James M. Stengle

Diurnal-Nocturnal Variations of Certain Blood Constituents in Normal Human Subjects: Plasma Iron, Siderophilin, Bilirubin, Copper, Total Serum Protein and Albumin, Haemoglobin and Haematocrit

THE iron content and total iron-binding capacity of the plasma are subjects of wide scientific and medical interest. Evidence is accumulating that certain diseases have a characteristic effect not only on the concentration of plasma iron and its rate of turnover (Laurell, 1952; Brendstrup, 1953) but also on the concentration of the plasma iron-binding protein, siderophilin. Iron-deficiency anaemia, malignant neoplastic disease and acute and chronic infections, with the exception of viral hepatitis, are characterized by the level of plasma iron being lower thali normal. The circulating siderophilin concentration is abnormally high in cases of iron-deficiency anaemia, sharply lowered in acute infections and somewhat less markedly depressed in chronic infections and malignancy. Several investigators, e.g., Vahlquist (1941), Hayer (1944) and Hemmelcr (1951), have reported data on the variations of plasma iron levels in normal subjects over a 24-hour period. Relatively little study has been made of the possible daily variations of their total iron-binding capacities. It was primarily with the intention of examining normal subjects in this respect that the present studies were undertaken. In addition to the plasma iron and total siderophilin lcvels of blood samples taken from twenty nornial subjects over a z4-hour test period, we estimated other blood constituents whose concentrations might be related. Total serum protein and albumin concentrations were determined in order to associate any observed variation in siderophilin, a globulin, with possible changes in total globulin concentrations. The plasma samples were analysed for their copper content to determine any possible interrelationship between plasma iron and copper levels in normal subjects, as reported by Hcilineycr, Keiderling and Stiiwe (1941) in their studies of clinical and experinientally induced infections. Bilirubin estimations were made on a number of sera to extend Laurells (1953) observations of parallel variation of morning and evening serum iron and bilirubin concentrations in normal subjects. Haemoglobin concentrations and hacmatocrit values were also determined.

Effects of chemotherapeutic agents on metabolism of human acute leukemia cells in vitro.

Summary 1. A method for studying the effects of known anti-leukemic agents on the glycolysis of intact leukemic leukocytes is reported. The possible applications of this method in evaluating other new and theoretically promising agents, and in selecting the most active agent in a particular clinical case, are indicated. 2. Methotrexate and 6-mercaptopurine inhibited the aerobic glycolysis of acute lymphatic leukemia cells. Methotrexate did not inhibit the equally large aerobic glycolysis of acute myelogenous leukemia cells, and 6-mercaptopurine did so only rarely. These metabolic findings parallel general clinical experience. 3. The bearing of these findings on the mechanism of action of certain cancer anti-metabolites (anti-folics and anti-purines) is pointed out.

Facilities for open heart surgery in the United States. Distribution, utilization and cost.

Data from 88 percent of institutions in the United States with facilities for performing open heart surgery were analyzed to determine the current pattern of distribution of these facilities and the extent of their use in the 5 years from 1967 to 1971. Although facilities for open heart surgery were distributed roughly according to population density, the patient case load per hospital varied greatly from institution to institution, ranging in 1971 from 1,616 cases in one hospital to 4 cases in another. A 250 percent increase in the utilization of these facilities occurred between 1967, 2 years before the general introduction of the aortocoronary bypass operation, and 1971. In turn, the percentage of hospitals performing 25 or fewer open heart procedures annually decreased from 52 percent in 1967 to 14 percent in 1971. In 1971 an estimated

Treatment of pulmonary embolism with urokinase. Results of clinical trial (phase 1).

249 million in professional fees and hospital costs was incurred by open heart operations alone. A 5 year projection based upon this rate of growth shows that significant improvement in utilization of existing facilities and skilled personnel will occur only if the acquisition of facilities for open heart surgery by additional hospitals is preceded by careful studies documenting need and potential for optimal usage.

THE HEMOPHILIAC'S DEMAND ON BLOOD RESOURCES: THE MAGNITUDE OF THE PROBLEM

THE RECENTLY completed, randomized, multi-institutional Urokinase-Pulmonary Embolism Trial, previously described on these pages,1 has demonstrated that a 12-hour infusion of urokinase followed by heparin therapy accelerates the resolution of pulmonary embolism within 24 hours, when compared to heparin therapy alone. This treatment effect favoring urokinase was established by statistically significant differences in 24-hour pulmonary arteriograms, lung scans, and hemodynamic measurements. The treatment difference was noted first in the arteriograms, then with the hemodynamic measurements, and finally in the lung scans. A summary of these findings is shown in table 1. A more detailed report has been submitted to the Journal of the American Medical Association.2 At the conclusion of the trial, 160 patients were studied with a 2-week mortality of 9% in the heparin-treated patients and 7% in the urokinase group. Recurrent pulmonary embolism during this period occurred in 19% and 15% of patients, respectively. Pulmonary embolectomy was not performed in any of these patients. The difference in lung scan resolution between urokinase and heparin-treated patients disappeared by the seventh post-treatment day, but in both treatment groups an average of 25% of the original scan defect remained on follow-up scans at 1 year in the 59 patients on whom these data are presently

The Urokinase-Pulmonary Embolism Trial

Modern treatment of the hemophilia patient is entirely dependent upon the availability of an adequate supply of donor blood from which either factor VIII or factor IX can be recovered. Anyone familiar with either the treatment of hemophilia or the operation of a blood bank is aware of the stresses and difficulties often encountered in procuring sufficient therapeutic materials to deal with the hemorrhagic crises in the individual patient. The Blood Resource Program of the National Heart and Lung Institute is concerned with the assurance on a national scale that an adequate, safe, and economically used blood supply be available for the treatment of all patients. Obviously, hemophilia treatment is only one of the demands placed on the blood supply. Other major demands on the blood resource must unfortunately compete for the limited supply. The need for red cells in surgical practice has rapidly increased as cardiac surgery becomes more common. The call for human albumin, the most widely used plasma protein. has quadrupled in the last five years. Increasing amounts of blood platelets and granulocytes to support modern cancer treatment are required. The numerous demands for blood components are on a collision course with each other unless the total supply is greatly increased and the practice known as component therapy is more widely used. The underlying philosophy of component therapy is that a unit of blood can be made to serve the needs of many patients instead of the one who traditionally received the whole-blood transfusion. This practice has justification not only in economy but in the sound medical premise that it is safer to give only the specific factor needed by the patient for his particular indication. The Blood Resource Program quickly perceived that hemophilia as a single disease entity exerted one of the most quantitatively important demands on the blood supply system, but reliable data on the real magnitude of the problem were totally unavailable. A certain amount of armchair, educated guesswork was conducted by NIH and its consultants. But it was apparent that in the absence of answers to simple questions, such as how many hemophiliacs there are, we could not hope to answer the more complex question of their blood requirements. It was for this reason that a “Pilot Study of Hemophilia Treatment in the United States” became one of the major elements in the National Heart and Lung Institute’s first major formal study of the national blood resource. The study was carried out under contract for the Institute by the Booz, Allen and Hamilton Company. It resulted in the publication in 1973 of three volumes, one of which is devoted to the Hemophilia Pilot Study. Many of you are already familiar with this publication. It is not my purpose here to summarize its contents, but rather to examine with you some of its conclusions and their implications for the blood supply system.