academy of Sciences, Prague, 1966. This paper presents a survey and summation of early and recent studies of taste sensitivity. Differences in taste thresholds have been found to be related to many factors, including medication, phases of the menstrual cycle, pregnancy, smoking habits, occurrence of duodenal (vs. gastric) u1cer, and dietary preferences. Tests in monozygotic and dizygotic twins and in sibling pairs indicate that genetic factors are involved in taste thresholds. Other grantor: National Institutes of Health. "STUDIES IN TASTE ACUITY." By Arnold R. Kaplan, PhD, Laboratory of Medical Genetics, Cleveland Psychiatric Institute, Ohio. Technical Quarterly 4/2:138-144, April-June 1967. Intrapair threshold differences for hydrochloric acid, L-quinine sulfate, and PROP (6-n-propylthiouracil) were investigated in pairs of one-egg twins, two-egg twins, and non-twin siblings. There were no significant differ- ences in intrapair variations between the two-egg twin pairs and the non-twin siblings. There were, also, no significant differences between the one-egg and two-egg twin pairs for hydrochloric acid and quinine, but there was a very significant difference for PROP. Therefore, the involvement of genetic factors in etiology of taste threshold was not demonstrated for sour-tasting hydrochloric acid or for bitter-tasting quinine, but was emphatically demon- strated for bitter-tasting PROP. Sensitive tasters of quinine and PROP indicated relatively large numbers of food dislikes and preference for relatively mild-tasting foods, compared to insensitive tasters, who indicated relatively few dislikes and preference for more strongly-tasting preparations. The sensitive tasters included a t`ela=-- tively high proportion of nonsmokers, compared to the insensitive tasters, who included a relatively high proportion of heavy smokers. Taste threshold was not found to be related to age or to sex when the data were controlled for differences in smoking habits. The heavy smokers, however, showed de- creased taste sensitivity associated with increased age. Other factors influencing taste sensitivity include phases of the men- strual cycle and ulcer pathology. Other grantor: National Institutes of Health. 50C)94 fl~,~? "ORALITY, IMPULSIVITY AND CIGARETTE SMOKING tr, MEN: FURTHER FINDINGS IN SUPPORT OF A THEORY." By Martin A. Jacobs, PhD, Luleen S. Anderson, PhD, Emily Champagne, MD, Nathaniel 16
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Karush, MD, Stephen J. Richman, MD, and Peter H. Knapp, MD, Division of Psychiatry, Boston University School of Medicine, Massachusetts. The Journal of Nervous and Mental Disease 143/3:207-219, 1966. (Grantee: Knapp) 76 college students and 58 industrial workers, average age 26 years, served as subjects in this third of three studies designed to test the hypothesis that heavy cigarette smoking in men reflects part of a pattern of underlying oral craving defended against by active, impulsive behavior. The paid vol- unteer subjects in this study took part in personal interviews after which they filled out a Parent-Child Questionnaire (PCQ), a personality inven- tory (BUPI), and a form specially designed to directly test response-set and social desirability. Volunteers in the previous investigations were unpaid and impersonally sent the completed forms by mail. The first two studies revealed significant differences between smokers and nonsmokers in the parental concepts of maternal control, coldness and harshness, and in self-descriptions of defiance, impetuousness, thrill-and danger-seeking, neurotic emotional lability, and oral preoccupations. In the last study, statistical comparison of mean scores for 54 cigarette smokers and 80 current nonsmokers supported the previous findings with the exception of the maternal malevolence concept. On an individual prediction basis, overall 62.7 percent of the sample was correctly designated as either smokers or nonsmokers using this psy- chologic measure alone (chi square = 9.45, 1 df, P <.01). Presumably other factors, such as sociologic and physiologic, enter into the determina- tion of who will become a cigarette smoker and continue with the habit, but this theory seems significantly related to this outcome and accounts for an important portion of the variance. "AN ATLAS OF FIGURE DRAWINGS: STUDIES ON THE PSYCHO- LOGICAL CHARACTERISTICS OF MEDICAL STUDENTS - Ill." By Caroline Bedell Thomas, MD, Johns Hopkins University School of Medicine, Baltimore, Maryland. Published by the Johns Hopkins Press, 1966. This third volume in the series, Studies on the Psychological Character- istics of Medical Students, presents the only compendium of figure drawings by healthy subjects to be found in the psychological literature. The figures in this volume were all drawn by 870 Johns Hopkins med- ical students who were participants in the long-term study of the Precursors of Hypertension and Coronary Disease. Drawings in this atlas are graded by degree of sophistication, and within such a grouping are arranged accord- ing to different parental histories in regard to coronary disease and hyper- tension, stroke, diabetes and obesity. Smoking habits and various other factors are also given, and a Strong Vocational Interest Test is included for each subject. Thus, this Atlas provides a definitive denominator for figure- drawing studies involving healthy young adults of superior Intelligence. Other grantors: Veterans Administration and the National Heart Institute. 17
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II. Cardiovascular Studies "INFLUENCE OF ANTIARRHYTHMIC AGENTS ON MY,OCARDIAL CONTRACTILITY." By E. T. Angelakos, MD, PhD, Department of Physi- ology, Boston University School of Medicine, Massachusetts. "Mechanisms and Therapy of Cardiac Arrhythmias," 14th Hahnemann Symposium, Phila- delphia, Apri126-29, 1965. Published by Grune & Stratton, 1966. , The ultimate therapeutic aim in the suppression of arrhythmias with an antiarrhythmic agent is to improve cardiac dynamics. If this aim is to be served, it is essential to know any direct effects that antiarrhythmic agents may have on myocardial contraction. Tests with the classical antiarrhythmics quinidine and procaineamide, and with the newer antazoline, all showed a distinct depression of myocardial tension. This depression of contractility seems to be a direct effect of the drugs on the myocardium. • Various mechanisms are proposed which could account for this de- pressant effect. However, the fundamental mechanisms which are actually responsible for the effect have not been identified. Practically all antiar- rhythmics (when given in sufficient doses and studied with appropriate technics), have been shown to have a myocardial depressant effect. At present it is not clear whether this property is inherent in antiarrhythmic activity or is a "side effect" related to similarities in the chemical moieties responsible for each action. In either case, since high pharmacologic speci- ficity is most desirable from a therapeutic point of view, the search must continue for the development of more active, more specific and less de- pressant antiarrhythmic agents. Other grantors: National Science Foundation and the U. S. Public Health Service. "ADRENERGIC EFFECTS OF NICOTINE ON CORONARY BLOOD FLOW AND BLOOD LIPIDS." By Samuel Bellet, MD, Division of Cardiology, Philadelphia General Hospital, Pennsylvania. Chapter IX (pp 74-84) in "Prevention of Ischemic Heart Disease," W. Raab, editor, Charles C. Thomas, Springfield, Illinois, 1966. The effects of nicotine and tobacco smoke on certain physiologic parameters, namely coronary blood flow and blood lipids, are discussed in this paper. Experiments with dogs showed that the nicotine-induced augmentation of coronary blood flow was considerably less marked in animals with artifi- cially-produced coronary insufficiency than in corresponding controls. Electrocardiographic changes were noted, and the response of other param- eters, such as cardiac output, oxygen consumption and coronary a-v differ- ence was also altered. These findings would appear td have a bearing on the clinical problem relative to the effect of nicotine and of nicotine-liberated catecholamines in human subjects with established coronary artery disease. 18
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A rapid and consistent rise in serum free-fatty acids was produced by nicotine in dogs and smoking in humans. Patients with myocardial infarction developed an elevation more than twice that of normal subjects and non- coronary patients. Other grantors: National Institutes of Health and the Foundation for Car- diovascular Research. "DIFFERENCES IN EFFECTS OF CIGAR AND CIGARETTE SMOK- ING ON FREE FATTY ACID MOBILIZATION AND CATECHOLA- MINE EXCRETION." By Alfred Kershbaum, MD, Samuel Bellet, MD, Jose Jiminez, MD, and Leonard J. Feinberg, PhD, Division of Cardiology, Philadelphia General Hospital, Pennsylvania. Journal of the American Medical Association 195/13:1095-1098, March 28, 1966. (Grantee: Bellet) In experiments conducted among 43 normal male subjects who were habitual moderate or heavy smokers of either cigars or cigarettes, the com- parative effect of cigar and cigarette smoking on free fatty acid (FFA) mobilization and catecholamine excretion was observed and the influence of inhaling and differences in absorption of smoke contents was determined. Results showed that there was a greater increase in FFA concentration in the serum with cigarette than with cigar smoking. Inhaling during smoking caused a greater FFA response than not inhaling, with both cigars and cigar- ettes. With tobacco containing glucose randomly labeled with radioactive carbon ("C), there was a greater absorption of '*C with cigarette smoking. Excretion of catecholamines followed the same pattern. The differences observed with the two forms of smoking probably result from the tendency to inhale with cigarette and not with cigar smoking and from the effect of this on nicotine absorption. Other grantora: American Medical Association Education and Research Foundation and the National Institutes of Health. "MODIFICATION OF NICOTINE-INDUCED HYPERLIPIDEMIA BY ANTIADRENERGIC AGENTS." By Alfred Kershbaum, MD, Jose Jimenez, MD, Samuel Bellet, MD, and D. Zanuttini, Division of Cardiology, Philadelphia General Hospital, Pennsylvania. Journal of Atherosclerosis Research 6:524-530, Nov.-Dec. 1966. (Grantee: Bellet) In an attempt to elucidate the role of sympathetic and catecholamine activity in the alteration of plasma free fatty acid levels, the effect of a Q-adrenergic receptor blocking agent (nethalide), an a-receptor blocking agent (phenoxybenzamine), and a central suppressor of adrenergic activity (chlorpromazine) on the lipid response to nicotine was studied in anesthe- tized dogs. Nicotine alone, in control experiments in 28 dogs, gave a maximal rise in FFA concentration of 34±4%. When the drugs were given without nico- 19
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tine to determine their intrinsic effect on serum FFA concentrations, netha- lide and phenoxybenzamine produced a significant rise in FFA levels whereas chlorpromazine had no significant effect. After nethalide, there was a signifi- cant suppression of the FFA response to nicotine. The other compounds did not affect the nicotine-induced FFA response. Nicotine caused a rise in serum triglyceride levels in eight dogs which was diminished by pre-treatment with nethalide. The results of these experiments emphasize the role of the sympatho- adrenal system in the hyperlipidemic effects of nicotine and suggest they are mediated by P-adrenergic receptors. Other grantors: National Institutes of Health and the U. S. Public Health Service. "SMOKING AS A FACTOR IN ATHEROSCLEROSIS: A REVIEW OF EPIDEMIOLOGICAL, PATHOLOGICAL, AND EXPERIMENTAL STUDIES." By Alfred Kershbaum, MD, and Samuel Bellet, MD, Division of Cardiology, Philadelphia General Hospital, Pennsylvania. Geriatrics 21/12:155-170, December 1966. (Grantee: Bellet) The role of tobacco smoking in the genesis and development of athero- sclerosis is examined by reviewing epidemiological, pathological and experi- mental studies. Outstanding among the findings in this investigation are the following: 1. Epidemiological studies have shown, with little contradictory evi- dence, a significant association between cigarette smoking and the morbidity and mortality of coronary heart disease. 2. Pathological studies of the coronary arteries in consecutive routine autopsies showed an association between cigarette smoking and the severity of coronary atherosclerosis. 3. The relatively few studies of the effect of nicotine on experimental atherosclerosis have shown inconsistent results. There is need for more investigation of this problem, using newer techniques and other species. Recently, much has been learned concerning the effect of smoking and nicotine on various metabolic, hematologic, hormonal, and circulatory proc- esses involved in atherogenesis. Some of these biological effects could con- tribute to the initiation and progression of atherosclerosis. Other grantors: American Medical Association Education and Research Foundation and the National Institutes of Health. "A NEW DIAGNOSTIC TEST FOR CORONARY ARTERY DISEASE." By Alberto Cohen, MD, Eide-Ditmar Lubs, MD, Edward J. Zaleski, MD, and Richard J. Bing, MD, Wayne State University School of Medicine, Detroit, Mich. Minnesota Medicine 49/1:17-21, January 1966. (Grantee: Bing) The diagnostic procedure here differentiates rapidly between the estab- lished findings that nitroglycerin increases coronary blood flow in normal 20
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individuals but not in patients with coronary artery disease, by the use of a positron emitter and a coincidence counting system. The test is technically simple and objective, and is made without catheterization, involving only intravenous infusion of rubidiume' and an arterial puncture to draw blood through the counter. The data are then processed by computer, which calcu- lates blood flow in ml/min, together with the standard deviations and the significance of the change in flow prior to and following the sublingual ad- ministration of nitroglycerin. It permits differentiation of patients with and without coronary artery disease with a reasonable degree of accuracy. Other grantors: U. S. Public Health Service, the John A. Hartford Founda- tion, and the American Medical Association - Education and Research Foundation. "ACUTE EFFECTS OF ALCOHOL ON THE HUMAN' MYOCAR- DIUM." By V. E. Wendt, R. Aljuni, T. A. Bruce, A. S. Prasad and Richard J. Bing. American Journal of Cardiology 17/6:804-812, June 1966. The effect of acute alcohol ingestion.(6 oz of 84 proof Vodka) was studied in 11 patients with a known history of chronic alcoholism. None had any evidence of vitamin deficiency nor of heart or liver disease. No significant changes appeared in pulse rate, blood pressure, cardiac output, stroke volume, arterial venous oxygen extraction or respiratory quotient. Despite the lack of these hemodynamic alterations, flattened and inverted T waves occurred in the electrocardiograms of two patients 30 minutes after the ingestion of alcohol. The significant metabolic findings included a rise in blood lactate, a decline in arterial pyruvate, a marked fall in blood glucose, a decline in free fatty acids and a rise in triglycerides one half hour after the ingestion of alcohol. Zinc was liberated by the heart in the majority of patients, and serum alcoholic dehydrogenase activity closely followed that of blood zinc. Phos- pholipid blood levels remained unchanged. It is suggested that repeated exposure to acute alcoholism could result in permanent alterations in myo- cardial metabolism which could lead to the development of irreversible alcoholic cardiomyopathy. Other grantors: U. S. Public Health Service, American Heart Association, Michigan Heart Association, Life Insurance Medical Research Fund, Bur- roughs Wellcome Fund, the John A. Hartford Foundation and the Heublein Company. "STIMULATION OF REPARATIVE PROCESSES FOLLOWING EX- PERIMENTAL MYOCARDIAL INFARCTION." By S. Gudbjarnason, John C. Fenton, Paul L. Wolf and Richard J. Bing. Archives of Internal Medicine 118/1:33-46, July 1966. The reparative processes in cardiac muscle following experimental myocardial infarction produced in dogs by ligation of thecoronary arteries were stimulated with anabolic hormones. Treatment with insulin increased the incorporation of glycine-2"C into protein of infarcted tissue by 94%, 21
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treatment with bovine growth hormone raised the incorporation by 168%, and treatment with both insulin and growth hormone raised the incorpora- tion by 251%, all within 24 hours of treatment. Treatment with an intravenous infusion of glucose, insulin, KCI, coenzymes and vitamins increased protein_synthesis in infarcted muscle 7 hours after infarction by-173%; repeated infusion led to a further rise within 24 hours after infarction. Ascorbic acid increased protein synthesis in the center of infarcted area by 122% and the anabolic steroid methandro- stenolone augmented incorporation into the center of infarct by 249%. Long-term treatment with insulin or the anabolic steroid prevented development of aneurysm, whereas animals fed a protein-free diet had a significantly thinner scar and frequent development of aneurysm. It should be reemphasized that the biochemical demonstration of protein synthesis in the infarcted myocardium does not imply synthesis of protein by necrotic heart muscle, but is due to fibroblastic proliferation in the injured area. Other grantors: U.S. Public Health Service (2), the John A. Hartford Foundation, Michigan Heart Association, and the American Medical Asso- ciation Education and Research Foundation. Other papers published by Dr. Bing and associates since the 1965-66 Report of the Scientific Director, with credit for support by The Council for Tobacco Research - U.S.A., follow. Other grantors are noted between parentheses. "THE METABOLISM OF THE HEART IN FAILURE." By S. Gudbjarn- ason and R. J. Bing. Acta Cardiologica 20/5:377-380, 1965. (PHS, MCHA, LIMRF, BWF, AMA-ERF and JAHF) "METABOLIC FACTORS IN THE CONTROL OF CARDIAC OUT- PUT." By V. E. Wendt, C. Wu, R. Balcon and R. J. Bing. Chapter in "Shock and Hypotension," publ. 1965, Grune & Stratton. (PHS, AHA, MCHA, LIMRF, BWF, JAHF) "CIRCULATORY CHANGES FOLLOWING MYOCARDIAL INFARC- TION." By V. E. Wendt, R. Balcon, J. Ribeilima and R. J. Bing. Chapter in "Shock and Hypotension," publ. 1965, Grune & Stratton. (PHS, AHA, MCHA, LIMRF, BWF, JAHF) "METABOLISM OF THE HEART IN FAILURE." By John C. Fenton, Sigmundur Gudbjarnason and Richard J. Bing. American Heart Association Monograph No. 1, Second Edition, April 1966:32-48. (PHS, MCHA, LIMRF, BWF, AMA-ERF, JAHF) "HYPOXIA IN THE GENESIS OF CARDIAC ARRHYTHMIAS." By John C. Fenton, S. Gudbjarnason and Richard J. Bing. from "Mechanisms and Therapy of Cardiac Arrhythmias," 14th Hahnemann Symposium, publ. 1966, Grune & Stratton: 58-63. (PHS, MCHA, BWF, ACS, AMA-ERF, JAHF ) 22
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"CAPILLARIES IN HEART AND SKELETAL MUSCLE OF DOG AND RABBIT." By K. Rakusan and W. du Mesnil de Rochemont. (Grantee: R,1, Bing). Proceedings of the Society for Experimental Biology and Medi- j~HRCj 3:838-840, March 1967. (PHS, JAHF, MCHA, AMA-ERF, ,,L'PFECTS OF ALPHA-METHYLDOPA ON THE MYOCARDIAL HLOOD FLOW, UTILIZING THE COINCIDENCE COUNTING wILTHOD. By Alberto Cohen, J. S. Maxmen, M. Ragheb, H. Baleiron, F;, J. Zaleski and R. J. Bing. Journal of Clinical Pharmacology and Journal ,VJ New Drugs 7/2:77-83, March-April 1967. (MSDRL, PHS, DGHRC) ,,IvIEASUREMENT OF THE SHORTENING OF CARDIAC FIBERS IN MAN." By Richard G. Madeira, Wolfgang du Mesnil de Rochemont, Charles W. Gadd, Thomas B. Stock and Richard J. Bing. American Journal 0J Cardlology 19/5:686-691, May 1967. (MCHA, DGHRC) --PERSISTENCE OF REFLEX SYMPATHETIC NERVOUS SYSTEM ACTIVITY IN MAN ON GUANETHIDINE OR RESERPINE." By Jay 1). Coffman, MD, Department of Medicine, Boston University Medical C'enter, Massachusetts. Circulation 35/2:339-346, February 1967. The effect of oral guanethidine or reserpine on the reflex vasoconstric- tion in the calf and foot resulting from a prolonged, generalized sympathetic stimulus (body cooling) was studied in 12 normal subjects. Large daily clinical-doses of guanethidine or reserpine were given for 2 and 3 weeks, respcctivcly. Foot and calf blood flows were measured by venous-occlusion, water plethysmography. Two control studies were performed on each sub- jcct, one before and another long after administration of the drug. Body cooling produced significant decreases in calf and foot blood flow and increases in vascular resistance in both control studies. Subjects evidenced drug effects by a significant decrease in pulse rate, postural hypo- tension, hypotension following exercise, and blockade or attentuation of thc Valsalva maneuver "overshoot." The attenuation of the sympathetic ncrvous-system vasoconstrictor reflex to general body cooling was not statis- tically significant. Since large clinical doses of guanethidine or reserpine administered orally for 2 or 3 weeks, respectively, did not inhibit the reflex vasoconstrictor effect of total body cooling, functional sympathetic neurotransmitter sub- stance cannot be said to be absent. Other grantor: National Institutes of Health. "REAPPRAISAL OF PHYSIOLOGIC PRINCIPLES IN THE TREAT- MENT OF ISCHEMIC HEART DISEASE." By Cecil E. Cross and Peter I,,. Salisbury, MD, Departments of Medical Research and Medicine, St. Joseph Hospital, Burbank, California. Internal Medicine Digest 1:29-39, February 1966. (Grantee: Cross) 23
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A course of treatment of ischemic heart disease based upon the main- tenance of blood pressure at the lowest level compatible with normal function of the patient's vital organs is presented in this paper. The recommended treatment is formulated upon a review of the current status of knowledge of the coronary circulation, consideration of recent discoveries and a reap- praisal of the physiological principles involved in acute, severe coronary disease. • In order to understand the important physiologic mechanisms involved, studies were undertaken of the interaction of coronary pressures and flows with the function of the heart. When coronary blood flow was measured in anesthetized dogs, the resistance of the coronary vessels remained constant within the "normal" range of cardiac outputs and of blood pressures. The coronary vessels did not dilate when the work of the heart increased nor did they constrict when the work of the heart decreased. Active coronary vessel constriction or dilation was observed only when highly abnormal states of the circulation (for example, intentionally produced high pressure in the aorta) were present. The physiologic observations and clinical measures noted here suggest the possibility of a future increase in the survival rate in ischemic heart disease. . Other grantors: National Heart Institute, U. S. Public Health Service and the Life Insurance Medical Research Fund. "COMPLICATIONS OF ATHEROMATOUS PLAQUES." By Ira Gore, MD, Department of Pathology, Boston University Medical Center, Massa- chusetts. Acta Cardiologica XI:89-108, 1966. In this review paper, the complications of atheromatous plaques, namely, thromboses, hemorrhage, aneurysms, ulceration, embolization and calcifi- cation, are considered in light of their relationship to the atherosclerotic process. . Studies of coagulation and platelet utilization cited in this review favor the concept that atherogenesis and occlusive thrombosis complicating intimal disease are both related to a common coagulative disturbance. A focal loss of the normal acid mucopolysaccharide determined anticoagulant properties of the intima, which is produced by the atherosclerotic process, complements the action of systemic influences in facilitating thrombotic complications. Localization of plaques, at least those formed by thrombotic deposits, is dependent upon the hydraulics of blood flow. Hemorrhage from thin-walled intimal capillaries appears to be an early event in atherogenesis, just as atheromatous ulceration, embolism, aneurysm and calcification appear, for various reasons, to be dependent upon the growth and extent of atheroscle- rotic plaques. Other grantor: National Heart Institute. "FIBRINOLYTIC ACTIVITY OF THE ENDOTHI;LIUM." By Takao Fujinami, MD, and Ira Gore, MD, Department of Pathology, University
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Hospital, Boston University Medical Center, Massachusetts. Japanese Cir- culation Journal 31/2:267-273, February 1967. (Grantee: Gore) Chemical and histological methods were used to study the fibrinolytic activity of the endothelium of blood vessels in guinea pigs, rats and rabbits. Fibrinolytic activity was demonstrated in rats and guinea pigs but not in the rabbit, which is the most susceptible animal to experimental atherosclerosis. The observed lytic activity might have been due to plasmin activator from the vessels, since the endothelium did not show any activity with heated fibrin. Activity was weak in the proximal aorta (which is the prevalent area for atherosclerosis in rodents), and became progressively stronger down the length of the aorta. The strongest activity was observed in the inferior vena cava. These findings suggest that fibrinolytic activity of the endothelium may be one of the important intrinsic factors in atherogenesis. Other grantor: National Heart Institute. "INHIBITION OF DIETARY ATHEROSCLEROSIS IN RABBITS BY NORETHYNODREL." By Ira Gore, Y. Iwanaga and Hazel Gore, Boston University Medical Center. Journal of Atherosclerosis Research 7:361-366, 1967. Norethynodrel administered to rabbits reduces the atherogenicity of a cholesterol diet in part through its effect on serum cholesterol. There is an increase of the aortic acid mucopolysaccharides of the treated animals, an observation which contradicts the theory that such accumulations predis- pose to the occurrence and localization of lipid deposits. Other grantor: National Heart Institute. "AN UNUSUAL VENOCONSTRICTION INDUCED BY ACETYL- CHOLINE." By A. J. Rice and J. P. Long, PhD, Department of Pharma- cology, College of Medicine, University of Iowa, Iowa City. The Journal of Pharmacology and Experimental Therapeutics 151/3:423-429, March 1966. (Grantee: Long) "LOCALIZATION OF VENOCONSTRICTOR RESPONSES." By A. J. Rice, C. R. Leeson and J. P. Long, PhD, Departments of Pharmacology and Anatomy, College of Medicine, University of Iowa, Iowa City. The Journal of Pharmacology and Experimental Therapeutics 154/3:539-545, Decem- ber 1966. (Grantee: Long) Experimental observation of an unusual drug-induced venoconstric- tion, made while studying the mechanism of venoconstriction produced by acetylcholine (ACh), stimulated an investigation of the site of these veno- constrictor responses. Details of these studies of the mechanism of venocon- striction are given in the present papers. In experiments designed to study the in vivo effect of ACh on the acces- sory cephalic vein of the dog,,it was noted that injections of high doses of ACh directly into the perfused vein produced a marked rise in perfusion pressure. The site of this ACh-induced venoconstriction was localized at 25
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the region of venous bifurcations. Several experiments suggested that the venoconstriction did not result from a compensatory reflex. The pressor response to ACh was blocked by atropine and phentolamine and it was antagonized by reserpine. Guanethidine, hexamethonium or chronic sympa- thectomy did not affect the response. The potentiation of the pressor response by cocaine and direct assay of the venous blood on the chick cecum help support the conclusion that the pressor response is mediated by a release of catecholamines from extraneural stores. Further investigation of this original observation was carried out by correlative tests of the responses of four veins in the dog to several vaso- constrictor stimuli. The agents used included nicotine, acetylcholine, nore- pinephrine and sympathetic nerve stimulation. Nicotine did not produce venoconstriction in any of the preparations. Localized responses were in- duced by acetylcholine, norepinephrine and vasoconstrictor nerve stimu- lation in the accessory cephalic and lateral saphenous veins. Histologic examination of these regions showed an area that contained valves and was richly invested with smooth muscle. Valves were present also in the external iliac and the splenic - the non-reactive veins; however, these veins lacked any appreciable amount of smooth muscle fibers in the tunica media. It would appear, then, that venoconstriction in these veins involved localized areas containing valves and rich in smooth muscle. Other grantor: American Medical Association - Education and Research Foundation. "STUDIES ON THE AURICULAR STIMULATING ACTION OF NICOTINE." By J. P. Long, PhD, and E. G. Gross, Department of Pharma- cology, College of Medicine, University of Iowa, Iowa City. Archives inter- nationales de pharmacodynamie et de therapie 161/1:30-37, May 1966. (Grantee: Long) This experiment was undertaken to study the mechanism by which nicotine produces an increase in auricular rate and force of contraction. In one phase of the experiment, isolated cat auricles were suspended in Locke-Ringer's solution, allowed to stabilize for at least 15 minutes, and then subjected either to variation of the pH of the medium or to vagal nerve stimulation. In another phase of the experiment, hemicholinium was admin- istered intravenously to 13 cats, and auricular activity was compared in cats subjected to a) the action of hemicholinium, b) vagal nerve stimulation, or c) the combined action of hemicholinium and vagal nerve stimulation. Data presented in this paper supports the following observations: 1. The stimulating action of nicotine is present at pH's of 8.3 and 7.4. The stimulating action appears to be more marked in a more alkaline medium but this was accompanied by an altered resting auricular rate. 2. Vagal nerve stimulation with the electrodes 1Slaced distally on the nerve in the isolated cat auricle preparation produced significant increase in the auricular rate but not a significant increase in the force of contraction. 26
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3. When hemicholinium was administered to cats in vivo and accom- panied with i'ight vagal nerve stimulation, the auricular stimulating actions of nicotine in the isolated auricular preparation was significantly antagonized. The evidence presented suggests nicotine acts on the parasympathetic nerves within the auricles and directly or indirectly produces release of norepine- phrine from the sympathetic nerve terminals. Other grantor: American Medical Association - Education and Research Foundation. "COMPARATIVE STUDIES OF ATRIAL RESPONSES FOLLOW- ING NICOTINE AND TRANSATRIAL STIMULATION." By E. G. Gross, T. S. Whitacre and J. P. Long, PhD, Department of Pharmacology, University of Iowa College of Medicine, Iowa City. Archives Internationales de Pharmacodynamie et de Th,4rapie 166/2:273-280, April 1967. (Grantee: Long) Atrial reactivity to nicotine and transatrial stimulation was evaluated in eight species (cats, dogs, frogs, guinea pigs, turtles, chickens, rats and rabbits). Wide species variations were observed following exposure to either nicotine or transatrial stimulation. Only the cat and rabbit demon- strated both positive and negative chronotropic and inotropic responses to nicotine. The cat, alone, demonstrated biphasic responses to transatrial stimulation. Little, if any, correlation was noted in responsiveness when comparing nicotine and transatrial stimulation. The great species variation recorded here suggest that care must be observed in evaluating the activity of compounds on isolated atria. Other grantor: American Medical Association - Education and Research Foundation. "THE HEMODYNAMIC CONSEQUENCES OF ARRHYTHMIAS." By Henry D. McIntosh and James J. Morris, Jr., Cardiovascular Laboratory, Duke University Medical Center, Durham, N.C. Progress in Cardiovascular Disease 8/4:330-363, January 1966. (Grantee: Mclntosh) The rate of an arrhythmia regardless of the type can be of significance at either extreme of the rate scale. The relation of atrial systole to ventricular systole determines if the normal atrial transport function will be present as well as determining the efficiency of atrioventricular valve closure. The site of origin and type of conduction of the pacing stimulus are important deter- minants of the effectiveness of ventricular systole and atrioventricular valve competency. The pathologic state of the heart as a pump determines how effectively and how long the adverse effects of arrhythmias may be tolerated. The integrity of the vasomotor control mechanism serves as the final site of adjust- ment to maintain adequate perfusion of the vital center of the total organism. Associated diseases determine how well a compromised circulation may be tolerated. Other factors influence each of the above mentioned parameters. 27
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The final hemodynamic effect of the arrhythmia, therefore, depends on the summation of the effects of numerous changes of varying importance. Other grantors: National Heart Institute (3), John A. Hartford Founda- tion, and the Life Insurance Medical Research Fund. "EFFECTS OF HYPERBARIC OXYGENATION ON CORONARY ARTERY OCCLUSION IN PIGS." By Robert H. Peter, MD, Ronald W. Rau, BSEE, Robert E. Whalen, MD, Mark L. Entman, MD, and Henry D. McIntosh, MD, Durham, N.C. Circulation Research 18/1:89-96, January 1966. (Grantee: Mclntosh) To evaluate more precisely the possible protective effect of hyperbaric oxygenation in experimental myocardial infarction, gradual occlusion of a coronary artery was produced in the pig. Ameroid constrictors designed to produce complete occlusion within 48 hours were placed on the left anterior descending coronary artery of 24 young farm pigs. Of these, 12 were placed in a hyperbaric chamber at 1.25 atmospheres absolute and allowed to breathe 100% oxygen for a maximum of 32 hours. For control studies 12 other pigs were handled in a similar manner outside the chamber while breathing air at normal atmospheric pressure. Pigs treated with hyperbaric oxygenation outlived the untreated pigs. Pathological and histochemical studies of the hearts revealed that pigs treated with hyperbaric oxygenation had a high incidence of myocardial infarction, whereas only two pigs in the untreated group showed any evidence of myocardial damage. These findings suggest that moderate but prolonged hyperbaric oxygenation may lengthen life during and after coronary occlu- sion. This prolongation of life may permit the development of pathologically detectable myocardial infarctions. Other grantors: U. S. Public Health Service, North Carolina Heart Associ- ation, American Heart Association, and Life Insurance Medical Research Fund. "POSTPERICARDIOTOMY SYNDROME AS A COMPLICATION OF PERCUTANEOUS LEFT VENTRICULAR PUNCTURE." By Robert H. Peter, MD, Robert E. Whalen, MD, Edward S. Orgain, MD, and Henry D. McIntosh, MD, Cardiovascular Laboratory, Department of Medicine, Duke University Medical Center, Durham, N.C. American Journal of Cardi- ology 17/1:86-90, January 1966. (Grantee: Mclntosh) Two cases of postpericardiotomy syndrome following percutaneous left ventricular puncture have been reported. Both had symptoms identical with the other "cardiotomy" syndromes and responded promptly to adrenal steroid therapy. The fact that one of the patients had a second episode of pericarditis four weeks following open heart surgery may mean that the development of this syndrome following left ventricular puncture may be associated with the development of the postpericardiotomy syndrome follow- ing cardiac surgery. Other grantor: National Heart Institute (2). 28
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"THE HEMODYNAMIC EFFECTS OF THE INJECTION OF CON- TRAST MEDIUM (ISOPAQUE)." By Henry D. McIntosh, MD, Victor W. Hurst, MD, Howard K. Thompson, Jr., MD, James J. Morris, Jr., MD, and Robert E. Whalen, MD, Cardiovascular Laboratory, Department of Medicine, Duke University Medical Center, Durham, North Carolina. Angiology 18/5:306-315, May 1967. (Grantee: Mclntosh) During studies evaluating the hemodynamic changes following the intravascular injection of a new contrast agent, sodium and N-methylgluca- mine metrizoate (Isopaque), it was found that within seconds after injection of the contrast medium into the heart and great vessels there was a prompt decrease of hematocrit, due to the loss of red cell water and a reduction of red cell volume. Observations by light microscopy of the effect of contrast medium on red cells indicated that these changes occurred rapidly enough to be complated during the initial transit of the contrast-medium-blood mixture. These agents alter the permeability of the cell membrane to potas- sium. Such changes in permeability were not produced by 5% sodium chloride, despite a similar rapid reduction of cell volume. It is suggested that similar changes may occur in endothelial cells. It is possible that the efflux of ions from these cells may have an effect on the downstream "receptor" cells and be responsible for certain of the hemo- dynamic changes observed following the injection of contrast medium. Other grantora: National Heart Institute (2), the John A. Hartford Foundation, and the Winthrop Laboratories. Other papers published by Dr. Mclntosh and associates since the 1965-66 Report of the Scientific Director, with credit for support by The Council for Tobacco Research - U.S.A., follow. Other grantors are noted between parentheses. "INFUNDIBULAR PULMONIC STENOSIS DUE TO A PERICARDIAL BAND." American Journal of Cardiology 16/2:262-266, August 1965. (NHI) "THE ASSOCIATION OF NOCTURNAL ANGINA PECTORIS WITH DREAMING." Annals of Internal Medicine 63/6:1040-1046, December 1965. (NIH(2), AHA) "ELECTRIC SHOCK HAZARDS IN RADIOLOGY DEPARTMENTS." American Journal of Roentgenology 95/4:976-980, December 1965. (NHI, NCHA ) "BILATERAL FUNCTIONAL SUBAORTIC STENOSIS IN THE ALLI- GATOR." Transactions of the American Clinical and Climatological Asso- ciation 78:119-128, 1966. (NHI, JAHF) "THE MANAGEMENT OF SUPRAVENTRICULAR ARRHYTH- MIAS." Medical Annals of the District of Columbia 35:525-527, 576, 1966. (NHI, JAHF, LIMRF) 29
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"HEMODYNAMIC RESPONSES TO LIFE WITHOUT BLOOD." (Third International Conference on Hyperbaric Medicine, Durham, N. C., 1965) National Research Council Publication #1404, 1966. (NHA(3), AHA, NCHA, LIMRF) "CINEANGIOCARDIOGRAPHY." Tice-Harvey Practice of Medicine V. II, 1966. "THE PROTECTIVE EFFECT OF HYPERBARIC OXYGENATION IN CEREBRAL ANOXIA." Archives of Neurology 14/1:15-20, January 1966. (PHS(3), NCHA, AHA) "EFFECTS OF HYPERBARIC OXYGENATION ON EXCESS LAC- TATE PRODUCTION IN EXERCISING DOGS." American Journal of Physiology 210/3:473-477, March 1966. (NHI(3), NCHA, AHA) "RELATIONSHIP OF FIBRILLATORY WAVES AND P WAVES IN THE ELECTROCARDIOGRAM." Circulation 33/4:599-606, April 1966. (NHI, NCHA, LIMRF) "THE PRECORDIAL HONK." American Journal of Cardiology 17/4: 509-515, April 1966. (PHS(2), AHA, NCHA) "ATRAUMATIC RIGHT VENTRICULAR ANEURYSM. REPORT OF A CASE." Circulation 34/7:123-126, July 1966. (NHI(3), JAHF, NCHA) "ELECTRICAL CONVERSION OF ATRIAL FIBRILLATION. IMME- DIATE AND LONG-TERM RESULTS AND SELECTION OF PA- TIENTS." Annals of Internal Medicine 65/2:216-231, August 1966. (NIH(2), NCHA) "VENTRICULAR VOLUME STUDIES IN A PATIENT WITH HYPER- TROPHIC SUBAORTIC STENOSIS." Circulation 34/4:579-584, October 1966. (NIH, AHA, NCHA) "A CLINICAL AND HEMODYNAMIC EVALUATION OF A NEW CONTRAST MEDIUM: ISOPAQUE 440 (SODIUM AND N-METHYL- GLUCAMINE METRIZOATE)." American Journal of Roentgenology 100/2:468-476, June 1967. (NHI, JAHF) "AGE AND DISEASE-RELATED ALTERATIONS IN FIBRINOGEN- EUGLOBULIN (FIBRINOLYTIC) BEHAVIOR." By Kenneth M. Moser, MD, and George C. Hajjar, MD, Department of Medicine, George- town University Medical School and The Enzyme Research Laboratory, D. C. General Hospital, Washington, D. C. The American Journal of the Medical Sciences 251/5:536-544, May 1966. (Grantee: Moser) Studies of fibrinogen concentration and fibrinolytic activity (euglobulin lysis time) were carried out in different patient groups. It was established 0 0 0 r 0 30 -4 (
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that there is no correlation between fibrinogen concentration and fibrinolytic activity. Attempts to define the day-to-day reproducibility of fibrinolytic activity and fibrinogen measurements indicated that fibrinogen levels remain quite stable and that corresponding measures of fibrinolytic activity are adequately reproducible, although fibrinolytic activity, in general, increases during the period between 9:00 a.m. and 2:00 p.m. Comparison of fibrinolytic behavior in groups of young, old and intermediate age normals, cirrhotics and dia- betics disclosed that such activity was significantly greater in the cirrhotics, most labile in the young normals. Fibrinogen levels in the diabetics were consistently higher than those in the other groups, while old normals had higher levels than young normals. The fibrinogen and fibrinolytic behavior observed in these studies may have implications with respect to thrombo-atherogenesis and the physiology of fibrinolysis which merit further investigation. Other grantors: The National Institutes of Health and The Office of Naval Research. "THERAPY OF ATRIOVENTRICULAR NODAL TACHYCARDIA." By Louis A. Soloff, MD, and William S. Frankel, MD, Cardiovascular Divi- sion, Department of Medicine, Temple University Medical School, Phila- delphia, Pennsylvania. From "Mechanisms and Therapy of Cardiac Arrhy- thmias," 14th Hahnemann Symposium, Philadelphia, April 26-29, 1965. Published by Grune & Stratton, 1966. (Grantee: Soloff) Atrioventricular nodal tachycardias are usually separated into paroxys- mal and non-paroxysmal types. Distinction of these two types is worthwhile because the first is usually benign and easily recognized, while the second is usually serious and hard to diagnose on clinical grounds. Therapy of the paroxysmal type is best accomplished by mechanical measures which increase vagal tone, sedation or digitalization. Digitalization is also indicated for non-paroxysmal arrhythmias except when they occur in the digitalized patient. In this case, the specific treatment is discontinuance of digitalis plus the possible use of anti-arrhythmia drugs such as procaineamide or quinidine sulfate. Other grantors: U. S. Public Health Service and the Arlene Dickler Grass Foundation, Heart Association of Southeastern Pennsylvania. "RELATIONSHIP BETWEEN GLUCOSE AND FATTY ACID IN MYOCARDIAL INFARCTION." By Louis A. Soloff, MD, and Heinz Schwartz, MD, PhD, Division of Cardiology, Temple University Medical Center, Philadelphia, Pennsylvania. Lancet 1:449-452, February 26, 1966. (Grantee: Soloff) The glucose and fatty acid responses to glucose loading were deter- mined in 15 patients who were convalescing from myocardial infarction, in 15 treatment-dependent diabetics, and in 15 patients or healthy volunteers who had no evidence of heart disease or of diabetes. I 31
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All ischemic patients satisfied the criteria of chemical diabetes. Five had a fatty acid response to glucose similar to, but actually greater than, the normal and 10 had a fatty acid response similar to the diabetics. These 10 patients were also characterized by a diminished inhibition of stearic acid release provoked by glucose. Furthermore, all coronary patients, the second group more than the first, had a diminished capacity to liberate lino- leic acid on demand. Other grantor: U. S. Public Health Service. "ON MEASURING LEFT VENTRICULAR VOLUME." By Louis A. Soloff, MD, Department of Medicine, Division of Cardiology, Temple Uni- versity Medical School, Philadelphia, Pennsylvania. The American Journal of Cardiology 18/ 1:2-5, July 1966. The institution of a satisfactory technic of determining left ventricular volume in man is extremely important, for without it one cannot determine the over-all power and performance of the heart muscle. Such a definitive technic, however, has not been developed as yet. In this review of the past 60 years' efforts to measure the volume of the heart as a whole and of the left ventricle, many technics are discussed. Methods considered include roentgenology; angiocardiography; direct volumetric measurement by indicators: the combination of radiopaque dilu- tion curves and angiography, and the use of change in a diameter or circum- ference as an index of change in volume. This last method appears promis- ing but it remains for the future to determine if such formulas are applicable to the normal human heart and also to clinical cardiac disorders. Other grantor: U. S. Public Health Service. "CARDIAC OUTPUT, BLOOD PRESSURE AND FREE FATTY ACID RESPONSES TO SMOKING IN THE NONBASAL STATE." By William S. Frankl, MD, MS, Ronald Friedman, MD, and Louis A. Soloff, MD, Department of Cardiology and the Cardiovascular Research Center, Temple University Medical Center, Philadelphia, Pennsylvania. American Journal of the Medical Sciences 252/1:39-44, July 1966. (Grantee: Soloff) Other studies have shown cardiac output, cardiac index, stroke volume and free fatty acids to rise after smoking in the resting, basal state, but the present studies were made in individuals in a non-basal state to determine the validity of smokers' claims that tensions are eased by smoking. Six healthy young habitual smokers, all familiar with the intravascular procedures used, were employed in these tests. After right heart catheteriza- tion and brachial arterial puncture, each subject smoked 2 standard sized filter tip cigarettes within 10 minutes. Cardiac and circulatory parameters were measured before smoking, during smoking, and 15, 30, 60, and 90 min- utes thereafter. , Cardiac output and free fatty acids were elevated prior to smoking. In none of the subjects was there a significant further rise in cardiac output or 32
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free fatty acids after smoking (except for a borderline significant rise in cardiac index immediately after completion of smoking). These findings cast some doubt on whether tobacco actually exerts any significant effect on cardiac output, stroke volume or blood free fatty acids in the non-basal state. Other grantor: U.S. Public Health Service. I "CIRCULATORY VALUES AND HEMOLYSIS DURING PENTO- BARBITAL DIAL-URETHANE ANESTHESIA IN DOGS PREMEDI- CATED WITH MORPHINE." By C. A. Papacostas, L. Weiss and L. A. Soloff, Departments of Pharmacology and Cardiology, Temple University Medical Center, Philadelphia, Pennsylvania. Life Sciences 6/11-1:1195- 1199, June 1967. (Grantee: Soloff) Thirty-four adult mongrel dogs were given morphine sulfate subcutane- ously and 30 minutes later were anesthetized with a mixture of pentobarbital and dial-urethane. From these dogs, control values were obtained for mean arterial pressure, heart rate, cardiac output, stroke volume and total peri- pheral resistance. All venous blood samples taken in this series showed evidence of moderate to marked hemolysis. Mechanical factors did not ap- pear to be responsible and hemolysis apparently resulted from the use of this often employed special anesthetic mixture. Other grantors: U. S. Public Health Service and the National Heart Institute. III. Carcinogenesis Studies "CARCINOGENIC ACTIVITY OF ISONIAZIDE, HYDRAZINE AND HYDRAZINE DERIVATIVES." By Cesare Biancifiori, MD, Division of Cancer Research, University of Perugia, Italy. Annali della Facolta di Medi- cina e Chirurgia della Universita degli Studi di Perugia 57/3:352-359, March 1966. "THE RELATION OF ISONIAZID (INH) AND ALLIED COM- POUNDS TO CARCINOGENESIS IN SOME SPECIES OF SMALL LABORATORY ANIMALS: A REVIEW." By Cesare Biancifiori, MD, and Lucio Severi, MD, Division of Cancer Research, University of Perugia, Italy. British Journal of Cancer 20/3:528-538, September 1966. "ISONIAZID AND ALLIED COMPOUNDS AS RELATED TO LUNG TUMORS IN ANIMALS." By Lucio Severi, MD, and Cesare Biancifiori, MD, Division of Cancer Research, University of Perugia, Italy. Growth 30/4:367-382, December 1966. These three papers summarize the present state of scientific knowledge concerning the possible carcinogenic activity of isoniazid (INH), a drug used widely in the treatment of tuberculosis. 33 , "
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Isoniazid and its allies, hydrazine and other hydrazine derivatives, have induced lung and liver tumors in various cancer-susceptible and -resistant strains of mice and rats, thus proving themselves to be very effective carcino- gens in certain small laboratory animals. Initial laboratory demonstrations were made of the carcinogenic action of isoniazid (INH), after which studies were instituted to identify the meta- bolic derivatives of INH and to determine whether INH is carcinogenic in itself or via its metabolites. INH, itself, has been shown to induce lung tumors in "albino," "dd," RIII, BALB/c, C57BI and CBA mice, and to enhance the development of Brown-Pearce tumors and tracheobronchial papillomas in rabbits. Since metabolic breakdown of INH results in the production of isoni- cotinic acid and hydrazine (which in turn is converted to ammonia), experi- mental investigations of hydrazine were undertaken. These studies demon- strated the effectiveness of hydrazine in the production of tumors of the lung in BALB/c/Cb/Se, BALB/c/An/Se, CBA /Cb/Se mice and Cb Lon- don rats and tumors of the liver in CBA/Cb/Se mice. With the implication of hydrazine as a potential carcinogen in man, efforts were made to determine the biological characteristics of hydrazine- induced tumors. In various experiments, induction time was determined, dose response was demonstrated, influence of route of administration was shown to be negligible and metastasis and malignant invasion of vessels by these tumors was exhibited. The effect of hydrazine sulfate on resistant species was tested in an experiment conducted with Cb/Se strain rats, a strain noted for its low incidence of pulmonary tumors. Of 32 treated rats, 25% had pulmonary tumors and 21% had adenomatous changes by the end of the experimental period. Other hydrazine derivatives have been shown to induce tumors of the lung and leukemia in BALB/c/Cb/Se mice, tumors of the lung and leukemia in CDZFI mice and tumors of the mammary gland in Osborne Mendel rats. The summation of these experimental facts plus some disturbing clin- ical observations suggest that INH and its allied compounds may be related" to the development of lung tumors in man. In this connection, other experi- mental observations have introduced the possibility that the hormones of the adrenal cortex are involved in the origin of lung tumors. Other grantor: Anna Fuller Fund, New Haven, Connecticut. "GENETIC STUDIES ON THE ETIOLOGY AND MORPHOLOGY OF MAMMARY TUMORS IN MICE." By William S. Murray, The Jackson Laboratory, Bar Harbor, Maine. Journal of the National Cancer Institute 36/2:249-257, February 1966. Experimental use of hybridization, one of the more effective methods for the study of the mammary tumorigenic complex, is hampered by several complicating factors. The present study deals with two of these factors: 1) 34
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, the control of viral transmission, and 2) the relationship of etiology to tumor morphology. Using mice of the strains C3H/HeJ (a strain highly susceptible to mouse mammary tumor virus (MTV) and known to carry the viral prin- ciple in active form), C3HeB/Fe (a strain highly susceptible to MTV but one that has a low mammary tumor incidence), and MA/My (a strain highly susceptible to MTV but one which has been observed to have no mammary tumors), four reciprocal crosses were carried out. The first filial generation females of these crosses were then bred and observed until they developed mammary tumor or died. Examination of the distribution and morphology of the observed tumors led to the following conclusions: 1) The milk-transported MTV stimulates the development of A and B type mammary adenocarcinomas in early age and early middle age. 2) The other mammary tumors found - type C, fibrosarcoma, heman- gioendothelioma, and adenoacanthoma, which characteristically develop in late middle age and old age and are independent of the direction in which reciprocal crosses are made - have a separate etiology. 3) The parallel between the time of occurrence of the late mammary tumors and the time spread of appearance of tumors in other organs suggests a common etiology for all late-appearing tumors. Other grantor: National Cancer Institute. "GENETIC STUDIES OF CARCINOGENESIS IN MICE." By William S. Murray, ScD, and Clarence C. Little, ScD, The Jackson Laboratory, Bar Harbor, Maine. Journal of the National Cancer Institute 38/5:639-656, May 1967. (Grantee: Murray) The reactions of physiologies produced by various genomes to the presence or absence of the mammary tumor virus (MTV) were studied throughout the lifespan of 3,630 F, female mice. Particular attention was paid to the relationship of age and of reproductive experience to the occur- rence of various types of mammary tumors. Using mice of the three aforementioned strains (C3H/HeJ, C3HeB/Fe, and MA/My) plus C57B1/6 (a strain highly resistant to, and believed free of, MTV), and A/He (a strain highly susceptible to MTV and one which carries the virus in active form), seven reciprocal crosses were carried out. The first filial-generation females of the 14 crosses were bred and then observed until they developed mammary tumor or died. Results showed that there was a great increase in tumor production when MTV was introduced by the female. The results also showed clearly that genetically different physiologies, when subjected to MTV stimulation, developed their tumors over characteristic age spreads that encompassed the 4th through 19th month; those physiologies which received no MTV stimu- lation developed the great bulk of their tumors at ages of 20 months or more. Therefore, age distribution of early tumors appears to depend on MTV 35
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stimulation and on method of transmission. Late-appearing tumors are inde- pendent of these factors. Certain speculations and hypotheses are presented dealing with male transmission of the mammary tumor virus and its relation to the nodulogenic virus. Other grantor: National Cancer Institute. "INTRINSIC FACTORS OF PULMONARY CARCINOGENESIS OF THE MOUSE: EFFECTS OF NEONATAL THYMECTOMY." By Rodolfo Ribacchi, DM, AV, and Gaetano Giraldo, DM, Division of Cancer Research, University of Perugia, Italy. Lavori dell'Istituto di ana- tomia e istologia patologica della Universita degli Studi di Perugia 26/11: 127-136, 1966. (Grantee: L. Severi) In this study of the effects of thymectomy upon lung tumor development, 204 male and female BALB/c/Cb/Se mice were divided into three groups. One group was thymectomized at birth, one "sham-operated" and one kept as a control. All mice, treated and untreated, received a single intraperi- toneal injection of 9 mg urethane at 10-14 days of age. Approximately 17 mice from each group were then sacrificed at 50, 70, 90 or 110 days after treatment. Among the mice sacrificed at 50 days, 100% of the thymectomized mice had multiple lung tumors, while only 66.6% of the "sham-operated" and 64.7% of the controls showed similar findings. This initial difference dis- appeared later, since all mice killed at 70, 90 and I10 days had multiple lung tumors. However, the average number of lung tumors per mouse was always higher in the thymectomized group than in either the "sham-operated" animals or the controls. The results of this experiment show that neonatal thymectomy favors the onset and development of urethane-induced lung tumors. Since thymec- tomy acts to reduce or inhibit the immunopoietic capacity of the mouse, it is considered that immunodependence constitutes a new intrinsic factor which, along with genetic, environmental and possible hormonal factors, influences pulmonary tumor development. IV. Studies at the Cellular Level "PHOSPHOLIPID SYNTHESIS IN THE LARGE PULMONARY AL- VEOLAR CELL: ITS RELATION TO LUNG SURFACTANTS." By Sue Buckingham, MD, H. O. Heinemann, MD, Sheldon C. Sommers, MD, and William F. McNary, PhD, Departments of Pediatrics, Medicine and Pathology, Columbia University College of Physicians and Surgeons, q and Francis Delafield Hospital, New York, N. Y., and the Department of 0 Anatomy, Boston University School of Medicine, Mass. American Journal ° of Pathology 48/6:1027-1041, June 1966. (Grantee: S. Buckingham) r 0 36 J r N
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In an attempt to confirm the preferential incorporation of acetate and palmitate into lung lecithin and to demonstrate the localization of these reactions in the large pulmonary alveolar cells, the uptake and distribution of labeled acetate and palmitate into lipid fractions of lung were studied in rabbits, and the cellular localization of the synthetic reactions was examined by means of serial autoradiographs. Similar studies were carried out on corresponding liver tissue for comparison. Three groups of three White New Zealand rabbits each were treated respectively with tritiated sodium acetate (specific activity, 145 mc per mM), tritium labeled palmitate (256 mc per mM) and tritium labeled palmitate (200 mc per mM). The animals were sacrificed 15 to 90 minutes after intravenous injection and lung and liver specimens were subjected to micro- scopic examination, autoradiography and lipid analysis. One-half as much palmitate was taken up by lung as by liver (gram for gram). In lung, however, palmitate was rapidly and preferentially incorpo- rated into phospholipids (85% ), most of it (60% ) into lecithin. In the liver, the label was equally distributed between the neutral and phospholipid fractions. Lung tissue per unit weight was twice as active as liver in incorporating 3H acetate into lipids. Acetate was also metabolized rapidly into phospho- lipids in the lung (90%), especially into lecithin (60%); the liver utilized acetate to form various lipid components. Within the phosphatides of lung, the C,s (palmitate) fraction accumu- lated nearly all the label following either acetate or palmitate; in the liver phosphatides, both precursors were distributed or converted into various fatty acids. Autoradiographic studies of lung tissue from treated rabbits showed silver granules, indicating radioactivity, in the cytoplasm of the large alveolar cells by 30 minutes after injection. No other tissue elements, except for an occasional alveolar macrophage, presented evidence of radioactive label- ing. These silver grains were found between, but not inside of, the character- istic cytoplasmic inclusions of these cells. These findings are discussed with reference to the formation and turn- over of lung surfactant phospholipids. Other grantor: United States Public Health Service. "PULMONARY ALVEOLAR LESIONS IN VAGOTOMIZED RATS." By Victor E. Goldenberg, MD, Sue Buckingham, MD, and Sheldon C. Som- mers, MD, Departments of Pathology and Pediatrics, Columbia University College of Physicians and Surgeons, and Francis Delafield Hospital, New York, New York. Laboratory Investigation 16/5:693-705, May 1967. .(Grantee: Buckingham) • Lungs of rats were studied by light and electron microscopy at I to 6 hours after vagotomy. The salient findings in the pulmonary alveoli of these 37 r
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rats were an early (1 hour) and progressive decrease in the osmiophilia of the special cytoplasmic inclusions and diminished numbers of multivesicular bodies in the large alveolar cells. Increased capillary endothelial pinocytosis was also found 1 hour postvagotomy. At later intervals the osmiophilic inclu- sions were replaced by vacuoles, with increased intracellular fluid accumu- lation and blunted microvilli. Late development of massive atelectasis in the lungs coincided with the finding of abnormal surface tension characteristics in some lung extracts. The relationship of the ultrastructural changes to the formation of surfactants is considered. Other grantor: U.S. Public Health Service (2). "QUANTITATIVE HISTOCHEMISTRY OF RAT MUCOSA: LAC- TATE AND MALATE DEHYDROGENASES." By Stanley J. Gerson, DDS, PhD, Julia Meyer, PhD, and Hermann Mattenheimer, MD, De- partment of Oral Pathology, University of Illinois College of Dentistry; Department of Biochemistry, University of Illinois College of Medicine, and Departments of Biochemistry and Medicine, Presbyterian-St. Luke's Hospital, Chicago. The Journal of Investigative Dermatology 47/6:526-532, December 1966. (Grantee: Meyer) Ultramicrochemical methods were used to assay lactate dehydrogenase (LDH) and malate dehydrogenase (MDH) activities in the histologically demonstrable layers of keratinizing oral epithelium. Specimens of palatine and buccal mucosa from young adult male Simonsen albino rats were frozen in liquid nitrogen, dried and dissected (usually into six layers). Comparison of enzyme activities in the six successive epithelial layers showed that LDH and MDH activity in both the palatine and the buccal epithelium decreased between the basal and horny layers. Although MDH activity was consistently higher than LDH activity in homologous layers and in the whole cellular layers, MDH activity decreased more rapidly with outward progression than LDH activity, thus reducing the discrepancy between them. Comparisons of palate and cheek epithelium showed similar levels of- enzyme activity in homologous layers and in the whole cellular layers, but differences were noted in the rates of peripheral decrease in the activity of both enzymes. Differences in enzyme activity could be correlated with differences in the distribution of dividing cells and of tonofibrils. Other grantor: U. S. Public Health Service. "NUCLEOLAR `CAPS' INDUCED BY FLYING SPOT ULTRAVIOLET NUCLEAR IRRADIATION." By P. O'B. Montgomery, MD, R. C. Reynolds, MD, and J. E. Cook, BSEE, Department of Pathology, University of Texas Southwestern Medical School, and The Laboratories for Cell u 0 0 ~ r 0 38 ,~ J r
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Research, Woodlawn Hospital, Dallas, Texas. The American Journal of Pathology 49/3:555-567, September. 1966. (Grantee: Montgomery) A shaped microbeam of low intensity heterochromatic ultraviolet light was applied to the nucleolus of living Chang liver cells and to the nucleus with the exclusion of the nucleolus. At varying time intervals these irradi- ated cells were appropriately fixed, embedded and serially sectioned for examination by electron microscopy. When examined, the nucleoli of these irradiated cells showed collapse of the nucleolonema, an apparent decrease in nucleolar size, and a reorgani- zation of the nucleolus resulting from the segregation of the various types of granular components of the nucleolus. Nucleolar plaques and light nucle- olar "caps" were formed in both groups of cells. In the cells in which the nucleoplasm alone was irradiated, segregation of the nucleolar granules resulted in the formation of dark nucleolar "caps" similar to those produced by the acridine derivatives and mitomycin C. Three chemicals, proflavine, acridine orange 'and mitomycin C, all compounds which form a complex with DNA and inhibit DNA and RNA synthesis, produce an effect on nucleolar ultrastructure which is identical to that produced by the ultraviolet irradiation of the nucleoplasm exclusive of the nucleolus. The effects of these agents which produce nucleolar "caps" support the hypothesis that the nucleolar lesion is the result of an injury at the DNA level of cellular metabolism. Other grantors: Atomic Energy Commission, Damon Runyon Memorial Fund, and the National Institutes of Health. V. Epidemiology "NEGRO-WHITE DIFFERENCES IN PULMONARY FUNCTION (VITAL CAPACITY, TIMED VITAL CAPACITY, AND EXPIRA- TORY FLOW RATE)." By Albert Damon, MD, PhD, Department of Anthropology, Harvard University, Cambridge, Massachusetts. Human Biology 38/4:380-393, December 1966. Marked and significant differences in three pulmonary functions were noted in tests conducted among 392 white and 61 Negro soldiers, aged 18-29, during the course of an anthropometric survey of U. S. Army drivers at Fort Devens, Massachusetts. The Negro soldiers had 13% smaller 1-second and total vital capacities as well as a 10% slower mid-expiratory flow rate. Mean age, height, weight, and chest circumference were similar in the two groups. The difference in lung function can be regarded as truly functional or physiological since it cannot be accounted for by differences in motivation, in smoking habits, or - more than minimally - to differences in physique. The white soldiers smoked more than the Negroes. Motivation was apparently equivalent, as shown by the stronger grips of the Negroes, who were also 39 0 v v ~
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much more mesomorphic and "masculine" in physique. The shorter trunk and reduced chest expansion of the Negroes could not account for much of the difference. Differences of this magnitude have been reported for almost 100 years, and prior pulmonary disease is unlikely to account for them. Implications for disease and for athletic performance are speculative at present. Other grantors: American Heart Association, Commission on Accidental Trauma of the Armed Forces Epidemiological Board and the National Science Foundation. "PREVIOUS PULMONARY DISEASE AND LUNG CANCER: A CASE-CONTROL STUDY." By Albert Damon, MD, PhD, and Jean P. McClung, Department of Anthropology, Harvard University, Cambridge, Massachusetts. Journal of Chronic Diseases 20/2:59-64, February 1967. (Grantee: Damon) In a study of the relationship between previous pulmonary disease and lung cancer it was shown that subsequent lung cancer was not associated with either total number of pulmonary diseases or with any specific pul- monary disease. Among more than 17,000 men examined medically and anthropomet- rically at Harvard University between 1880 and 1920, 130 had died of lung cancer by January 1, 1966. For control purposes, each lung cancer decedent was matched with the next man of the same age to be examined. Of the controls, 87 had died and 43 were still alive on January 1, 1966. The lung cancer decedents and the controls did not differ in the number or nature of prior pulmonary diseases reported during their medical examina- tion at Harvard. Among the controls, significantly more of those without early pulmonary disease were still alive than of those with early pulmonary disease. Other grantor: American Heart Association. "EPIDEMIOLOGY OF CHRONIC BRONCHITIS." By Donald Massaro, MD, and Linda Bottoms, RN, Pulmonary Disease Research Laboratory, V.A. Hospital, Washington, D. C. and the Department of Medicine, Georgetown University School of Medicine, Washington, D.C. Medical Times 95/2:12 1 - 128, February 1967. (Grantee: Massaro) The factors which predispose to chronic bronchitis and avenues which might be followed to prevent or ameliorate the disease are examined in this review paper. Smoking, age, air pollution and host variation are the factors most seriously considered in recent studies of bronchitis prevalence here and abroad. The importance of smoking and air pollution in the epidemiology of bronchitis is stressed. Ameliorative or preventative measures recommended include the curtailment of personal air pollution in the form of cigarette smoking and the enforcement of an effective attack on generalized air pollution. 40
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VI. Pulmonary Physiology '-CARDIOPULMONARY EFFECTS OF TOBACCO AND RELATED SUBSTANCES: I. THE RELEASE OF HISTAMINE DURING INHAL- ATION OF CIGARETTE SMOKE AND ANOXEMIA IN THE HEART- LUNG AND INTACT DOG PREPARATION." By Domingo M. Aviado, MD, Milan Samanek, MD, and Luis E. Folle, MD, Department of Pharma- cology, School of Medicine, University of Pennsylvania, Philadelphia. Archives of Environmental Health 12/6:705-711, June 1966. (Grantee: Aviado) "CARDIOPULMONARY EFFECTS OF TOBACCO AND RELATED SUBSTANCES: 111. PULMONARY VASCULAR EFFECTS OF CIGAR- ETTE SMOKE AND NICOTINE." By Luis E. Folle, MD, Milan Samanek, MD, and Domingo M. Aviado, MD, Department of Pharmacology, School of Medicine, University of Pennsylvania, Philadelphia. Archives of Envir- onmental Health 12/6: 712-716, June 1966. (Grantee: Aviado) "CARDIOPULMONARY EFFECTS OF TOBACCO AND RELATED SUBSTANCES: III. PULMONARY VASCULAR EFFECTS OF CIGAR- ETTE SMOKE AND NICOTINE." By Milan Samanek, MD, and Domingo M. Aviado, MD, Department of Pharmacology, School of Medicine, Uni- versity of Pennsylvania, Philadelphia. Archives of Environmental Health 12/6:717-724, June 1966. (Grantee: Aviado) It has been shown formerly that there are three important participating mechanisms involved in the effects of tobacco on the tracheobronchial air- ways: 1. direct action of tobacco smoke on the smooth muscle of the airways; 2. stimulation of the nervous structures in the lung, and 3. release of humoral agents. The present series of experiments was designed to test whether these three mechanisms also influence the cardiopulmonary system, specifically the pulmonary circulation, coronary circulation and heart muscle. In Part I of this series, the role of the humoral agent, histamine, in mediating any change in function of the heart muscle was explored. Experi- ments were conducted both on dogs with intact cardiovascular systems and on heart-lung preparations. Results showed striking differences between the effect of cigarette smoke upon the isolated heart-lung preparations and its effect upon the anesthetized dog with an intact cardiovascular system. There was a striking stimulation of force of myocardial contraction in the intact dog but no stimulation or depression of force and ventricular per- formance in the heart-lung preparation. These effects with cigarette smoke did not conform with previously reported effects of nicotine on the heart. The release of histamine from the lungs was demonstrated in some lungs for both cigarette smoke and anoxemia. In a study of the effects of inhalation of cigarette smoke on the coronary circulation of the anesthetized dog, the perfused coronary artery did not show local vasoconstriction in response to exposure of the blood perfusate to cigarette smoke. The same perfused coronary artery showed vasocon- 41
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striction in response to injected nicotine and to systemic effect of cigarette smoke. The third of this series of experiments dealt with the effects of cigarette smoke and nicotine on the pulmonary circulation. Results showed that the inhalation of cigarette smoke or the injection of nicotine caused constriction of the pulmonary blood vessels. Because of the inconsistent results obtained with cigarette smoke, nicotine was used primarily as the test substance. The vasoconstriction elicited by nicotine in the perfused lung of the anesthetized dog was independent of the bronchoconstrictor response. It was seen that the vasoconstriction persisted after acute vagotomy and administration of atropine but was completely blocked by the administration of a local anes- thetic agent. The possibility that the vasoconstriction was brought about by the release of histamine is discussed. "OXYGEN CONSUMPTION AND ALVEOLAR VENTILATION DUR- ING INTERMITTENT POSITIVE PRESSURE BREATHING." By Stephen M. Ayres, MD, and Stanley Giannelli, Jr., MD, FCCP, De- partments of Medicine and Surgery, St. Vincent's Hospital and Medical Center, New York City, and New York University School of Medicine. Diseases of the Chest 50/4:409-414, October 1966. (Grantee: Ayres) The significance of the role of intermittent positive pressure breathing devices (IPPB) in the treatment of emphysema is dependent upon the ability of IPPB to significantly decrease the work of breathing in addition to increas- ing minute ventilation. The present paper reports studies of the mechanical work and oxygen consumption of the respiratory muscles before and during assisted ventilation with a volume-cycled IPPB apparatus. In this study, oxygen consumption, alveolar ventilation and arterial gas tensions were measured in eight patients with abnormal respiratory gas exchange following recovery from an episode of respiratory acidosis. The patients - six with severe obstructive emphysema and two with neurological disease involving the chest wall - were studied at rest and during IPPB. Results showed that the oxygen cost per unit of ventilation decreased an average of 34 per cent during IPPB. Dead space ventilation was unchanged, but the alveolar-arterial oxygen difference was increased in all patients, indicating that the distribution of ventilation with IPPB is different from that with spontaneous respiration. These studies indicate the properly admin- istered IPPB increases the efficiency of the respiratory muscles and decreases their entropy. Other grantors: American Thoracic Society and the New Jersey Medical Research and Teaching Fund. "RESPONSES OF UPPER RESPIRATORY MUCOSA TO DRUGS AND VIRAL INFECTIONS." By Frederik B. Bang, MD, Betsy G. Bang, AB, and Marie A. Foard, AB, Department of Pathobiology, School'of Hygiene and Public Health, The Johns Hopkins University, Baltimore, Maryland. American Review of Respiratory Diseases 93/3-11:142-149, March 1966. (Grantee: F. B. Bang) 42 vn 0 0 .~ ~ 0 J ~ i
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The present paper summarizes and analyses results obtained in a series of experiments dealing with the effects of certain drugs and other agents on upper respiratory mucosal function. Since a virus must have access to a susceptible cell in order to produce infections, agents were tested to determine whether they might alter suscepti- bility to a virulent strain of Newcastle Disease virus. To obviate the question- able aspects of in vitro studies, experiments were conducted mostly on the nasal mucosa of normal, unanesthetized chicks. In the study of the differential effects of agents on the components of the mucociliary system, it was shown that dehydration, pilocarpine and vitamin A deficiency primarily affected mucus secretion; cocaine, xylocaine and lowered temperature affected ciliary function, and cyclaine, severe vitamin A deficiency and viruses (influenza in ferrets, laryngotracheitis in chicks) affected cellular integrity. Viruses, which seem to act by destroying the cells of the mucosa, leave behind an epithelium which, during regeneration, has at first few or no cilia. This destruction, which involves both ciliated and mucous cells, exposes the denuded mucosa to absorption of other toxic substances. Regeneration of the two component parts of the epithelial system does not always proceed at the same rate. As the motion of the mucociliary blanket depends on the con- certed activity of mucous cells and cilia, lack of movement of the blanket does not necessarily mean that ciliary action itself has been inhibited. Actual ciliary paralysis induced by cocaine did increase the number of infected cells by 10 to 50 times over the control values. Other grantor: National Science Foundation. "LARYNGOTRACHEITIS VIRUS IN CHICKENS." By Betsy G. Bang, AB, and Frederik B. Bang, MD, Department of Pathobiology, School of Hygiene and Public Health, The Johns Hopkins University, Baltimore, Maryland. Journal of Experimental Medicine 125/3:409-427, March 1967. (Grantee: F. B. Bang) Infectious laryngotracheitis can be produced in chickens as an experi- mental model of severe nonfatal rhinitis and sinusitis. This study presents a morphological appraisal of the effects of laryngotracheitis on the tissue systems of the nasal fossa. Unaesthetized white Leghorn baby chicks received intranasal inocula- tions of a suspension of this virus and pathological changes of the nasal tissues were followed sequentially from the earliest demonstrable lesions thlough the 4th month of convalescence. The resultant viral infections, while remaining limited to the nasal fossa, produced acute desquamation of all nasal epithelia, resulted in functional recovery of the respiratory epithelium, but left important residual abnormalities. Initial lesions were first identifiable in the mucociliattd cells of the shallowest portion of the epithelium about 21 hours after inoculation. After a three to seven day period of acute sloughing, repair (initiated by the u 0 0 ~ r 43 0 -4 J 1O
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rapid spread of a sheet of epithelial cells over the infiltrated submucosa) began and lasted for eight to 21 days. After convalescence, however, eight specimens all showed complete metaplasia of the olfactory organ to muco- ciliated epithelium, all showed abnormal formation and alignment of mucous acini, and about 50% had severe persistent sinusitis. Other grantor: National Science Foundation. "ACUTE VENTILATORY FAILURE IN CHRONIC OBSTRUCTIVE LUNG DISEASE." By Franklin B. Saksena, MD, and Benjamin Burrows, MD, Department of Medicine, University of Chicago, Illinois. Diseases of the Chest 50/2:176-179, August 1966. (Grantee: Burrows) Ten episodes of acute ventilatory failure in eight chronically hyper- capneic patients are reported. Acute ventilatory failure, generally defined as an abrupt increase in carbon dioxide tension, is a common complication of chronic obstructive lung disease, particularly in chronically hypercapneic patients under the stress of acute respiratory infection or with exacerbation of congestive heart failure. With milder episodes of acute ventilatory failure, patients usually respond satisfactorily to management of the underlying cardiopulmonary disorder, requiring neither analeptic drugs nor mechanical ventilatory assistance. "THORACIC COMPLIANCE IN CHRONIC OBSTRUCTIVE LUNG DISEASE." By Franklin B. Saksena, MD, and Benjamin Burrows, MD, De- partment of Medicine, University of Chicago, Illinois. Journal of Laboratory and Clinical Medicine 68/3:427-432, September 1966. (Grantee: Burrows) A weighted spirometer technique was used in this study to measure total thoracic compliance in 17 patients with the emphysema-bronchitis syn- drome. In 8 patients, lung and chest wall compliances were also determined. With this method, total thoracic and chest wall compliance appeared essen- tially normal. This contrasted with the low total thoracic and chest wall com- pliances found in similar patients when measurements were made with the negative pressure body box technique. It is suggested that the low chest wall compliance obtained by the latter procedure and noted by others with the relaxation pressure method may have been due to incomplete relaxation of the thoracic muscles of patients with this type of respiratory insufficiency. It is doubtful that chest wall compliance can be measured with accuracy in such patients with any of the methods mentioned. Other grantor: U.S. Public Health Service. "CARBON DIOXIDE TENSION AND VENTILATORY MECHANICS IN CHRONIC OBSTRUCTIVE LUNG DISEASE." By Benjamin Burrows, MD, Franklin B. Saksena, MD, and Carl F. Diener, MD, Department of Medicine, University of Chicago, Illinois. Annals of. Internal Medicine 65/4:685-700, October 1966. (Grantee: Burrows) . Carbon dioxide retention tends to vary greatly in patients with irre- 44
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versible airways obstruction of uncertain etiology. This report, which is based on studies of ventilatory mechanics in 34 male patients, attempts to explain this variability. Studies of the relationship between carbon dioxide tension and ventila- tory characteristics indicate that frank carbon dioxide retention is espe- cially likely to occur in patients who, in addition to having alveolar under- ventilation and a limited ventilatory capacity, show a rapid, shallow breath- ing pattern. This type of breathing requires that a greater portion of the minute volume be wasted in ventilating the anatomical dead space and aggravates the existing tendency to hypcrcapnia. It is proposed that pul- monary compliance is a factor in determining breathing pattern and, hence, in regulating the tendency to carbon dioxide retention. Patients with relatively low lung compliances, shallow respirations, high inspiratory resistances, and hypercapnia show clinical and physiological features which suggest that bronchitis and parenchymal inflammatory changes are important in the pathogenesis of their disease. Such patients (who have been found to have relatively slight emphysematous destruction of the lung parenchyma at postmortem examination) have been designated as having type B or "bronchial type" disease. In contrast, type A ("emphy- sematous type") patients, who have features that indicate severe anatomical emphysema, generally show normal or high lung compliances, have a deep, slow breathing pattern, and show a lesser tendency to hypercapnia. Other grantor: U. S. Public Health Service. "THE INFLUENCE OF CIGARETTE SMOKE ON LUNG CLEAR- ANCE." By Charles W. LaBelle, PhD, Dorothea M. Bevilacqua, MA, and Heinrich Brieger, MD, Department of Preventive Medicine, Jefferson Med- ical College, Philadelphia, Pennsylvania. Archives of Environmental Health 12:588-596, May 1966. (Grantee: LaBelle)* Unanesthetized rabbits were exposed intermittently to concentrations of cigarette smoke in such a way as to approximate the pattern of smoking by human beings. The effect of the smoke of filter and nonfilter cigarettes was examined on an acute and a subchronic exposure schedule. Two different radioactive test particulates were used in order to assay rapid and delayed pulmonary clearance following the imposition of insoluble particles. In none of the experiments did interference with pulmonary clearance occur. Fluid retention and phagocytosis were studied in additional experiments on rats. The lung-weight to body-weight ratios were the same in the experi- mental and in the control animals. The carbon-induced stimulation of phagocytosis was not mitigated by the inhalation of cigarette smoke; it was actually increased by exposure to the smoke of nonfilter cigarettes. "RADIOLOGIC CONTRIBUTIONS TO THE NOSOLOGY OF OB- STRUCTIVE LUNG DISEASE ENTITIES." By Mauricio J. Dulfano, MD, t 0 * Deceased 0 ~ r 45 © 4
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and John Hewetson, MD, The Lung Station (Tufts) and Department of Radiology, Boston City Hospital, Boston, Massachusetts. Diseases of the Chest, 50/3:270-280, September 1966. (Grantee: Segal) Criteria for clinical classification of patients with the "obstructive lung disease syndrome" are described. These criteria, based upon the considera- tion of simple clinical, physiologic and radiologic data, are usually sufficient for making a differential diagnosis of the patient's condition as (1) asthma, (2) chronic bronchitis, (3) chronic pulmonary emphysema or (4) com- binations thereof. Four case reports are given in illustration. Emphasis is placed on more decisive interpretation of the plain chest X-ray film, particu- larly in recognizing chronic bronchitis. Other grantor: National Heart Institute of the U. S. Public Health Service. VII. Neurophysiology "POSTGANGLIONIC NATURE OF PARASYMPATHETIC INNER- VATION OF PIG IRIS SPHINCTER." By U. Schaeppi, Laboratory of Neurophysiology and Neuropharmacology, Worcester Foundation for Ex- perimental Biology, Shrewsbury, Mass. American Journal of Physiology 210/1: 91-94, January 1966. The widely-accepted notion that the parasympathetic nerve supply of the iris is postganglionic has not excluded the possibility that this innervation is in part preganglionic. To clarify the nature of the parasympathetic inner- vation of the iris, in vitro studies were made of isolated iris sphincters of pigs, a species with a strong parasympathetic innervation. Two weeks after ciliary ganglionectomy, isolated iris sphincters showed enhanced muscle tone, in- creased spontaneous autonomous activity, supersensitivity to acetylcholine, and marked decrease in electrical excitability, all of them symptoms of post- ganglionic denervation. The feeble electrically-induced contraction which occurred in these sphincters was in part resistant to treatment with phentolamine and artopine. A similar electrically-induced contraction occurred in sphincters from normal eyes which had been treated with these two blocking agents. The feeble protracted electrically-induced contraction appears then to result from direct action of the electrical current upon the iris tissue. These observations lead to the conclusion that the parasympathetic innervation of the iris sphincter is entirely postganglionic. The observation that nicotine produced contraction of normal iris sphincters but failed to produce contraction of denervated sphincters sug- gests that nicotine acts by stimulation of postganglionic parasympathetic nerve endings which induces the subsequent release of cholinergic transmitter. "NON-GANGLIONIC PARASYMPATHOMIMETIC ACTION OF NICOTINE UPON THE ISOLATED CAT IRIS." By U. Schaeppi, B. L. Dennison and M. Dodd, Shrewsbury, Mass. Journal of Pharmacology and 46 3,
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Experimemal Therapeutics 154/2: 216-223, November 1966. (Grantee: Schaeppi) Pupillary changes of isolated intact cat irides were investigated in vitro. Normal irides reacted to nicotine with miosis followed by mydriasis. The threshold dose of nicotine for miotic effects varied from 1 to 10 mg (added to the bath fluid). The response of the irides decreased or disap- peared completely when the injection of nicotine was repeated, even after intervals as long as two hours. Nicotine in doses as high as 10 mg had no effect on the response of the cat iris to electrical stimulation. Chronically parasympathetically denervated irides reacted to nicotine with mydriasis, while chronically sympathetically denervated irides reacted with miosis. These findings together with the effects of atropine, physostig- mine and hexamethonium upon electrically induced responses of normal irides further support the earlier conclusion that nicotine-induced sphincter contraction resulted from postganglionic stimulation of parasympathetic nerve fibers. "DEMONSTRATION OF AVERAGED OPERANT POTENTIALS 1N THE HUMAN EEG." By Alfredo J. Vazquez, MD, and James E. P. Toman, PhD, Division of Behavioral Sciences, Chicago Medical School, Illinois. Electroencephalography and Clinical Neurophysiology 21:381-384, 1966. (Grantee: Toman) The averaged EEG activity preceding a voluntary motor act in man was studied for the purposes of : 1) searching for both reproducible and modifiable features of the EEG in the pre-decision period and 2) developing useful methodology for such research. Demodulated taped EEGs from subjects operating a key-press on the basis of an initial general instruction were fed to a Mnemotron 400 B Com- puter of Average Transients which summed pre-action EEG traces (AOP: averaged operant potentials). The intrinsic difficulties of such an analysis are duly noted. A significant cluster of small amplitude waves was found commonly present in bipolar recordings from the contralateral parietal area, in the period from 330 to 140 msec pre-trigger, in particular a 300 msec positive peak. Other grantor: National Institutes of Health. "PHARMACOLOGICAL ANALYSIS OF EVOKED POTENTIALS IN RABBIT CORTEX." By A. J. Vazquez, MD, H. C. Sabelli, MD, R. I. Ludmer, MD, and J. E. P. Toman, PhD, Department of Pharmacology and Therapeutics, Chicago Medical School, Illinois. Chapter 5 (pp 51-71) in "Recent Advances in Biological Psychiatry," Volume VIII, Plenum Press, 1966. (Grantee: Toman) This report deals primarily with drug-induced changes, of the entire evoked response of the rabbit sensorimotor cortex from I msec to I see after brief stimulation of subconvulsive intensity. Experiments were conducted on unanesthetized, lightly restrained rabbits (1 to 2 kg), chronically im- planted with a triangular electrode array. Test drugs included cholinergics, 47 0
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antimuscarinics, convulsants, anticonvulsants, psychotomimetics, and adren- ergic precursors, mimetics, releasers, and blockers. The "muscarinic" (N4) potentialwas the only one to display a clear pattern of pharmacological sensitivity; all other components were affected by most drugs, but were not abolished by any of the synaptic inactivators tested. Thus, it appears that the corresponding endogenous chemicals do not play an essential role in cortical synaptic transmission, but a secondary modulating function. Overall results suggest that cholinergic esters and picrotoxin-sensitive modulators may play a role in the modulation of cortical electrical activity, but suggest that other endogenous chemicals, probably unknown as yet, have still more essential function in cortex.. Other grantors: U. S. Public Health Service (2), Abbott Laboratories, and Consejo Nacional de Investigaciones Cientificas y Tecnicas (Argentina). "DRUG INDUCED RAGE IN CATS." By Alfredo J. Vazquez, MD, and Hector C. Sabelli, MD, PhD, Department of Pharmacology, The Chicago Medical School, Illinois. The Chicago Medical School Quarterly pp 137-144, Fall 1966. (Grantee: Toman) In this study of the role of acetylcholine as a chemical mediator respons- ible for the triggering of rage, cats receiving intraperitoneal injections of cer- tain drugs (cholinergics, cholinergic muscarinics, atropinics and psycho- tomimetics) were observed for overt signs of excitation, stereotyped hostility, directed hostility and stereotyped activity. Tremorine, oxotremorine, arecoline, pilocarpine and muscarine pro- duced a hostile reaction which included hissing, scratching and biting. Prior to the development of affective changes, a period of intense parasympathetic stimulation was noted. LSD-25 produced signs of directed and undirected hostility, as well as different types of stereotyped movements. The signs of hostility were milder than those observed with muscarinic drugs. In contrast, hissing and jumping were more frequent than with the cholinergic drugs. Atropinic agents produced stereotyped movements. The following drugs given prior to the administration of any of the rage-producing agents pre- vented the rage response: atropine, scopolamine, diethazine hydrochloride and JB-329. Although the specific site of action is not known, it is demonstrable that the response is triggered at central cholinergic receptors. On the basis of these tests, it is assumed that the fundamental neuronal pathway involved in drug-induced rage in cats is of a cholinergic nature, but normally is held in abeyance by a strychnine sensitive presynaptic inhibitory mechanism. Other grantor: U. S. Public Health Service (2). VIII. Cheniistry and Biochemistry "DETERMINATION OF BLOOD CARBON MONOXIDE CONTENT BY GAS CHROMATOGRAPHY." By Stephen M. Ayres, MD, Antoinette Criscitiello, and Stanley Giannelli, Jr., MD, Cardiopulmonary Laboratory, 48
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St. Vincent's Hospital and Medical Center, and the Departments of Medicine and Surgery, New York University, New York City. Journal of Applied Physiology 21/4: 1368-1370, July 1966. (Grantee: Ayres) This paper describes a simple gas chromatographic technique for measuring small concentrations of CO which equals the accuracy of the most satisfactory methods available up to now and has the additional advan- tage of allowing modification for the analysis of nitrogen, neon and other inert gases. Small amounts of blood CO were measured by this method following vacuum extraction in a Van Slyke manometric apparatus. The coefficient of variation for 23 consecutive duplicate determinations on blood samples containing 0.0113-2.3830 ml/100 ml averaged 1.95%. In a larger series of samples obtained from 22 nonsmokers and 33 smokers, blood CO content was 0.096± 0.056 (mean ± SD) in the'nonsmokers and 0.549 ±0.446 ml/100 ml in the smokers. Other grantor: The Health Research Council of the City of NevV York. "CELLULOSE COLUMN CHROMATOGRAPHY FOR THE FRAC- TIONATION AND ISOLATION OF ACID MUCOPOLYSACCHAR- IDES." By Yukio Tanaka, MD, and Ira Gore, MD, Department of Path- ology, University Hospital, Boston University Medical Center, Massachu- setts. Journal of Chromatography 23/2:254-260, 1966. (Grantee: Gore) This paper describes in detail a laboratory procedure for the sharp separation of the acid mucopolysaccaride (AMPS) mixture found in human arteries based upon the use of a single cellulose column. A human arterial AMPS mixture may be separated into its individual constituents by eluting the cetyl pyridinium complexes from a cellulose column with 0.35 M and 0.6 M NaCl, disrupting the complexes with 90% ethyl alcohol and eluting further with 30 and 10% concentrations of ethanol. Acetate paper electro- phoresis, infrared spectra, chemical analysis, hydrolysis with hyaluronidase and paper chromatography of products of acid hydrolysis of AMPS are used to identify the separated components and to ascertain the adequacy of separation. Other grantor: National Heart Institute. "URINARY EXCRETION OF CONJUGATE FORMS OF 1-(3- PYRIDYL)ETHANOL AFTER ADMINISTRATION OF 3-ACETYL- PYRIDINE." By Herbert McKennis Jr., Lennox B. Turnbull, Edward R. Bowman, and C. Norman Lukhard, Department of Pharmacology, Medical College of Virginia, Richmond. Journal of Biological Chemistry 241/8:1878- 1881, April 25, 1966. (Grantee: McKennis) Oral administration of 3-acetylpyridine to the dog led to the excretion of 1-(3-pyridyl)ethanol in two acidic conjugate forms which were fraction- ated with the aid of ion exchange resins. The more acidic of the conjugate forms had the properties of a sulfate ester in comparison with synthetic material. Acidic hydrolysis of the sulfate ester fraction led to the release of (-)-1-(3-pyridyl)ethanol. Acidic hydrol- 49
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ysis of the other conjugate form, which had properties of a glucuronide, led to the release of 1-(3-pyridyl)ethanol which after chromatographic purifi- cation was approximately 95% pure on the basis of extinction coefficient and which was approximately 60% in the levorotatory form on the basis of optical rotation. The pyridylethanol separated after the hydrolysis of the glucuronide contained, in addition, two other Koenig-positive materials. By the chromatographic behavior of some of the latter and by analogy to the metabolism of phenyl-1,2-ethanediol, the formation of a glucuronide of (3-pyridyl)-1,2-ethanediol is suggested. Other grantors: National Institutes of Health, American Medical Associ- ation Education and Research Fund, and American Tobacco Company. "THE FATE AND DISTRIBUTION OF 1-(3-PYRIDYL)ETHANOL METHIODIDE IN RELATION TO THE TOXICITY OF 1-(3-PY- RIDYL)ETHANOL AND 3-ACETYLPYRIDINE." By John P. Bederka Jr., Eskil Hansson, Edward R. Bowman, and Herbert McKennis Jr. Bio- chemical Pharmacology 16/1:1-10, January 1967. (Grantee: McKennis) There was a rapid elimination of the radioactivity of (+; )-N-methyl- "C-3-(1-hydroxymethyl)pyridinium iodide following intravenous adminis- tration to mice. In common with the established behavior of many other quaternary ammonium compounds, this compound showed no great tend- ency to pass the blood-brain barrier. The radioactivity of the compound was eliminated largely (78-90% ) by way of the urine within 24 hours, as was the case upon intraperitoneal administration of the same compound to rats. This excreted radioactivity was predominantly in the form of the admin- istered cation. Other grantors: National Institutes of Health, American Medical Associa- tion Education and Research Foundation, American Tobacco Company, and Swedish Tobacco Company. "STUDIES ON THE SEPARATION OF ACIDIC METABOLITES OF NICOTINE BY GAS CHROMATOGRAPHY." By Herbert McNennis Jr., E. R. Bowman, and Mohammad Saeed Dar. Virginia Journal of Science 18 N.S./1:13-18, January 1967. (Grantee: McKennis) As part of an investigation of procedures for the gas chromatographic determination of mammalian metabolites of nicotine, a synthetic mixture of the methyl esters of nicotinic acid, 3-pyridylacetic acid, y-(3-pyridyl) butyric acid, y-(3-pyridyl)-y-oxobutyric acid, and 5-(3-pyridyl) tetrahydrofura- none-2 was investigated and found to give adequate separation on a Carbo- wax 20M column (5.6% on Anakrom ABS). Aqueous solutions of synthetic (±)-y-(3-pyridyl)-y-methylamino- butyric acid, prepared by an improved procedure, were converted by the apparatus and column conditions to cotinine as determined by comparison with the response of equimolar amounts of cotinine in a flame ionization detector. Cotinine, in contrast to methyl y-(3-pyridyl)-y-ozobutyrate and 5- (3-pyridyl) tetrahydrofuranone-2, provided essentially no signal to the 50
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electron-capture detector. The ease with which y-(3-pyridyl)-y-methylam- inobutyric acid can be converted to cotinine appears to afford a basis for the quantitative determination of the methylamino acid. Other grantora: American Medical Association Education and Research Fund, and American Tobacco Company. "OBSERVATIONS ON SOME EFFECTS OF THE SODIUM SALTS OF CERTAIN MONOCARBOXYLIC ACIDS ON ESTABLISHED CELL LINES." By Donald M. Pace, PhD, Byron Th. Aftonomos, Alice Elliott, and Steven Sommer, Institute for Cellular Research, Department of Zoology and Physiology, University of Nebraska, Lincoln. Canadian Journal of Biochemistry 45/1:81-88, January 1967. (Grantee: Pace) Some of the steam-volatile organic acids found in polluted air and tobacco smoke were studied to obtain information regarding their toxicity in cells cultivated in vitro. Quantitative and qualitative determinations were made of the action of the salts of 10 monocarboxylic acids (formate, acetate, propionate, buty- rate, valerate, caproate, oenanthylate, caprylate, caprate and benzoate) on several established cell lines (HeLa, strain L, human lung and human skin). All of these compounds at a concentration of 10 mg % were toxic to the cell lines tested with the exception of formate, acetate and benzoate on strain L, and of valerate and caprylate on human lung. At a concentration of 1 mg %, on the other hand, all the compounds either stimulated prolifera- tion or had no significant effect except caproate and benzoate, which were toxic to human lung and human skin cells, respectively. Other grantor: U. S. Public Health Service. "CHLOROGENIC ACIDS AND RELATED DEPSIDES." By Ernest Sondheimer, PhD, Department of Chemistry, State University College of Forestry, Syracuse University, New York. The Botanical Review 30/4:667- 712, Oct.-Dec. 1964. In this review paper, the chemistry, natural distribution, biosynthesis and important properties of the chlorogenic acids and their related depsides are discussed. "THE DETERMINATION OF D-QUINIC AND D-SHIKIMIC ACIDS BY MICROBIOLOGICAL ASSAY IN THE CHARACTERIZATION OF CHLOROGENIC AC1DS AND RELATED COMPOUNDS." By Gerald Cookman and Ernest Sondheimer, PhD, Department of Chemistry, State University College of Forestry, Syracuse University, New York. Phyto- chemistry 4:773-775, 1965. (Grantee: Sondheimer) In this report, a microbiological assay for the quantitative, stereospecific determination of microgram quantities of D-quinic and D-shikimic acids is described and the application of the procedure to structural work with chlorogenic acid and related depsides is demonstrated. An Aerobacter aero- genes mutant, shown previously to be suitable for microbiological assays of quinic and shikimic acids, was used in these tests. 51
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IX. Pharmacology tatd Psycho-Pharmacology "RELEASE OF 5-HYDROXYTRYPTAMINE FROM ISOLATED DOG INTESTINE BY NICOTINE." By T. F. Burks and J. P. Long, PhD, Depart- ment of Pharmacology, College of Medicine, University of Iowa, Iowa City. British Journal of Pharmacology and Chemotherapy 30/2:229-239, June 1967. (Grantee: Long) Nicotine and dimethylphenylpiperazinium (DMPP), both powerful stimulants of autonomic ganglia, significantly enhanced release of 5-hy- droxytryptamine (5-HT) into the venous effluent of perfused dog intestinal segments and also stimulated the intestinal smooth muscle. On the other hand, the smooth muscle stimulating and 5-HT releasing properties of nicotine and ACh were significantly antagonized by atropine. When isolated intestinal segments were perfused with Ca+{-free solu- tion, spasmogenic responses to nicotine were completely eliminated and the responses of the intestinal muscle to 5-HT and morphine were greatly reduced. Upon investigation of the action of C6 (hexamethonium), a selective and potent ganglionic blocking agent, it was seen that C6 did not antagonize the increase in intestinal motility by nicotine and DMPP; in fact, contrary to expectations, there was a non-significant increase in the response to nicotine after C6 treatment. Both nicotine and DMPP were significantly antagonized on the isolated intestinal section by 500 microgram doses of nicotine. Possibilities are considered that nicotine and DMPP could enhance 5-HT release and motility in this preparation by stimulation of extragangli- onic nervous structures, by direct action on the cholinergic receptors or, perhaps more likely, by stimulating a population of ganglion cells which are exceptionally resistant to C6 blockade. Other grantors: American Medical Association - Education and Research Foundation and the U.S. Public Health Service. "EFFECT OF GROUP SIZE AND CAGE DESIGN ON VOLUNTARY RUNNING ACTIVITY OF AMPHETAMINE-TREATED MICE." By Duane G. Wenzel, PhD, and L. L. Broadie, Division of Pharmacology, School of Pharmacy, The University of Kansas, Lawrence. Archives Inter- nationales de Pharmacodynamie et de Therapie 159/1:154-160, 1966. (Grantee: Wenzel) The interrelationship of group size and cage design in the measurement of voluntary running activity of mice was studied. Male albino CFW mice were placed in activity cages for a one and one- half hour period of acclimatization after which either d-amphetamine or sa- line solution was administered intraperitoneally, and voluntary running activ- ity was recorded for 60 minutes. Groups of two, three, four, and five control or experimental mice per group were tested in single-beam (unreflected), single-beam reflected and triple beam photoelectric activity unit designs. 52
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Results showed that, with the three cage designs employed, cage design and group size effected variability to only a limited extent. However, sensi- tivity to increases in voluntary running activity was found to be closely related to both design and group size. With all three designs, a relatively low number of counts were obtained with groups of two or three animals, but the triple beam cage design was more efficient than either of the single beam cage designs for measurement of the higher number of counts obtained with four or five animals per group. Other grantor: National Science Foundation. "STIMULATORYEFFECTOF NICOTINE ON THE METABOLISM OF MEPROBAMATE." By Duane G. Wenzel, PhD, and Larry L. Broadie, Division of Pharmacology and Toxicology, School of Pharmacy, The Uni- versity of Kansas, Lawrence. Toxicology and Applied Pharmacology 8/3:455-459, May 1966. (Grantee: Wenzel) The effect of semichronic nicotine administration upon the in vivo response to, and the metabolism of, meprobamate is presented in this paper. Thirty male mice trained to balance on a "rotarod" were used to measure the duration of ataxia produced by the intraperitoneal injection of 200 mg/kg of ineprobamate. The administration of 2.28 mg/kg/day of nicotine alkaloid in drinking water caused an immediate and significant decrease in the period of ataxia produced by the meprobamate. A similar, although lesser, effect resulted from the administration of ineprobamate alone at 2-day intervals. Stopping the nicotine treatment restored ataxic times to the orig- inal levels. Nicotine, administered in vivo, enhanced the in vitro metabolism of meprobamate by mouse liver homogenate, an effect which was apparently one of enzyme induction since the administration of ethionine blocked the effect. Other grantor: National Science Foundation. "INFLUENCE OF PROPRANOLOL ON HEMODYNAMIC CHANGES AND PLASMA CATECHOLAMINE LEVELS FOLLOWING CIGAR- ETTE SMOKING AND NICOTINE." By Thomas C. Westfall, PhD, P. B. Cipolloni, and A. C. Edmundowicz, Departments of Pharmacology and Medicine, West Virginia University Medical Center, Morgantown. Proceed- ings of the Society for Experimental Biology and Medicine 123/1:174-179, October 1966. "ACCUMULATION OF NOREPINEPHRINE IN RAT TISSUE FOL- LOWING TREATMENT WITH THREE BETA-ADRENERGIC AN- TAGONISTS." By Thomas C. Westfall, PhD, Department of Pharma- cology, University of Virginia.School of Medicine, Charlottesville. Archives Internationales de Pharmacodynamie et de Th9rapie 161/1:69-79, May 1967. (Grantee: Westfall) 53
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These papers present two different aspects of the effects of beta- I adrenergic antagonists upon cardiovascular hemodynamics and catechola- ~ mine levels in the plasma and tissues of laboratory animals. The first paper details a study of the effect of propranolol, a beta- adrenergic antagonist, on the hemodynamic and catecholamine releasing properties of cigarette smoke inhalation and nicotine administration in the dog. Cigarette smoke inhalation or intravenous infusion of nicotine,pro- duced a marked increase in cardiac output, stroke volume, arterial blood pressure and plasma epinephrine and norepinephrine levels with a reflex decrease in heart rate in the morphine-pentobarbital anesthetized dog. Fol- lowing beta adrenergic blockade with 0.2 mg/kg propranolol intravenously, cigarette smoke inhalation and nicotine infusion resulted in a marked alter- ation of cardiac output, stroke volume, heart rate and mean arterial pressure without significant changes in caval plasma catecholamine levels. It is concluded that beta adrenergic blockade produced by propranolol does not modify the release of catecholamines from the adrenal glands of dogs in response to smoking and nicotine and that the "unmasking" of alpha receptor activity causes a marked increase in systematic peripheral resistance and comprises left ventricular function. The effect of three of the newer beta-adrenergic antagonists (prone- thalol, propranolol and iproveratril) on the endogenous and infusion levels of norepinephrine (NE) in rat tissues is the burden of the second study. Pronethalol produced a significant decrease in endogenous levels and a significant inhibition of the accumulation or uptake of infused NE into the heart in the anesthetized rat. These two observations were seen only at doses larger than necessary to block the beta-adrenergic receptor and are prob- ably unrelated to the blocking properties of the drug. Propranolol failed to alter either the endogenous amine level or the uptake of infused NE, while iproveratril produced a significant decrease in endogenous levels but only a slight and insignificant inhibition of uptake of NE. Other grantors: West Virginia Heart Association and the National Heart- - Institute. X. Pregnancy Studies "STUDIES ON NICOTINE ABSORPTION DURING PREGNANCY. I. LDSO FOR PREGNANT AND NONPREGNANT RATS." By J. Edward King, AM, and R. Frederick Becker, PhD, Department of Anatomy, Labora- tory of Perinatal Studies, Duke University Medical Center, Durham, North Carolina. American lournal of Obstetrics and Gynecology 95/4:508-514, June 1966. "STUDIES ON NICOTINE ABSORPTION DURING PREGNANCY. II. THE EFFECTS OF ACUTE HEAVY DOSES ON MOTHER AND 54
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NEONATES." By R. F. Becker and J. E. King. American Journal of Obstet- rics and Gynecology 95/4:515-522, June 1966. (Grantee: Becker) These two studies deal with nicotine absorption during pregnancy and its effect upon mother and neonate. Initially, the 50 per cent lethal dose of nicotine for pregnant and non- pregnant female rats of the Osborne-Mendel strain and for neonates of this strain was determined before estimating doses that could be administered in chronic studies. All rats were injected subcutaneously with heavy doses of a 2 per cent solution of pure nicotine. Pregnant rats received the drug on the twenty-first day, one day before expected delivery. The following values were obtained: Osborne-Mendel rats LDSO (mg/kg) Pregnant adults, 140 to 150 days of age 27.4 Nonpregnant females, 140 to 150 days of age 33.5 Neonates, 6 to 24 hours old 14.55 Pregnant rats tended to die significantly later than nonpregnant rats, but their tolerance for nicotine was considerably less. Also, pregnant versus nonpregnant differences in respect to tolerance for nicotine were the reverse of those consistently encountered with barbiturates. In the second study, primipara pregnant rats, 140-150 days old, received a single heavy subcutaneous injection of nicotine on the twenty-first day of pregnancy. Pregnant rats responded differently from nonpregnant females the same age, similarly treated. The pregnant animals tolerated less drug and hyperventilated excessively while body temperature depression was not as marked as in the nonpregnant rat. Many of the treated animals failed to build adequate nests or to take proper care of their young. Delivery was delayed 2 to 4 days beyond term, the young tended to be lighter in weight than normal, and the young survived poorly through the• first critical 48 hours of life. The data presented here do not support the idea of an extremely rapid elimination of nicotine from tissues when it is present in near-lethal amounts. Other grantor: Duke University Research Council. XI. Other Studies "EXTENSION OF ELECTRON AFFINITIES AND IONIZATION PO- TENTIALS OF AROMATIC HYDROCARBONS." By Ralph S. Becker, PhD, and Edward Chen, Department of Chemistry, University of Houston, Texas. The Journal of Chemical Physics 45/7:2403-2410, October 1966. (Grantee: Becker) The electron affinities of 14 aromatic hydrocarbons are reported in this paper. Data reported here and earlier show that it 4s possible to determine molecular electronegativities [X=~h (ionization potential + electron affinity)], and that these are essentially constant for the aromatic u! 0 0 r 55 0 ~ t 0
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hydrocarbons. From the molecular electronegativity values either electron affinity (E.A.) or the ionization potential (LP.) can be determined, depend- ing upon which is known. There exists a linear relationship between E. A. and the energy of the iLa transition (1La hv„) for the hydrocarbons studied. From lLa-hvao val- ues, a large number of E.A. values can be predicted. It does not appear reasonable to relate the intercept resulting from extrapolation of the afore- mentioned plot to hv=O to the work function of graphite. Based on the measured electron affinities, it is possible to deduce a relationship with methyl affinities and calculate oE,o, between neutral hydrocarbons and their mononegative ions. Certain theoretical approaches can be successfully employed to estimate electron affinities of aromatic hydrocarbons. Other grantor: U. S. Public Health Service. 56
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. Recipients of Grants Following is a list of all recipients of grants approved by the Scientific Advisory Board since initial grants were made in late 1954. Some of the projects have been completed. GRANTEE AND INSTITUTION CLARENCE M. AGRESS, M.D., Chief, Cardiovascular Laboratory, Veterans Administration Center, Los Angeles; Associate Clinical Professor of Medi- cine, University of California, Los Angeles. ANTHONY A. ALBANESE, PH.D., Di- rector, Nutrition and Metabolic Re- search Division, The Burke Rehabilita- tion Center, White Plains, N. Y. ANTHONY P. AMAROSE, PH.D., F.R.- M.S., Assistant Professor, Department of Obstetrics and Gynecology, The Al- bany Medical College of Union Uni- versity, Albany, N. Y. E. T. ANGELAKOS, M.D., PH.D., Pro- fessor of Physiology, Boston University School of Medicine, Boston. D. MURRAY ANGEVINE, M.D., Pro- fessor of Pathology, University of Wis- consin Medical School, Madison. DOMINGO M. AVIADO, M.D., Profes- sor of Pharmacology, University of Pennsylvania School of Medicine, Phil- adelphia. PROJECT TITLE Measurement of the functional status of the human heart by frequency spec- trum analysis of its vibrational energy The effect of nicotine on protein and amino acid metabolism in humans Effect of nicotine on human metabolism of amino acids Chromosome patterns in patients with car- cinoma of the lung, before, during, and after treatment Release of catecholamines from the iso- lated heart Pathologic-anatomic study of cellular changes in human bronchi Effects of nicotine and cigarette smoking on neurogenic mechanisms in the lung Tolerance of lungs to tobacco with special reference to pulmonary emphysema and vascular occlusive lesions STEPHEN M. AYRES. M.D., Director, Cardiopulmonary Laboratory, St. Vin- cent's Hospital, New York City. FREDERIK B. BANG, M.D., Professor and Chairman, Department of Patho- biology, The Johns Hopkins University, School of Hygiene and Public Health, Baltimore. Measurement of alveolar-arterial nitrogen difference by gas chromatography The diffusing capacity of the alveolar membrane in pulmonary emphysema Relation of air pollution to development of chronic pulmonary disease The effects of measured small amounts of carboxy hemoglobin on cardiorespira- tory function in man Interaction of viruses with mucosa of the respiratory tract, and the effect of varia- tion in function of the mucociliary sys- tem 57
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GRANTEE AND INSTITUTION BRODA O. BARNES, M.D., PH.D., Pro- fessor (affiliate) of Physiology, Colorado State University, Fort Collins. FREDERICK W. BARNES, JR., M.D., PH.D., Associate Professor of Medicine and Physiological Chemistry, Johns Hopkins University School of Medi- cine, Baltimore. Md. (now Professor of Medical Science, Brown University, Providence, R. 1.) T. C. BARNES, D.Sc., Research Scien- tist, Philadelphia State Hospital, Phila- delphia. R. FREDERICK BECKER, PH.D., Asso- ciate Professor of Anatomy and Direc- tor, Laboratory of Perinatal Science, Duke University Medical Center, Dur- ham, N. C. RALPH S. BECKER, PH.D., Professor of Chemistry, University of Houston, Houston, Texas. SAMUEL BELLET, M.D., Director, Di- vision of Cardiology, Philadelphia Gen- eral Hospital. B. BHAGAT, PH.D., Assistant Professor in Pharmacology, New York Medical College, New York. CESARE BIANCIFIORI, M.D., Division of Cancer Research, University of Pe- rugia, Perugia, Italy. PROJECT TITLE A. Epidemiology of lung cancer. Exami- nation of such factors as inheritance, autopsy reports on relatives, residence in unfavorable atmosphere, working conditions relative to health hazards, personal habits, past illnesses, etc. B. The role of the decrease in tuberculosis in the rise of lung cancer, emphysema and myocardial infarction The role of hyperplasia in tissue response to chronic damage The effect of inhalation of cigarette smoke (and injected nicotine) on learning con- ditioned reflexes in rats and on the acquired neurotic head twitch in iso- lated mice Possible effects of maternal intake of nicotine upon the developing fetus and neonate: A study with the rat and guinea pig An investigation of spectral parameters of aromatic hydrocarbons A spectral investigation of aromatic hy- drocarbons and their complexes with proteins The effect of nicotine on cardiac irritation in the presence of reserpine, and the ef- fect of nicotine on coronary blood flow of dogs with coronary insufficiency Effects of nicotine on the morphology of coronary arteries and aorta; fibrinolytic effects of nicotine on human and ani- mal plasma; effects of cessation of smoking on serum cholesterol levels of chronic smokers; the effects of cigarette smoke on free fatty acid levels of sub- jects with myocardial infarctions The effect of nicotine on various param- eters of cardiovascular function The mechanism of nicotine-induced re- lease of catecholamines Lung tumorigenesis by isoniazid (INH), its metabolite hydrazine sulphate (hs.) and derivatives of hydrazine. New po- 58
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I GRANTEE AND INSTITUTION HYLAN A. BICKERMAN, M.D., Asso- ciate Clinical Professor of Medicine, and ALVAN L. BARACH, M.D., Con- sultant in Medicine, College of Physi- cians and Surgeons, Columbia Univer- sity; Columbia University Research Service, Goldwater Memorial Hospital New York. RICHARD J. BING, M.D., Professor of Medicine and Chairman, Department of Medicine, Wayne State University College of Medicine, Detroit. ' FRF.D G. BOCK, M.S., PH.D., Senior Cancer Research Scientist, Roswell Park Memorial Institute, Biological Station, Springville, N. Y. (see Moore) HERMAN V. BOENIG, PH.D., Head, Cheniistry and Biochemistry Depart- ment, Spindletop Research Center, Lex- ington, Kentucky. JAMES F. BONNER, PH.D., Professor of Biology, California Institute of Tech- nology, Pasadena. WALTER M. BOOKER, PH.D., Professor and Head, Department of Pharmasol- ogy, Howard University, Washington, D.C. 59 PROJECT TITLE tential carcinogens for the human lung (INH & h.s.) have been demonstrated in previous experiments on mice. The aims of this project are: I. To study whether the carcinogenic action of INH and h.s. will take place in species of laboratory animals other than mice; and II. To study whether other derivatives of hydrazine are carcinogenic for mice. Non-irritant cigarette smoking with ob- servations on the carbon monoxide concentration of arterial blood and alveolar gas after smoking with inhala- tion and after non-inhalation smoking The effect of a non-inhaling technique of cigarette smoking on the carbon monox- ide blood levels and ventilatory func- tion of healthy subjects and patients with chronic respiratory disease The effect of smoking on the coronary blood flow and certain phases of myo- cardial metabolism in patients with arteriosclerotic or hypertensive cardi- ovascular disease Studies in cellular physiology of heart muscle Measurement of coronary blood flow by means of radioactivated albumin The effect of smoking on coronary blood flow in patients with arteriosclerotic heart disease and the effect of nicotine on storage of amines in heart muscle Measurement of coronary blood flow with a system using coincidence counting; the effect of nicotine and change in heart rate on cardiac metabolism and related subjects Studies on cardiac metabolism with spe- cial reference.to myocardial anoxia Investigation of the biological effects of cigarette smoke An initial study of the effect of model free radicals in carcinogenesis Enzymatic study of methylation reactions in plant tissue Studies on the possible sensitization of the vascular mechanism to catecholamines following nicotine administration
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GRANTEE AND INSTITUTION TOM G. BOWERY, PH.D., Pesticide Res- idue idue Laboratory, Chemistry Depart- ment, North Carolina State College, Raleigh. (now Extramural Operations and Procedures Officer, Department of Health, Education and Welfare, Be- thesda, Maryland) GEOFFREY L. BRINKMAN, M.D., As- sociate Professor of Medicine, Wayne State 'University School of Medicine, Detroit. BARBARA B. BROWN, Ptt.D., Research Professor of Experimental Psychiatry, Californis College of Medicine, Los Angeles. JOSEF BROZEK, PH.D., Professor and Chairman, Department of Psychology, Lehigh University, Bethlehem, Pa. SUE BUCKINGHAM, M.D., Assistant Professor of Pediatrics, Columbia Uni- versity, College of Physicians and Sur- geons, New York City. BENJAMIN BURROWS, M.D., Associ- ate Professor of Medicine, University of Chicago, Chicago. E. M. BUTT, M.D., Chief Pathologist, Los Angeles County Hospital, Los Angeles, California. . RICHARD U. BYERRUM, PH.D., Pro- fessor of Chemistry, Michigan State University, East Lansing. SISTER M. EMILY CAHILL, PH.D., Chairman, Chemistry Department, Regis College, Weston, Mass. WILLIAM H. CARNES, M.D., Professor of Pathology, University of Utah Col- lege of Medicine, Salt Lake City. MARCUS N. CARROLL, JR., PH.D., Chief, Division of Pharmacology, The Brookdale Hospital Center, Brooklyn, N. Y. , 60 PROJECT TITLE TDE and endrin residues in cigarette smoke The effect of cigarette smoking on the ultra microscopic structure of the bron- chial mucosa Nicotine and smoking effects on electro- encephalogram correlates of behavior, emotional responsiveness and visual perception in cats Biological characteristics of men and their smoking habits Studies on the development and biology of lung surfactant Thoracic compliance in chronic obstruc- tive lung disease A correlation of severity of symptoms of chronic obstructive lung disease with environmental factors Pathologic-anatomic study of cellular changes in human bronchi Study of trace metal storage of pulmon- ary and liver tissue by spectrographic and chemical methods Biosynthesis of the pyridine ring of nico- tine Comparison of analytical methods by determining the percent recovery of arsenic added at known levels to to- bacco samples and a broad survey of the amount of arsenic present in to- bacco samples from a wide variety of sources Pathologic-anatomic studies of cellular changes in human bronchi Central nervous system-evoked arrhy- thmias and coronary blood flow .W
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GRANTEE AND INSTITUTION LEOPOLD CERECEDO, PH.D., Profes- sor of Biochemistry and Nutrition, University of Puerto Rico, School ot Medicine, San Juan (formerly Profes- sor of Biochemistry, Fordham'lJniver- sity, New York) NAITER M. CHOPRA, PH.D., Associate Professor of Chemistry, The Agricul- tural and Technical College of North Carolina, Greensboro. WILLIAM G. CLARK, Px.D., Clinical Associate Professor of Physiological Chemistry, University of California ' Medical Center, Los Angeles. HANS T. CLARKE, D.Sc., Professor of Biochemistry, Columbia University Col- lege of Physicians and Surgeons, New York. (retired, see Gottschall) JAY D. COFFMAN, M.D., Section Head, . Peripheral Vascular Laboratory, Uni- versity Hospital, Boston. DANIEL COHEN, D.V.M., M.P.H., As- sistant Professor of Veterinary Epidemi- ology and Public Health, School of Veterinary Medicine, University of Pennsylvania, Philadelphia. JULIUS H. COMROE, JR., M.D., Direc- tor, Cardiovascular Research Institute, University of California Medical Cen- ter, San Francisco. DEAN M. CONNORS, M.D., Associate Director, Department of Laboratory Medicine, St. Mary's Hospital, Madi- son, Wisconsin. PHILIP COOPER, M.D., Chief, Surgical Service, Veterans Administration Hos- pital, Bronx, N. Y.; Clinical Professor PROJECT TITLE A study of early chemical changes in the lungs of tumor-bearing rats and mice The degradation of DDT, TDE and Diel- drin in the cigarette mainstream and sidestream smokes Effect of nicotine and related substances on amine levels in the nervous system Proteolytic activities of the white blood cells of men and the effect on white blood cell activities, of carcinogens, nutrition and other influences The effect of Rauwolfia and Guanethidine (catecholamine depleting or blocking agents) on the sympathetic vasocon- striction induced by tobacco smoking and by environmental body cooling. The role of catecholamine release from the adrenal medulla in causing the cir- culatory effects seen during tobacco smoking Tobacco smoking in human subjects dur- ing beta receptor blockade To survey radiographically the lungs of all dogs passing through the veterinary clinics and hospital of the University of Pennsylvania Veterinary School in order to determine the prevalence of pulmonary abnormalities detectable by this method-a comparative pulmon- ary disease study to define the patterns of respiratory disease in animals in- timately sharing mari s environment and provide information on the effects of air pollution The effect of smoking upon airway resist- ance Analysis of case histories on emphysema A study of the alterations in the human bronchial wall occurring with aging, with particular emphasis on elastic tis- sue changes and associated changes in the bronchial lumen size A study of the effects of cigarette smoking on levels of gastric acid, pepsin, and uropepsin 61
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GRANTEE AND INSTITUTION of Surgery, Albert Einstein Medical College, Bronx. (formerly Professor of Clinical Surgery, Boston University School of Medicine and Chief of Surgi- cal Service and Director of Surgical Re- search Laboratory, Veterans Adminis- tration Hospital, Providence, R. I.) JOHN E. CRAIGHEAD, M.D., Associ- ate in Pathology, Harvard Medical School, Boston. ROBERT L. CRAIN, Ptt.D., Assistant Professor of Sociology, University of Chicago. (see E. Katz) T. TIMOTHY CROCKER, M.D., Profes- sor of Medicine, Department of Internal Medicine, University of California Med- ical Center, San Francisco. CECIL E. CROSS, Research Department, St. Joseph Hospital, Burbank, Califor- nia. (see Salisbury) ALBERT DAMON, M.D., PH.D., Assis- tant Professor of Medical Anthropol- ogy, Department of Industrial Hygiene, Harvard School of Public Health, Boston. R. F. DAWSON, Ptt.D., formerly Profes- sor of Botany, Columbia University, New York. ANDREW S. DIBNER, PH.D., Execu- tive, Psycho-Research, The Age Center of New England, Inc., Boston, Mass. (see Whiskin) EDWARD F. DOMINO, M.D., Professor of Pharmacology, University of Mich- igan, Ann Arbor. RALPH L. DORFMAN, PH.D., Director of Laboratories, Worcester Foundation fot Experimental Biology, Shrewsbury, Mass. (now at Syntex Corporation, Palo Alto, Calif. - see McNiven ) JAMES J. DYAR, PH.D., As$istant Pro- fessor of Biology, Bellarmine College, Louisville, Ky. PROJECT TITLE A study of the effect of extracts of tobac- co on cultures of tumor and normal cells. Animal transplants of tumor tis- sue from tissue cultures Study of combined effect of injected viral agents and environmental factors, in- cluding carcinogens and tobacco smoke, on the tracheobronchial tree and pul- monary parenchyma of experimental animals and on tissues in organ culture Studies on the combined effects of influen- za viruses and sulphur dioxide on lung pathogenesis in Syrian hamsters Biology and cytopathic effects of respira- tory and oncogenic viruses in organ cultures of human respiratory tract tissue Social and psychological correlates of adoption and discontinuation of cigar- ette smoking Biologic activity of tobacco tar on respi- ratory mucosa of rodents, canines and primates in organ culture; a histologic and autoradiographic study Effects of smoking and of nicotine on the heart and circulation: An integrative study Body form, smoking, and alcohol con- sumption among Italian-American men An investigation of the metabolism of pyridine compounds in the tobacco plant Psychological and behavioral characteris- tics of inhalers among smokers Effects of tobacco smoke and nicotine on the central nervous system Evaluation of tobacco consumption on the basis of nicotine or nicotine meta- bolites in body fluids and carbon mon- oxide content of blood Nornicotine conversion and resulting pig- ment changes in certain varieties of tobacco 62
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GRANTEE AND INSTITUTION RICHARD H. EARLE, M.D., Chief, Pul- monary Function Laboratory, Assistant Professor of Medicine, University of Chicago, Chicago. JOHN W. ECKSTEIN, M.D., Assistant Professor of Internal Medicine, College of Medicine, State University of Iowa, Iowa City. B. EICHEL. B.S., D.D.S., Director, Insti- tute of Stomatological Research, Sci- ence Resources Foundation, Cam- bridge, Mass. HYMAN ENGELBERG, M.D., Attend- ing Physician, Cedars of Lebanon Hos- pital, Los Angeles. CARLTON K. ERICKSON, PH.D., As- sistant Professor of Pharmacology and Toxicology, School of Pharmacy, The University of Kansas, Lawrence. WALTER B. ESSMAN, PH.D., Professor of Psychology, Queens College of the City of New York, Flushing. HANS L. FALK, PH.D., Senior Research Associate, Department of Pathology, University of Southern California School of Medicine. Los Angeles. (now Head, Chemistry Section, Carcinogene- sis Studies Branch, National Cancer Institute, Bethesda, Md.) DANA L. FARNSWORTH, M.D., Henry K. Oliver Professor of Hygiene and Di- rector of University Health Services, Harvard University, Cambridge, Mass. (see Heath and McArthur) FRANK C. FERGUSON, JR., •M.D., Chairman, Department of Pharrnacol- ogy, Albany (N. Y.) Medical College. PROJECT TITLE Expanded analysis of pulmonary function data using computer techniques Responses of the peripheral veins in man to the intravenous administration of nicotine Foot blood flow responses to smoking in the presence of hyperlipemia and hy- pertension Metabolic interrelationships between to- bacco smoke and the human mouth Smoking and the thrombosis of human blood: mechanism and prevention Mechanism of learning facilitation by nicotine Studies of nicotine action upon memory consolidation Examination of cigarette paper and cigar- ette smoke condensates for aromatic polycyclic hydrocarbons A compilation of fluorescence spectra of polycyclic aromatic hydrocarbons and closely related compounds which are of interest in the study of air pollutants, and cigarette smoke in relation to lung cancer etiology The effects of tobacco smoke condensate on the defense mechanisms of the rat in detoxification of polycyclic aromatic hydrocarbons and the competitive in- hibition between the polycyclic hydro- carbons in condensate with regard to carcinogenesis ' The physical and chemical properties of mucus under normal conditions and following exposure to aerosol irritants Personality and smoking in college grad- uates; a fifteen-year follow-up study Effects of tobacco smoke upon the func- tion of the cardiovascular system in animals and man 63
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GRANTEE Ah., ,.'gTITLTION THEODORE. 1` ate Professu. v;~ FY, M.D., Associ- sity of New N•. 'lrcrne, The Univer- Albuquerquc ~ ' rchool of Medicine, WILLIAM 1. j s-- the direction .riN, M.D. (under MAN v';;fUEL L. ANDEL- of , M Health), .U. t .!,:H Commissioner , cago Board o.`~ ~:?rdemialogist, Chi- h. RUSSELL S. ical Examiner M D., Chief Med- : fessor of Legu ;i of Maryland; Pro- Maryland Mcc, , rine, University of chool, Baltimore. B. L. FREEDI.f, of Cancer Rf -,4M.D., DirecJor . pital and Mc(,. , Mount Zion Hog- cisco. (deceas,,• enter, San Fran- French) FREDERICK A, ; ; , •, 'CH, A.B., Direc- tor of Cancer ` Mount Zion ,;, ",herapy Research, Center, San 1.""al and Medical lander) ~co. (see Freed- )ACK FREUNI), V , sor of Pharnru",,, ' Assistant Profes- of Virginia, Medical College . ..,1. v. H. FRIEDEI.I., IA ry Senior Research Associate, Can. ~ ~ ~~„ search Institute, New England ton. s Hospital, Bos- .kRTHUR FURS1, 1•, f) , Director, In- of stitute San of Cheiu r,,,lFrancisc~r~ ,,,l /b„logy, University ; EORGE O. Gf,1'. M.D., Director, Finney-Howel! Research Lab- .~ratory; AssocirUr llt~ of Sur- ~f ;ery, Johns Hopi it," t tniessor versity oSchool Medicine, Balti„u,,~ Md. PROJECT TITLE Effect of cigarette smoking on lipids and morphology of alveolar lining material and macrophages Patho-physiology of lung in geriatric pa- tients Pathologic-anatomic study of cellular changes in human bronchi Experiments on the possible carcinogenic and cocarcinogenic action of tobacco products Carcinogenicity, cocarcinogenicity and anti-carcinogenicity of dietary factors in relation to pulmonary tumors. Pos- sible interrelationship of tobacco bases and dietary factors. Chemical studies on pyridine bases including niacin analogs Correlation of multitechnical procedures performed on the peripheral circulation of normal individuals in recumbent and erect positions and after exercise before and after sham and actual smoking A study of the effects of cigarette smoking on the peripheral circulation of indi- viduals with arteriosclerosis obliterans and other peripheral vascular diseases, ultilizing multitechnical procedures The pathogenesis of human bladder can- cer A controlled study to evaluate the effect of administration of trace metals (with or without exposure to cigarette smoke) on the incidence of pulmonary adeno- mas in Strain A mice Nickel in relation to the smoking and lung cancer problem Fellowships for studying the culture of human lung tissue and the effects of known and possible carcinogenic agents upon such tissue Characteristics of*normal cell growth in culture in relation to invasive carcin- oma, especially in the lung 64
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GRANTEE AND INSTITUTION THOMAS M. GOCKE, M.D., Associate Professor of Preventive Medicine and Community Health, New Jersey State College of Medicine and Dentistry, Jer- sey City, N. J. (now at State University of N. Y., Upstate Medical Center) PAUL GOLDHABER, D.D.S., Associate Professor of Perodontology, Harvard School of Dental Medicine, Boston. DAVID M. GOLDENBERG, Sc.D., M.D., Head, Department of Clinical and Experimental Oncology, Chirurgische Klinik, University of Erlangen-Niirn- berg, West Germany. LEONIDE GOLDSTEIN, D.Sc., Re- search Scientist, Bureau of Research in Neurology and Psychiatry, Neurophar- macology Section, New Jersey Neuro- psychiatric Institute, Princeton. IRA GORE, M.D., Professor of Pathol- ogy, Boston University School of Med- icine; Chief of Laboratory Service, Veterans Administration Hospital, West Roxbury, Mass. GERTRUDE Y. GOTTSCHALL, PH.D., Assistant Professor of Biochemistry, Department of Pathology and Micro- biology, The Rockefeller Institute for Medical Research, New York. (see Clarke ) A. CLARK GRIFFIN, Px.D., Head of Biochemistry Department, M. D. An- derson Hospital and Tumor Institute, University of Texas Medical Center, Houston. ARTHUR L. GROSS. M.S., Senior Bio- chemist, Southwest Research Institute, San Antonio, Texas. MORTON I. GROSSMAN, PH.D., M.D., Associate Clinical Professor of Medi- cine, University of California Medical Center, Los Angeles. CARL C. GRUHZIT, PH.D., M.D., Asso- ciate in Physiology and Pharmacology, University of Pennsylvania Graduate School of Medicine, Philadelphia (now Lecturer in Physiology, University of Hong Kong) FRANK E. GUTHRIE, PH.D., Professor, and ERNEST HODGSON, PH.D., As- sistant Research Professor, Depa/Iment of Entomology, North Carolina State College, Raleigh. PROJECT TITLE A study of the nasal and pharyngeal bac- terial flora of smokers, non-smokers and ex-smokers The production of antibodies to tobacco smoke condensate or smoke in animals and humans Heterotransplantation studies with human lung cancer A study of bioelectric differences between nicotine-habituated and non-habituated organisms by use of high energy phos- phate compounds The influence of environmental factors on arterial intimal constituents and func- tions Interactions of arterial acid mucopolysac- charides Proteolytic activities of the white blood cells of man and the effect on white blood cell activities of carcinogens, nu- trition and other influences The effect of exposure to cigarette smoke on the induction of cancer by chemical compounds The correlation of acetonitrile in body fluids to tobacco usage The effect of smoking on certain gastric functions Pharmacologic study of nicotine and re- lated alkaloids Biological oxidation of carbamate insecti- cides 65
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CRAI\7'EE AND INSTITUTION H. B. HAAG, M.D., Professor of Phar- macology, Medical College of Virginia, Richmond. (deceased, see Larson) F. J. HADDY, M.D., Px.D., Professor and Chairman, Department of Physiol- ogy, University of Oklahoma Medical Center, Oklahoma City. (now at Mich- igan State University, East Lansing, Mich.) JOSEPH H. HAFKENSCHIEL, M.D., (now at Medical Department, Sandoz Pharmaceuticals, San Francisco, Calif.) RICHARD J. HAVEL, M.D., Assistant Professor of 1Nedicine, University of California Medical School, San Fran- cisco. HERBERT R. HAWTHORNE, M.D., Chairman, Department of Surgery, Uni- versity of Pennsylvania Graduate School of Medicine. Philadelphia. CLARK W. HEATH, M.D., Professor of Medicine and Director of Health Serr- ices, Tufts University, Medford, Mass. (see Farnsworth and McArthur) NORMAN W. HEIMSTRA, PH.D., As- sociate Professor of Psychology and Di- rector, Driver Behavior Laboratory, Department of Psychology, University of South Dakota, Vermillion. PAULINE HEIZER, PH.D., Research Associate in Cytology and Cytochem- istry, San Francisco Institute of Medi- cal Sciences, San Francisco. (see Rich- ards) LAWRENCE L. HESTER, JR., M.D., Professor and Chairman, Department of Obstetrics and Gynecologv, Medical College of South Carolina, Charleston. EBBE CURTIS HOFF, PH.D., M.D., PROJECT TITLE Preparation for publication of a book on the biologic aspects of tobacco and smoking Local effects of the inhalation of tobacco smoke upon the pulmonary, peripheral and coronary vascular beds Measurement of coronary blood flow, cardiac work and cardiac oxygen and carbohydrate metabolism in normoten- sive subjects before and after intra- venous nicotine and after smoking standard cigarettes A study of the effects of smoking and nicotine administration on sympatho- adrenal function and fatty acid meta- bolism Attempts to induce pulmonary neoplasms in experimental animals by exposure of the tracheobronchial system to to- bacco smoke Personality and smoking in college grad- uates: a fifteen-year follow-up study Effects of smoking on sustained perform- ance in a simulated driving task A comparative study of early histologica! and DNA changes in the epidermis of two strains of mice (C57 Blacks and Swiss Websters) after daily applica- tions of whole cigarette smoke con- densate (alone and combined with croton oil) and the carcinogens 20- methylcholanthrene and 3,4-benzpy- rene The relationship of the use of tobacco products to the outcome of pregnancy Biochemical studies of nicotine and its Professor and Chairman, Division of Psychiatric Research, Medical College of Virginia, Richmond. intermediate metabolites and their ef- fects upon cerebral autonomic mechan- isms tn Cerebral autonomic changes produced by 0 tobacco smoke, nicotine or cotinine, a ~ metabolite of nicotine 66
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GRANTEE AND INSTITUTION RUSSELL L. HOLMAN, M.D., Profes- sor and Head, Department of Pathol- ogy, Louisiana State University School of Medicine, New Orleans. (deceased, see McGill and Strong) OLE A. HOLTERMANN, M.D., Re- search Scientist, Lobund Laboratory, University of Notre Dame, Notre Dame, Ind. FREDDY HOMBURGER, M.D., Presi- dent and Director, Bio-Research Insti- tute, Inc., Cambridge, Mass. ROBERT W. HULL, PH.D., Professor of Biological Sciences, Florida State Uni- versity, Talahassee. GEORGE JACOBSON, M.D., Professor and Head of Radiology, University of Southern California School of Medi- cine, Los Angeles. JERRY HART JACOBSON, M.D., Di- rector of Electrophysiology, New York Eye and Ear Infirmary, New York. JULIUS H. JACOBSON II, M.D., Asso- ciate Professor of Surgery and Director of Surgical Research, College of Medi- cine. University of Vermont, Burling- ton. (Now Director of Tumor and Vas- cular Research, Mt. Sinai Hospital, New York, N. Y.) MURRAY E. JARVIK, PH.D., Associate Professor of Pharmacology, Albert Einstein College of Medicine, Bronx, N. Y. OSWALD R. JONES, M.D., St. Luke's Hospital, New York. PROJECT TITLE Pathologic-anatomic study of cellular changes in human bronchi The influence of tobacco smoking on acute myocardial infarction A. An investigation of the in vitro trans- formation of germ-free mammalian cells by chemical carcinogens B. An investigation of the relationship of leukemogenesis to antigenic stimulation Studies on carcinogenesis and the bio- assay of carcinogenic agents Comparative studies of effects of various tobacco smoke condensates on skins of mice Systemic effects of three tobacco smoke condensates Biological effects of cigarette smoke Photodynamic activation of carcinogenic hydrocarbons: (a) standardization of assay techniques utilizing protozoa; (b) investigation of the mechanisms of activation and response to aromatic carcinogens by protozoa The influence of certain environmental factors in the genesis of neoplastic disease in tuberculosis patients and in children A comparison of electroretinography as a means of evaluating the effect of vasoconstrictor drugs upon cerebral and retinal circulation with other tech- niques for this determination Lung homotransplantation Pilot study of habituation to nicotine by means of rhesus monkeys Carbon monoxide uptake and diffusion capacity in children. This test, together with others, will be used to evaluate pulmonary function in children start- ing at the earliest age of cooperation. This evaluation of pulmonary function will be applied to normal children, those 67
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GRANTEE AND INSTITUTION ANDREW A. KANDUTSCH, PH.D., Assistant Director of Research, Roscoe B. Jackson Memorial Laboratory, Bar Harbor, Me. ARNOLD R. KAPLAN, PH.D., Director, Laboratory of Medical Genetics, Cleve- land Psychiatric Institute and Hospital. HRATCH KASPARIAN, M.D., Assist- ant Director, Cardiovascular Labora- tory Instructor in Medicine, Hahne- mann Medical College and Hospital, Philadelphia. ELIHU KATZ, Ptt.D., Associate Professor of Sociology, University of Chicago. (see Crain) SHIRLEY L. KAUFFMAN, M.D., As- sociate Professor of Pathology, Down- state Medical Center, State University of New York, Brooklyn. ANCEL KEYS, Px.D., Professor of Phys- iological Hygiene and Director, Lab- oratory of Physiological Hygiene, Uni- versity of Minnesota School of Public Health, Minneapolis. JOSEPH B. KIRSNER, M.D., Professor of Medicine, University of Chicago School of Medicine. PETER H. KNAPP, M.D., Research Pro- fessor of Psychiatry, Boston University School of Medicine, Boston. KENNETH P. KNUDTSON, M.D., As- sistant Chief, Laboratory Service, Vet- erans Administration Hospital, Seattle, Wash.; Professor of Pathology, Uni- versity of Washington Medical School, Seattle. PROJECT TITLE with asthma, bronchitis, or chronic pneumonia, which conditions were sub- sequent to infections of all kinds, partia ularly those caused by known viral agents. To determine to what extent tobacco 'tar' mimics the action of carcinogenic hydro- carbons in the skin and other tissues Examination of the extent of, and con- stitutional basis for, correlations be- tween the following: (1) taste thresh- olds for quinine and 6-n-propylthiour- acil, (2) constitutional predisposition to pathologic variables, (3) individual differences in smoking practices, and (4) food dislikes The effect of tobacco smoking on the cali- ber of the coronary arteries Social and psychological constraints on the translation of motives into action: The case of cigarette smoking To investigate the pathogenesis of ure- thane induced lung adenomas in mice; specifically the identification of the cells which give rise to the adenomas, and the fine structural changes in these cells during neoplasia Cell proliferation in lung following car- cinogens Characteristics of men, including smok- ing, in populations differing in the in- cidence of coronary heart disease The effect of tobacco smoking upon basal gastric secretions in man Investigation of personality features as- sociated with extremes of smoking behavior Pathologic - anatomic study of cellular changes in human bronchi
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GRANTEE AND INSTITUTION ALVIN I. KOSAK, PH.D., Associate Professor of Chemistry, Washington Square College, New York University, New York. ROBERT A. KUHN, M.D., All Souls Hospital, Morristown, N. J. and Asso- ciate Professor, Division of Neuro- surgery, Department of Surgery, New Jersey State College of Medicine, Jer- sey City, N. J. MARVIN KUSCHNER, M.D., Professor of Pathology, New York University College of Medicine; Director of Pa- thology, Bellevue Hospital, New York. CHARLES W. LA BELLE, Px.D., As- sistant Professor of Environn:ental Hygiene, Department of Preventive Medicine, Jefferson Medical College, Philadelphia. (deceased) THOMAS C. LAIPPLY, M.D., Professor of Pathology, Northwestern University Medical School; Chairman, Depart- ment of Pathology, Wesley Memorial Hospital, Chicago. PAUL S. LARSON Prt.D., Haag Profes- sor of Pharmacology, Medical College of Virginia, Richmond. (see Haag and McKennis) ROGER K. LARSON, M.D., Chief of Medicine, and JOSEPH R. McCLIN- TIC, PH.D., Associate Professor of Bi- ology, Fresno County Hospital, Fresno, California. GUSTAVE A. LAURENZI, M.D., As- sociate Professor of Medicine and Di- rector, Division of Respiratory Diseases, New Jersey State College of Medicine, Jersey City, N. J. PROJECT TITLE The isolation and identification of certain lower-boiling components of cigarette smoke Possible effects of smoking and nicotine upon cerebral circulation Pathologic - anatomic study of cellular changes in human bronchi Effect of cigarette smoke on pulmonary clearance Pathologic - anatomic study of cellular changes in human bronchi Classification, prognosis and etiologic fac- tors of primary tumors of the lung Evaluation of morphologic changes in tracheobronchial tree in patients from selected study group (See Fishbein) Comparison of changes in tracheobron- chial epithelium in smokers and non- smokers, with special reference to lung carcinomas in non-smokers Preparation for publication of a book on the biologic aspects of tobacco and smoking Enzymatic transformations of nicotine and related compounds The possible effect of tobacco smoke and nicotine on ascorbic acid metabolism Subsidy requirement by the Williams & Wilkins Company for publication of a supplement to the monograph, "To- bacco" Mechanisms of resistance to pulmonary pathogens in mice exposed to cigarette smoke To test more thoroughly the hypothesis that the susceptibility to develop or not to develop emphysema in smokers is genetically determined Studies in bronchitis: a correlated investi- gation of (a) the effect of smoking on the bacteriology of the respiratory tract of humans, and (b) the effect of ciga- rette smoke and sulfur dioxide (air pol- 69
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GRANTEE AND INSTITUTION CECILIE LEUCHTENBERGER, PH.D., Head, Department of Cytochemistry, Swiss Institute of Cancer Research, and Professor, associated with the Medical School, University of Lausanne, Swit- zerland. (Formerly Senior Biologist and Chemist, Sias Memorial Laboratories, Brooks Hospital, Brookline, Mass.) AVERILL A. LIEBOW, M.D., Chairman, Department of Pathology, Yale Univer- sity School of Medicine, New Haven, Conn. ESTEN O. LINDSETH, M.D., PH.D., As- sistant Professor of Surgery, University of Minnesota Medical School, and Sta,e' Physician, Surgical Service, Veterans Administration Hospital, Minneapolis. (now at St. Joseph's Hospital, St. Paul, Minn. ) ROBERT H. LINNELL, PH.D., Associate Professor of Chemistry, University of Vermont. Burlington. (now at National Science Foundation, Washington, D.C.) HERBERT L. LOMBARD, M.D., M.P.H., Research Institute, New England Dea- coness Hospital, Boston. J. P. LONG, PH.D., Professor of Pharma- cology, State University of Iowa College of Medicine, Iowa City. CLAYTON G. LOOSLI, PH.D., M.D., Hastings Professor of Medicine and Pathology, University of Southern Cali- fornia School of Medicine, Los Angeles. DONALD B. LOURIA, M.D., Associate Professor in Medicine, Cornell Univer- sity Medical College, New York. KENNETH MERRILL LYNCH, M.D., Sc.D., LL.D., Chancellor and Professor of Pathology, and FORDE A. McIVER, M.D., Associate Professor of Pathology, PROJECT TITLE lutant) on the clearing of bacteria from the respiratory tracts of small animals (mice, rats) Effect of cigarette smoke on pulmonary resistance to infection The effect of cigarette smoke on the na- ture and function of the alveolar macro- phage: (a) mobilization; (b) metabolic activity; (c) phagocytic activity; and (d) bacteriostatic-bactericidal capacity A correlated histological, cytological and cytochemical study of the tracheo- bronchial tree of mice exposed to ciga- rette smoke The interrelation between influenza virus infections, exposure to cigarette smoke and other factors in the development of pulmonary and bronchial lesions in mice To investigate the formation of pulmon- ary surfactant in fetal animals and its presence in the newborn Measurement of the differential blood flow in the mammalian lung during the acute period of smoke inhalation, using the open chest animal and the method and principle of gamma emitting radio- active graded microspheres The oxidation of nicotine by gaseous oxygen: mechanism, products and ki- netics The autoxidation of nicotine Epidemiological factors in lung cancer Cardiovascular properties of nicotine Further studies concerning the sympatho- mimetic actions of nicotine Lung tissue reactions to airborne chemical and biological agents Studies on micotoxins in tobacco Environmental factors and pulmonary dis- ease. I. Asbestos dust II. Asbestos and co-carcinogens, viral and chemical 70
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GRANTEE AND INSTITUTION Medical College of South Carolina, Charleston. INES MANDL, PH.D., Assistant Profes- sor of Biochemistry, College of Physi- cians and Surgeons, Columbia Univer- sity, New York. JOHN H. MANHOLD JR., D.M.D., Pro- fessor and Director of Pathology and Oral Diagnosis, New Jersey College of Medicine and Dentistry, Jersey City. DAVID E. MANN, JR., Ptt.D., Associate Professor of Pharmacology, Temple University School of Pharmacy, Phila- delphia. JOHN P. MANOS, M.D., Instructor in Virology and Bacteriology, Medical College of South Carolina, Charleston. CHRISTOPHER M. MARTIN, M.D., Formerly Assistant Professor of Medi- cine and Director, Division of Infec- tious Diseases, N. J. State College of Medicine, Jersey City, N. J. (Now at Georgetown Univ. School of Med., Wash., D.C.) DONALD J. MASSARO, M.D., Associ- ate Professor of Medicine, Duke Uni- versity Medical Center, Durham, North Carolina. CHARLES C. McARTHUR, Ptt.D., Psychologist to the University Health Services, Harvard University, Cam- bridge, Mass. (see Heath and Farns- worth ) CHARLES B. McCANTS, PH.D., Asso- ciate Professor of Soils, School of Agri- culture, North Carolina State College, Raleigh. HENRY C. McGILL, JR., M.D., Acting Head, Department of Pathology, Loui- siana State University School of Medi- cine, New Orleans. (see Holman and Strong) PROJECf TITLE The role of hereditary elastase inhibitor deficiency in the etiology of pulmonary emphysema To study the purported relationship be- tween smoking and changes in human oral tissue in vivo by routine micros- copy, differential staining, and micro- respirometer methods, and to further examine statistically two series of data presently in the principal ....est:gator's possession Effect of tobacco smoke and tobacco res- idues on methylcholanthrene-induced skin carcinogenesis in mice The separation of the various subcellular neoplastic particles by ultra filtration methods and their characterization in laboratory animals and in tissue cul- tures of various cell lines Possible interactions of viruses and sub- stances in tobacco smoke condensate Comparative racial prevalence of chronic bronchitis Alveolar cells: protein and glycoprotein biosynthesis Protein synthesis and secretion by tracheal mucosa Social and personal determinants of smok- ing behavior The social mediation of smoking behavior Arsenic content of soils and absorption by the tobacco plant The effects of environmental factors on development of atherosclerosis as re- (s1 vealed by autopsy of accident victims 0 0 +O 0 0 71 0 J
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GRANTEE AND INSTITUTION HENRY D. McINTOSH, M.D., Professor of Medicine and Director, Cardiovascu- lar Laboratory, Duke University Medi- cal Center, Durham, N. C. EDWARD McKEE, M.D., Professor and Acting Chairman, and WILLIAM M. DAVIS, M.D., Research Assistant, De- partment of Pathology, Medical College of South Carolina, Charleston. (see Pratt-Thomas) KELLY T. McKEE, M.D., Associate Pro- fessor of Medicine, Medical College of South Carolina, Charleston. HERBERT McKENNIS, Jtt., Px.D., Pro- fessor of Pharmacology, Medical Col- lege of Virginia, Richmond. (see Lar- son) VICTOR A. McKUSICK, M.D., Profes- sor of Medicine, with RICHARD M. GOODMAN, M.D., Fellow in Medi- cine, Johns Hopkins University School of Medicine, Baltimore, Md. ROSS L. McLEAN, M.D., Associate Pro- fessor of Medicine, Emory University School of Medicine, Atlanta. WILLIAM F. McNARY, JR., PH.D., Asso- ciate Professor of Anatomy, Boston University School of Medicine, Boston. NEAL L. McNIVEN, PH.D., The Worces- ter Foundation for Experimental Biol- ogy, Shrewsbury, Mass. (see Dorfman) JULIA MEYER, PH.D., Associate Profes- sor of Oral Pathology, University of Illinois College of Dentistry, Chicago. BERNARD J. MILLER, B.S., M.D., As- sistant Professor, The Daniel Baugh In- stitute of Anatomy of the Jefferson Medical College, Philadelphia. JAMES G. MILLER, M.D., PH.D., Pro- fessor of Psychiatry and Psychology, and Director, Mental Health Research Institute, University of Michigan, Ann Arbor. HUGH MONTGOMERY, M.D., Associ- ate Professor of Medicine, University of Pennsylvania Medical School, Phila- delphia. PROJECT TITLE A study of the effects of hyperbaric oxy- genation on coronary artery disease in the experimental animal and man Carcinogenesis in the laboratory animal: a comparison of species response to standardized sites of application Study of lung function in smokers and non-smokers Enzymatic transformations of nicotine and related compounds A combined genetic, physiologic, clinical and epidemiologic study of Buerger's disease A study of Buerger's disease among the Jewish ethnic groups in Israel Tobacco and coagulation: A study of genetic factors in vascular disease To make recordings of normal and patho- logic breath sounds The histology, histochemistry and ultra- structure of normal and diseased lung Nicotine and its metabolites in body fluids of smokers An oral cytologic study of non-smokers and smokers An investigation of the blood supply of metastatic and primary malignant tumors of the lung The behavioral effects of smoking under stress Influence of tobacco smoking on the blood flow of skin and of muscles of extremities in sympathectomized and unsympathectomized subjects 72
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GRANTEE AND INSTITUTION P. O'B. MONTGOMERY, JR., M.D., Pro- fessor of Pathology, and ROLLAND C. REYNOLDS, M.D., Assistant Profes- sor of Pathology, University of Texas, Southwestern Medical School, Dallas. GEORGE E. MOORE, PH.D., M.D., Di- rector, Roswell Park Memorial Insti- tute, Buffalo, N. Y. (see Bock) KENNETH M. MOSER, M.D., Assistant Professor of Medicine, Georgetown University Medical School, Washing- ton, D. C. HURLEY LEE MOTLEY, M.D., Profes- sor of Medicine and Director, Cardio- Respiratory Laboratory, University of Southern California School of Medi- cine, Los Angeles. EDMOND ANTONY MURPHY, M.D., Sc.D., Associate Professor of Biostatis- tics and Medicine, University of Color- ado Medical Center, Denver. WILLIAM S. MURRAY, Sc.D., Senior Sta,B Scientist, Emeritus, Roscoe B. Jackson Memorial Laboratory, Bar Har- bor, Me. DONALD M. PACE, Ptt.D., Professor of Physiology and Director, Institute for Cellular Research, University of Nebraska, Lincoln. 73 PROJECT TITLE Influence of nicotine (i.v.) and tobacco smoking on blood flow in human skin and skeletal muscle Investigation of the role of the nucleolus in the normal and the malignant cell. Nuclear changes produced by chemical carcinogens An investigation of the physiological ef- fects of direct inhalation of tobacco smoke by laboratory animals and the study of the biological response of laboratory animals to continuous in- gestion of diet-tobacco product mix- tures Effects of acute and chronic cigarette smoking upon fibrinolytic activity and blood coagulation in man Smoker-nonsmoker differences in activa- tion of fibrinolytic and coagulation sys- tems A study of the effects of smoking on pul- monary function It is proposed to work out in detail an ap- propriate means of determining the dur- ation of survival of the human platelet. The production of genetically controlled animals and tumors for use in experi- mental research on tobacco in relation to health Studies of the mammary tumor-promot- ing qualities of a virus-like principle, under varying hormonal and aging conditions Genetic studies of carcinogenesis Fellowship for training in tissue culture techniques Study of the effects of tobacco smoke constituents on various strains of tissue cells cultivated in vitro Investigations on respiration and glyco- lysis, as well as possible chromosomal variations in established cell lines which have been exposed to cigarette smoke and single constituents of smoke Investigations on effects of carcinogens and study of the effect of ethanol and ~
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GRANTEE AND INSTITUTION ALBERT B. PALMER, PH.D., and NOR- MAN W. HEIMSTRA, PH.D., Assist- and Professors of Psychology, Depart- ment of Psychology, University of South Dakota, Vermillion. (Dr. Palmer now at the University of Toledo, Ohio) ROSE MARIE PANGBORN, B.S., M.S., Assistant Food Technologist and Lec- turer, Department of Food Science and Technology, University of California, Davis, California. MARY STEARNS PARSHLEY, PH.D., Assistant Professor of Anatomy in Ob- stetrics and Gynecology, College of Physicians and Surgeons, Columbia University, New York. EDWARD W. PELIKAN, M.D., Chair- man and Professor of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston. OTAKAR J. POLLAK, M.D., PH.D., Executive Director, Dover Medical Re- search Center, Inc., Dover, Del. MORRIS POLLARD, Px.D., Director, Lobund Laboratory, University of Notre Dame, Ind. C. M. POMERAT, PH.D., Director of Biological Research, Pasadena Founda- tion for Medical Research, Pasadena, Calif. (deceased) S. N. PRADHAN, M.D., PH.D., Professor of Pharmacology, Howard University College of Medicine, Washington, D.C. H. R. PRATT-THOMAS, M.D., Dean and Professor of Pathology, Medical College of South Carolina, Charleston. (see E. McKee) MARTIN S. PROTZEL, B.S., D.D.S., Chief, Department of Oral Pathology, Newark City Hospital, Newark, N. J. 74 PROJECT TITLE carcinogens on physiological, metabolic, and morphological changes in diploid cells under aerobic and anaerobic con- ditions Personality correlates of smoking and non-smoking in adolescents Interactions of gustatory, olfactory, tac- tile, and thermal stimuli among smokers and non-smokers Effect of constituents of tobacco smoke on normal and malignant human respira- tory epithelium in vitro Studies of structure-activity relationships among drugs which affect nicotine- sensitive physiological mechanisms Possible effect of tobacco derivatives on arterial and myocardial tissue cultures Chemical and viral carcinogenesis in the axenic ("germfree") animal Fellowships for studying the culture of human lung tissue and the effects of known and possible carcinogenic agents upon such tissue Effect of nicotine on behavior Pathologic - anatomic study of cellular changes in human bronchi Application of a new bioassay technique in examination of cigarette smoke con- densates for possible carcinogens Carcinogenesis in the laboratory animal: a comparison of species response to standardized sites of application A comparative study of the effects of 3- methylcholanthrene and cigarette smoke condensate applied to the oral tissues of Swiss 'mice (ICR) condi- tioned with alcohol and/or carbon tetrachloride 4W
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GRANTEE AND INSTITUTION WALTER REDISCH, M.D., Associate Professor of Clinical Medicine, New York University School of Medicine, and NYU Research Service, Goldwater Memorial Hospital, New York. (see Sulzberger) HOBART A. REIMANN, M.D., Profes- sor of Medicine, Hahnemann Medical College and Hospital, Philadelphia. VICTOR RICHARDS, M.D., Chief of Surgery, Presbyterian Medical Center, San Francisco, Calif. (see Heizer) R. H. RIGDON, M.D., Professor of Pa- thology and Director, Laboratory of Experimental Pathology, University of Texas Medical Branch, Galveston. SYDNEY C. RITTENBERG, PH.D., Pro- fessor of Bacteriology, University of Southern California, Los Angeles. JOSEPH H. ROGERS, M.D., Holy Name of Jesus Hospital, Gadsden, Alabama. BENSON B. ROE, M.D., Associate Pro- fessor of Surgery, Department of Sur- gery, University of California School of Medicine, San Francisco. CHARLES L. ROSE, A.M., Senior Direc- tor, Veterans Administration, Outpa- tient Clinic, Boston, Mass. BENJAMIN A. RUBIN, PH.D., Assist- ant Professor of Public Health and Preventive Medicine, Baylor University College of Medicine, Houston. Texas. (now Manager, Biological Products De- velopment, Wyeth Laboratories, Phila- delphia) PROJECT TITLE A comparative study of the effects of in• duced liver damage on the development of tumors of the oral mucosa and skin following the application of tobacco tar in inbred Swiss Webster mice Vascular responses to tobacco smoking in patients with vascular disease Vascular responses of the skin microcircu- lation and cerebral circulation to to- bacco smoking in man The effect of tobacco smoking on physio- logic and pharmacologic vasomotor stimuli The possible effect of tobacco or nicotine in periodic disorders, a newly-recognized syndrome A comparative study of the effects of whole and fractional extracts of ciga- rette smoke and those of known car- cinogens on (1) the cytology and nu- clear DNA content of epidermis in various strains of mice and/or (2) the cytology and nuclear DNA content of lung and epithelium of the bronchial tree of mice and hamsters Effects of tobacco smoke condensate on the respiratory tract and other tissues of the duck The bacterial degradation of nicotine and related compounds. The objective of the project is the elucidation of the intermediary metabolism of nicotine oxidation A study of the incidence of fatal heart at- tacks, strokes and pulmonary embolism in pulmonary emphysema Study of the action of negatively charged ions on tracheobronchial ciliary action in the human patient Social predictors of longevity An evaluation of the phenomenon of tumor growth enhancement as an assay for carcinogens among the polycyclic hydrocarbons and related compounds 75
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GRANTEE AND INSTITUTION HENRY I. RUSSEK, M.D., F.A.C.P., Consultant in Cardiovascular Disease, U. S. Public Health Service Hospital, and President, The Russek Foundation, Inc., Staten Island, N. Y. WILLIAM O. RUSSELL, M.D., Patholo- gist-in-chief, M.D. Anderson Hospital and Tumor Institute, University of Texas Medical Center, Houston. PETER F. SALISBURY, M.D., Px. D.. Head, Intensive Treatment Center, Saint Joseph Hospital, Burbank, Calif. (de- ceased - see Cross) PAUL D. SALTMAN, PH.D., Assistant Professor of Biochemistry, University of Southern California School of Med- icine, Los Angeles. ULRICH H. SCHAEPPI, M.D., Director of Neuropharmacology, Mason Re- search Institute, Worcestei, Massachu- setts. ., ALVIN R. SCHMIDT, PH.D., Director of Counseling, Tufts University, Med- ford, Mass. ISAAC SCHOUR, D.D.S., PH.D., D.Sc., Professor of Histology and Embryology and Dean, University of Illinois Col- lege of Dentistry, Chicago. (deceased) MAURICE S. SEGAL, M.D., Clinical Professor of Medicine, Tufts Univer- sity School of Medicine, Boston, Mass.; Director, Department of Inhalation Therapy, Boston City Hospital. CARL C. SELTZER, Px.D., Research Fellow in Physical Anthropology, Har- vard University, Cambridge; Mass., and Department of Nutrition, Harvard School of Public Health, Boston. PROJECT TITLE Interrelationship between emotional stress (occupational), tobacco consumption and coronary heart disease Stress reactions in smokers and non- smokers as determined by urinary cate- cholamine excretion Pathologic - anatomic study of cellular changes in human bronchi Influence of nicotine and catecholamines upon coronary vasomotor tonus in nor- mal and atherosclerotic dogs The enzymatic mechanism for the dark fixation of C02 by tobacco Some aspects of amino acid metabolism in tobacco leaves Investigation of the direct stimulation of parasympathetic nerve terminals by nicotine Nicotine administration to rostral areas of the cat brain: effects upon EEG and autonomic system Study of attitudes toward, as well as ex- tent, type and history of, tobacco smok- ing in a young college population. Study of some of the relationships of smoking and non-smoking to family history, type of secondary schooling, academic inter- ests, academic achievement, and, social relationships characteristics Histologic changes in the oral, pharyngeal and nasal tissues of experimental ani- mals and humans subjected to tobacco smoke Effects of cigarette smoking on lung func- tion in normal subjects and patients with certain respiratory disease condi- tions Relationship of cigarette smoking to chronic (obstructive) pulmonary em- physema An integrated study of ancillary and newly developed parameters to delineate the different types of the chronic bronchitis syndrome and their evaluation Chronic bronchitis entities Morphology and smoking in college gradu- ates: a fifteen-year follow-up study Harvard-Johns Hopkins study of body form as related to smoking, and the 76
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I GRANTEE AND INSTITUTION LUCIO SEVERI, M.D., Director, Insti- tute of Morbid Anatomy and Histology, Division of Cancer Research, University of Perugia, Perugia, Italy. CHARLES E. SHERWOOD, M.D., As- sistant Professor of Radiology, Univer- sity of Rochester School of Medicine and Dentistry, Rochester, N. Y. DAVID L. SIMON, M.D., Instructor in Medicine and Fellow in Cardiovascu- lar Research, University of Cincinnati College of Medicine and Cardiac Lab- oratory, Cincinnati General Hospital. GENE M. SMITH, PH.D., Assistant Pro- fessor of Psychology, Harvard Medical School, Massachusetts General Hospi- tal, Boston. LOUIS A. SOLOFF, M.D., Professor of Clinical Medicine and Chief, Division of Cardiology, Temple University Med- ical Center, Philadelphia. SHELDON C. SOMMERS, M.D., Profes- sor of Pathology, College of Physicians and Surgeons, Columbia University, New York. ERNEST SONDHEIMER, PH.D., Pro- fessor of Plant Biochemistry, State University College of Forestry at Syra- cuse University, Syracuse, N. Y. T. M. SONNEBORN, PH.D., Distin- guished Service Professor of Zoology, Indiana University, Bloomington. SAM SOROF, PH.D., Head, Dept. of Macromolecular Chemistry, The Insti- tute for Cancer Research, Philadelphia, Pa, ALEXANDER SPOCK, B.S., M.D., As- sistant Professor of Pediatrics, Duke University Medical Center, Durham, North Carolina. FREDERICK J. STARE, M.D.., PH.D., Professor of Nutrition, Harvard School of Public Health, Boston. PROJECT TITLE precursors of hypertension and coro- nary artery disease An approach to the study of internal fac- tors in lung carcinogenesis. Influence of hormones Investigation into the natural history of carcinoma of the lung with particular teference to the radiographic appear- ance of such processes, the earliest manifestation of cancer on chest X- ray photographs and the tabulation of the relationship of smoking habits and occupation with the incidence of lung cancer The effects of chewing tobacco on the cardiovascular system of man The effects of pipe smoking and cigar smoking on the cardiovascular system of man The relations between smoking and per- sonality The effect of tobacco smoking on sur- factant, specific fatty acids, cardiac per- formance and metabolism of adipose tissue Host factors in chronic pulmonary inflam- mation, emphysema and lung cancer The purification and structure determina- tion of compounds closely related to chlorogenic acid Checking and extending the Stephano Paramecium test for carcinogenicity Chemical and physical studies of the tissue proteins involved in chemical carcinogenesis The influence of cigarette smoke on ciliary activity and histology of the tracheo- bronchial tree.of the rabbit Experimental studies of cancer utilizing a new technique to see if various 'tars' extracted from tobacco may in- cite the formation of lung tumors 77
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GRANTEE AND INSTITUTION C. HAROLD STEFFEE, M.D., Director of Laboratories, Methodist Hospital, Memphis, Tenn. JACK P. STRONG, M.D., Associate Professor of Pathology, Louisiana State University School of Medicine, New Orleans. (see Holman and McGill) MARION B. SULZBERGER, M.D., Pro- fessor and Chairman, Department of Dermatology and Syphilology, New York University-Bellevue Medical Cen- ter, New York. (retired, see Redisch) RENATO TAGIURI, PH.D., Associate Professor of Psychology, Graduate School of Business Administration, Harvard University, Boston. CAROLINE BEDELL THOMAS, M.D., Associate Professor of Medicine, Johns Hopkins University School of Medi- cine, Baltimore, Md. JEROME F. THOMAS, PH.D., Professor of Sanitary Engineering, University of California, Berkeley. TISSUE CULTURE ASSOCIATION JAMES E. P. TOMAN, PH.D., Professor and Chairman of Pharmacology, Chi- cago Medical School, Institute for Medical Research. PROJECT TITLE The influence of cigarette smoke inhala- tion on histologic changes produced by intravenous hexachlorofluorobutane in rats The effects of environmental factors on development of atherosclerosis as re- vealed by autopsy of accident victims Investigation of the effects of tobacco on the human vascular system, based on the fact that certain tobacco effects are due to allergic susceptibility of specific individuals rather than to obli- gatorily toxic products in tobacco smoke, and that patients with occlusive vascular diseases respond differently than healthy smokers Critical review of literature on psychol- ogy of smoking The significance of different individual patterns of circulatory response to cig- arette smoking Studies of genetic differences between smokers and non-smokers Studies of psychological differences be- tween smokers and non-smokers as shown by comparison of figure draw- ings Psychological characteristics of healthy young adults and their biological im- plication; a continuing study in depth, with special reference to the precursors of hypertension and coronary heart dis- ease and to smoking habits A study of the precursors of hypertension and coronary disease The development of a microbiological screening system for assay of airborne carcinogens To assist in establishing of summer train- ing course in tissue culture techniques at University of Colorado Medical School, Denver, Colorado, and Univer- sity of Wisconsin Mechanisms of the psychotropic effects of nicotine The study of actions of nicotine upon cen- tral synapses and its correlation with the mechanism of action of behavior- ially active drugs 78
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GRANTEE AND INSTITUTION JANET TRAVELL, M.D., Associate Pro- fessor of Clinical Pharmacology, Cor- nell University Medical College, New York. LIE SHA TSAI, Px.D., Research Associ- ate, Department of Pathology, Yale University School of Medicine, New Haven. ROMEO A. VIDONE, M.D., Associate Professor of Pathology, Yale University School of Medicine, New Haven. E. D. WARNER, M.D., Professor of Pa- thology, State University of Iowa Col- lege of Medicine, Iowa City. SHIELDS WARREN, M.D., Director of Laboratories, Cancer Research Insti- tute, New England Deaconess Hospital Boston. BARBARA K. WATSON, PH.D., Assist- ant Bacteriologist, Massachusetts Gen- eral Hospital; Research Associate, De- partment of Bacteriology and Immu- ology, Harvard Medical School. JOHN S. WAUGH, PH.D., Professor of Chemistry, KERRY W. BOWERS, PH.D., Assistant Professor of Chemis- try, Massachusetts Institute of Tech- nology, Cambridge. RICHARD L. WECHSLER, M.D., Clini- cal Physiologist, Montefiore Hospital Institute of Research, Pittsburgh, Pa. A. WEINSTOCK, PH.D., Research Bio- chemist, Life Sciences Division, IIT Re- search Institute, Chicago. RUSSELL W. WELLER, M.D., Patholo- gist, Memorial Hospital of Chester County, West Chester, Pa.; Associate Professor of Pathology, Hahnemann Medical College, Philadelphia. SIMON H. WENDER, PH.D., Research Professor of Biochemistry, University of Oklahoma, Norman. PROJECT TITLE Effects of nicotine in the rabbit with ex- perimental coronary atherosclerosis Study on the activity of histidine decarbox- ylase during the development phase of collateral circulation in the lung of the rat with ligated pulmonary artery Histochemistry of epithelial mucins in car- cinoma of the lung Pathologic-anatomic study of cellular changes in human bronchi Correlation of bronchial epithelial changes with comparable changes in other or- gans-a pathologic-anatomic study The pattern of metastasis of carcinoma of the lung in man Histopathology of human lung cancer Immunologic and virologic studies on the role of influenza virus in malignant cell transformation Electron spin resonance spectroscopy of paramagnetic species derivable from tobacco and related systems Effect of cigarette smoking on cerebral blood flow, cerebral metabolism, blood gases, blood pH, arterial pulse pres- sure curves, electrocardiograms, and electroencephalograms Effects of tobacco smoke on cellular res- piration Pathologic-anatomic study of cellular changes in human bronchi A selected, extended and detailed study of human bronchial mucosa A qualitative and quantitative study of the individual polyphenol content of cigarette tobacco and the smoke and 'tars' resulting from cigarette smoking and also study of the fate of these compoutids in the animal respiratory system The identification of individual polyphe- 79
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.L GRANTEE AND INSTITUTION DUANE G. WENZEL, PH.D., Professor of Pharmacology, School of Pharmacy, University of Kansas, Lawrence. THOMAS C. WESTFALL, PH.D., Assist- ant Professor of Pharmacology, Univer- sity of Virginia, Charlottesville, Vir- ginia. FREDERICK E. WHISKIN, M.D., C.M., Director, Division of Health and Per- sonality Equilibrium, The Age Center of New England, Inc., Boston. (see Dibner) ROGER J. WILLIAMS, PH.D., Professor of Chemistry and Director, Clayton Foundation Biochemical Institute, The University of Texas, Austin. J. EDWIN WOOD, M.D., lnstructor in Medicine, Boston University School of Medicine, Boston. (now Professor of Medicine, Medical College of Georgia, Augusta. ) SUMNER WOOD, JR., M.D., Assistant Professor of Pathology, Department of Pathology, Johns Hopkins University, Baltimore, Md. JOHN P. WYATT, M.D., Professor of Pathology, St. Louis University School of Medicine, St. Louis, Mo. (now Pro- fessor and Director, Department of Pathology, University of Manitoba, Winnipeg, Canada.) PROJECT TITLE nolic compounds present in the smoke from cigarettes and the preparation, where feasible, of these compounds for studies on their metabolism and possible effect on human health Effect of cigarette smoke and its compo- nents on free proline in animal tissue cultures The determination of the chronic effects of orally administered nicotine on serum cholesterol and phospholipids, the electrocardiographic response to ergonovine, and the vascular pathology of cholesterol-fed rabbits A study of antihypertensive activity of nicotine Action of nicotine on subcellular distri- bution of catecholamines and serotonin in brain and heart Pilot study of smoking habits of Age Center members An investigation of biochemical factors associated with susceptibility to lung cancer The effect of prolonged inhalation of to- bacco smoke and of prolonged abstin- ence from the use of tobacco on the peripheral vascular response to acute inhalation of tobacco smoke in man Evaluation of etiologic factors, such as occupational hazards and habits, and pathologic peculiarities in the long- term survival of patients following re- section for bronchogenic carcinoma An investigation into the nature of the pigmentary lesions in centrilobular em- physema 80

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