A 3-million electron volt generator is being installed in the radiation wing of the Clinical Center, to be used for experimental research on the radiochemical and biological effects of X-rays and electron energy.

BIOSTATISTICAL STUDIES

A report on "Geographic Distribution of Mortality from Cancer of the Lung in the United States, 1948-49" was completed. Similar data for cities of 100,000 and over are complete and under analysis. A report presenting an analysis of the 10-city cancer morbidity survey was completed and prepared for printing as a Public Health Monograph. Several new epidemiological and statistical studies were undertaken to obtain additional data on the possible relationship between cigarette smoking and lung cancer.

SUPPORT OF RESEARCH AND CONTROL

Research grants totaling $7,552,188 were recommended for 669 projects by the National Advisory Cancer Council and approved by the Surgeon General for payment during 1954. Of these, 135 grants in the amount of $2,632,687 were made for work related to the chemotherapy of cancer. The council also recommended 85 field investigation grants totaling $1,228,356. Research fellowships were awarded to 177 applicants. The construction program was terminated with payment of the last active cancer research construction grant in June. Fifty of the fifty-five construction projects for which funds were made available in former years were completed by the end of the year.

In addition, grants totaling more than $2,273,000 were made to 82 medical schools, 42 dental schools, and 6 schools of osteopathy for undergraduate teaching. During the year, 154 physicians received training stipends for advanced clinical study in 71 schools. Cancer control programs in the States received financial assistance in the amount of $2,250,000.

STUDIES SUPPORTED BY GRANTS

A Subcommittee on Chemotherapy of the National Advisory Cancer Council was established to spearhead a national program designed to bring about earlier solutions to problems that seriously limit the chemotherapeutic attack on cancer, including leukemia. Mechanisms for closer cooperation, including the rapid exchange of information, has expedited progress in this promising field.

Grant-supported scientists found that cortisone therapy in large doses by mouth produced significant, though brief remissions of metastatic breast cancer. The measurement of calcium excretion proved to be a better index than histological appearance or clinical behavior in differentiating skeletal metastatic breast cancer which

reacts to or is unaffected by estrogen therapy. This permits an early decision as to whether estrogen therapy should be continued or not. Progress was made in the evaluation of cancer therapy by supervoltage radiation (in excess of 1 million electron volts) to learn whether it will offer more effective therapy for cancer than the more conventional (250,000 electron volts) levels generally in use. One grantee has developed a new technique utilizing supervoltage radiation for the diagnosis of lung cancer. Clinical evaluation of this technique may demonstrate its possible use as an X-ray lung cancer screening device for large segments of the population.

The cytology test continued to prove its effectiveness as a diagnostic aid in the detection of uterine cancer at an early stage when chances for cure are greatest. At the end of the year, screening of 63,661 women was completed, with discovery of 475 cancers, 60 percent of which were unsuspected prior to examination.

A film produced jointly by the institute and the American Cancer Society, "Oral Cancer-The Problem of Early Diagnosis," was completed and made available for professional use.

Dental Research

The National Institute of Dental Research conducts and sponsors research in the most prevalent dental and oral diseases. These include dental caries, periodontal disease, malocclusion, cleft palate, harelip, and oral cancer. For the past 5 years, annual appropriations of $221,000 have been used to help support about 24 research projects each year in dental schools and other institutions. Additional studies are conducted in the Institute's facilities and the Clinical Center.

A research grant project at the University of Illinois has shown that the general health of individuals is reflected in the tissues of the mouth. The results so far suggest that certain changes in the oral tissues may serve as a guide to early recognition and diagnosis of systemic disease.

At Yale University, a research grant is supporting studies on the transplantation of embryonic "tooth germs" into the eyes of experimental animals, where their further development can be directly observed. It has been found that a cancer-inducing agent, known as methylcholanthrene, had changed the microscopic appearance of the "tooth germ" transplants to resemble that of malignant tumors.

During the year, a special technique was developed in the Institute's laboratories for isolating and cultivating a group of bacteria associated with dental caries and periodontal disease. Experimental animals are being studied to evaluate the use of antibiotics and other therapeutic agents. Certain of the new antibotics, such as bacitracin, show some promise.

Studies on the metabolism of ingested fluorides received increased attention during the year. Epidemiologic studies on fluoridation of public water supplies in Michigan, Maryland, and Illinois continue to demonstrate striking reduction in the incidence of dental caries. The Institute recently completed a 10-year field study in two Texas towns, where medical and dental examinations of over 200 residents showed that no physiological changes attributable to fluoride could be detected in persons who had long used water supplies naturally containing eight times the amount of fluoride recommended for caries control.

Other projects included electron-microscope studies of dental and related tissues, and nutrition research into the incidence of caries in animals receiving processed or natural foodstuffs. The latter studies indicate that overprocessed foods lead to increased tooth decay in rats. Research projects now under way at the Clinical Center include: a study on developmental abnormalities of the face and jaws, including harelip and cleft palate; evaluation of methods for the treatment of malocclusion; evaluation of various clinical procedures in the treatment of periodontal disease; and a study of vitamin therapy in wound healing following surgery in the oral cavity.

Heart and Circulatory Research

Research conducted by the National Heart Institute expanded during the year. The opening of the Clinical Center permitted a balanced and integrated program of laboratory and clinical investigation of the Nation's leading causes of death.

Heart research in universities and hospitals throughout the country, supported by the Institute through grants, also made important contributions to knowledge of heart and blood vessel diseases. More than 600 research grants amounting to $7,120,146 were made to 140 institutions in 41 States, the District of Columbia, and Hawaii.

Increased emphasis was given in 1954 to Institute programs designed to help relieve scarcities of medical, scientific, and other personnel especially qualified in the cardiovascular diseases. Research fellowships totaling $597,972 were awarded to 127 individuals, and clinical traineeships amounting to $396,900 were awarded to 116 physicians. One hundred and eighteen grants, amounting to $2,692,708, were made to medical schools and other institutions for undergraduate and graduate training in cardiovascular medicine and public health.

Resources of the Institute also assisted the progress made in 1954 in development of community programs for controlling heart disease. This aid, provided in conjunction with the Bureau of State Services, included technical assistance and grants to the States and Territories.

RESEARCH ADVANCES AT NHI

Atherosclerosis underlies coronary heart disease, as well as the many other manifestations of hardening of the arteries. Studies aimed at understanding its development constitute a major area of Institute research. Because atherosclerosis is related to the abnormalities of fat content of the blood, the mechanisms by which fat is handled by the body are now under study. Studies of the heparin-containing "clearing" system, which breaks down the large fat-laden molecules to smaller entities, have been extended and its role in the body evaluated. The concentration of fatty substances in the blood is increased when substances which tie up the heparin in the body are administered. This indicates that the clearing system, heretofore studied in the test tube, affects the normal regulation of blood fat in the human body. Studies of the formation and release of heparin and the distribution of "clearing" activity in body tissues are in progress. The abnormalities which may be present in relatively young individuals who have suffered attacks of coronary thrombosis are under study. The effect on blood fats of administering certain hormones is being evaluated.

The series of events leading to congestive heart failure-the abnormal retention of salt and fluid-has received further study by a number of approaches. Development of a technique for inducing heart failure in dogs provides a tool for the study of the mechanism of heart failure itself, as well as for the study and evaluation of the effect of drugs on the failing heart. It has been shown that the adrenal glands play an important role both in experimental heart failure and in human heart disease. A promising lead currently being exploited is an indication that there may be, in the circulating blood, a hormone necessary for the normal contraction of the heart muscle. Using the beat of the heart muscle itself as a method of measuring this substance, studies intended to isolate and identify it are under way. Their ultimate purpose is to determine the source of this substance and its role in the maintenance of normal heart function.

Investigations aimed at improving the treatment of heart disease through the development of new drugs have been prosecuted vigorously. Studies of the way in which drugs are broken down in the body have led to the isolation of an enzyme system which apparently converts most of the drugs in general use to inactive compounds. Using this system, it may be possible to determine whether drugs may be rendered inactive too rapidly to be useful or so slowly as to be undesirable. Also, using information on the way drugs are broken down, it may be possible to improve them. A search for new drugs to control irregularities of the heart beat has produced several encouraging leads. Such disturbances of the heart rhythm are an old and persistent problem in many forms of heart disease, but the need

for a solution has been greatly accentuated by the frequency of serious irregularities in patients whose body temperature must be reduced for the performance of certain surgical operations on the heart and blood vessels.

Drugs are being sought to reduce the blood pressure in hypertensive patients. The first compound isolated and identified in the Institute's laboratories has now been given preliminary trial in patients. This particular substance, andromedotoxin, derived from Rhododendron, will probably not become an important agent for the treatment of hypertension; however, it may provide a starting point for the development of drugs with more desirable characteristics.

New techniques and scientific instruments often lead to major advances in research. An instrument recently perfected in the Institute's laboratories makes possible the chemical analysis of minute amounts of a number of compounds by the fluorescence which they emit when excited by light of the proper wave length. Currently under development is an instrument which it is hoped will permit the accurate analysis of salts (sodium and potassium) in volumes as small as one one-millionth of a cubic centimeter of body fluids. This might make it possible to analyze the content of single body cells.

RESEARCH GRANTS ACCOMPLISHMENTS

Notable advances were made by scientists whose research was supported by grants from the National Heart Institute. The following illustrations represent only a small fraction of the important contributions of grantees during the past year.

Clinical studies in rheumatic fever showed that a new antiserum test is a sensitive and reliable indicator of rheumatic activity if other unrelated pathologic processes are excluded. The substance used, known as C-reactive protein (CRP) antiserum, indicates the presence of an underlying inflammatory condition in the body. CRP is a specific protein, not present in normal blood serum, which appears in response to a number of inflammatory conditions. Since rheumatic fever often exists without definite outward manifestations, the antiserum test promises to be a valuable aid in diagnosing the condition.

Important progress was made in the use of drugs for treatment of high blood pressure. One drug, obtained from the root of the Indian Snakewood plant (Rauwolfia serpentina), has been found effective in reducing blood pressure in mildly hypertensive patients. Headache, fatigue, and shortness of breath are relieved, and patients frequently express a sense of relaxed well-being. Studies have shown also that patients with more severe forms of hypertension may beneĥt from Rauwolfia used in combination with other more powerful drugs. In combined therapy, beneficial effects of the other drugs may be