Showing papers in "Journal of Clinical Investigation in 1952"

Lung function studies. VIII. Analysis of alveolar ventilation by pulmonary N2 clearance curves.

Abstract: A comprehensive analysis of pulmonary fuinction must include measurements of pulmonary ventilation, diffusion, and circulation. An accurate measurement of alveolar ventilation, independent of diffusion and circulation, is desirable. To date, no method has been wholly satisfactory (3). One approach has been by study of the time course of equilibration of alveolar gas with a "foreign" inspired gas, such as H2 (4), He (5-7) or pure 02 (8-15). A principal difficulty has been to differentiate between the effects of an enlarged respiratory dead space and of uneven alveolar ventilation, both of which can retard the completion of equilibration. The development by Lilly and Hervey of the N2 meter, for continuous analysis of N2 concentration of respired gas, permits an automatic breath-by-breath analysis of gas expired during and after the change from breathing air to uninterrupted breathing of 02. The ensuring progressive elimination of pulmonary N2 represents the process of equilibration with a N2-free gas, and may be analyzed in terms of alveolar ventilation. This paper presents the pulmonary N2 clearance curves obtained from healthy persons and patients with cardiorespiratory disease, and a method for analysis of these curves which yields a comprehensive picture of the volume and time characteristics of alveolar ventilation. The

The Effects of l-Epinephrine and l-Nor-Epinephrine Upon Cerebral Circulation and Metabolism in Man

Abstract: Studies comparing the effects of epinephrine and nor-epinephrine, the two sympathomimetic amines which occur naturally in the mammalian body, show that these two closely related substances differ in many of their pharmacodynamic properties. The metabolic rate in man has been shown to increase after epinephrine (1, 2), whereas there is no significant change produced by nor-epinephrine (2). Systemic administration of epinephrine to man has been shown to result in a decrease in total peripheral resistance (1, 3), indicating that vasodilatation has occurred in many portions of the body; in contrast, nor-epinephrine appears to be predominantly vasoconstrictor in its action, for total peripheral resistance is increased (3). These differences may be manifestations of the specific functions which these substances perform in the body; von Euler (4) believes that nor-epinephrine is the sympathetic mediator for general purposes, while epinephrine acts as an adjuvant for more special functions, especially in regard to metabolic actions. In view of the importance of epinephrine and nor-epinephrine in physiological processes, their occurrence in pheochromocytomas, their use as therapeutic agents, and the possible relation of nor-epinephrine to essential hypertension (3), information regarding their effect on cerebral blood flow and cerebral metabolism is desirable. A preliminary report by Sensenbach, Madison, and Ochs (5) indicates that nor-epinephrine is a powerful cerebral vasoconstrictor. The animal studies upon epinephrine have yielded conflicting

Lipoprotein patterns of serum obtained by zone electrophoresis

Abstract: For a number of years the lipoproteins of serum have been classified as alpha and beta types according to their electrophoretic mobility. Despite this designation very few studies of their electrophoretic properties have been reported. This is chiefly due to the fact that it is very difficult to determine exactly where the lipoproteins migrate when patterns of whole serum are obtained by the classical Tiselius method. Isolation of the lipoproteins can be achieved by chemical (1, 2) and ultracentrifugal methods (3, 4). However, even if turbidity and solubility problems in the electrophoretic separation of the isolated lipoproteins are overcome, some question remains as to whether the mobilities of these delicate complexes are the same in the isolated state as they are in whole serum. To circumvent these difficulties and to supplement the information obtained from the ultracentrifuge by Gofman, Lindgren and Elliott (3), Green, Lewis and Page (4), and Turner and associates (5) and that obtained from chemical fractionation by Lever and associates (2) and Russ, Eder and Barr (6, 7), the new technique of zone electrophoresis was applied to this problem. This method has the advantage that the electrophoretic components can be isolated directly so that lipid analyses can be carried out. The results obtained in the present study indicate that lipoprotein patterns can be obtained on whole serum and can be correlated in terms of relative electrophoretic mobility with the other proteins of serum.

Evidence for the presence of insulin in blood serum; a method for an approximate determination of the insulin content of blood.

Abstract: In recent years the carbohydrate metabolism of the isolated rat diaphragm has been widely studied (1-8). Using this preparation, Gemmill (2, 3) succeeded in demonstrating in vitro the stimulating effect of insulin on the glucose utilization and glycogen synthesis of an isolated muscle. It has since been shown that a quantitative relationship exists between the amount of insulin present in the incubation medium and its effect on the glucose metabolism of the diaphragm (5, 6). Furthermore, it was found that the diaphragms of young rats are sensitive to extremely small concentrations of insulin (9). This investigation was intended to determine if the glucose metabolism of the isolated rat diaphragm could be used to demonstrate the presence of insulin in blood serum and to determine the concentration of this hormone in blood.

Iron metabolism; iron stores in man as measured by phlebotomy.

Abstract: Hemosiderin and ferritin represent storage iron, available for hemoglobin synthesis when need arises. Previous observations (1, 2) have indicated that these stores must be depleted before iron deficiency becomes manifest in the circulating red cell mass. The depletion of iron stores associated with normal hematological measurements may therefore be regarded as the \"preclinical \" phase of iron deficiency. Interest in the pathogenesis of iron deficiency anemia has led us to further methods of evaluating iron stores. A rough estimate of iron reserves may be obtained by examination of sternal marrow for hemosiderin (2). A more quantitative measurement may be made by determination of iron mobilized for red cell production following phlebotomy. Data obtained by the latter technique are presented to define the size of the iron storage compartment in order to determine its availability and rate of replenishment in normal adult males and in subjects with abnormalities of iron metabolism.

Blood levels of 17-hydroxycorticosteroids following the administration of adrenal steroids and their relation to levels of circulating leukocytes.

Abstract: occurrence of neutrophilia and lymphopenia following the administration of ACTH or adrenal cortical extracts to mice. In 1948 these findings were confirmed in man by Hills, Forsham and Finch (2), who noted, in addition, a pronounced fall in eosinophils. These changes in the blood have been used widely as an index of adrenal cortical activity. With the development of a method for the determination of 17-hydroxycorticosteroids in small quantities of blood or plasma (3) it has become possible to determine the relationship of the changes in blood steroid levels to the changes in leukocytes. In order to investigate this relationship, standard doses of various corticosteroids were administered to normal individuals and the alterations in blood 17-hydroxycorticosteroids and in leukocytes were observed at intervals thereafter.

Thyroid function in nephrosis

Abstract: Since hypometabolism and hypercholesterolemia are common to both hypothyroidism and nephrosis, it was postulated that thyroid activity was subnormal in nephrotic patients. However, Epstein found that remarkably large doses of thyroid hormone could be given to nephrotic patients without inducing hypermetabolism (1). Such tolerance to thyroid medication is unusual among patients with true hypothyroidism. It has therefore been suggested that the hypometabolism and increased serum cholesterol in nephrosis are due not to decreased thyroid function but to other causes, as yet unknown (2). The recent demonstration that the concentration of protein-bound iodine in the serum is reduced in nephrosis (3) has once more raised the question of whether thyroid function is impaired in this syndrome. The present study is an attempt to answer this question.

A study of the nutritional defect in wernicke's syndrome: the effect of a purified diet, thiamine, and other vitamins on the clinical manifestations

Abstract: The salient clinical features of Wernicke's syndrome (1) are partial to complete paralysis of extra-ocular muscles (most commonly the external recti), nystagmus, ataxia and mental disturbances Postmortem examination reveals changes in the nervous structures adjacent to the third and fourth ventricles and the aqueduct The lesions are characterized by varying degrees of necrosis of both nerve cells and nerve fibers with appropriate reactions of microglia and astrocytes, alteration of the small blood vessels, and in some cases, petechial hemorrhages (2-5) The syndrome is usually associated with chronic alcoholism and for that reason has sometimes been attributed to a neurotoxic effect of the alcohol; but the occurrence of the same clinical sequence in non-alcoholic patients with malnutrition (1, 2, 4-8) has directed attention to nutritional deficiency as the etiological basis Moreover, similar pathological lesions have been produced in the rat (9, 10), fox (11, 12), and pigeon (3, 9, 13, 14), by maintaining these animals on thiamine-deficient diets

Effects of anxiety and morphine on discrimination of intensities of painful stimuli

Abstract: The testing of analgesics, especially morphine, has yielded a great deal of conflicting evidence concerning the effects of drugs on pain perception. The recent reviews by Wikler (1) and Edwards (2), and the monograph by Wolff and Wolf (3), cover thoroughly the studies that have attempted to measure changes in the pain perception threshold. Although many investigators have reported rises in the pain perception threshold of some of their subjects following the administration of morphine, the majority have obtained variable results. Wolff, Hardy, and Goodell (4) found consistent rises following the administration of morphine under certain conditions. Using the same technique, Andrews (5), Isbell (6), Denton and Beecher (7), and Chapman and Jones (8) found, following morphine, that the pain perception threshold might be elevated, lowered or unchanged. Similar results were obtained by Isbell and Frank (9) in studies on the effect of analgesics on tooth pain perception thresholds. It would seem that the discrepancies were not due to faulty apparatus or lack of objectivity in handling the data. Rather, the reasons appear to lie in conditions that were not held constant or that were beyond the control of the experimenters. One such variable that has been mentioned in several studies as possibly contributing to unpredictability of results is the "emotional" status of the subject at the time the experiment is performed. Included would be such factors as response of the subject to the experimental room, to the complex apparatus, to the attitude of the experimenter, and to the expected painful stimuli. The uncontrolled variable in the subject's behavior would then seem to comprise that class of responses which is termed anticipatory, i.e., especially effectively toned responses that are anticipatory of pain. This, of course, is one type of fear or "anxiety." Isbell and Frank (9) also studied the effect of morphine on the ability of subjects to estimate intensities of painful stimuli. In their investigation, the pulp nerve of a tooth containing a silver amalgam filling was stimulated electrically at intensities three times the absolute perception threshold value. These stimuli, which served as standards, were definitely painful. After morphine the subjects were required to manipulate rheostat knobs on the stimulating apparatus until the test stimuli were reported as being equal to the standard. (The apparatus was so adjusted that turns of the knob did not correspond with the intensity of stimuli or with dial scale readings.) No change in the accuracy of estimation of painful stimuli was observed following the administration of morphine. However, analysis of the conditions under which the studies were conducted indicates that considerable effort was expended to reduce anxiety in the subjects; they were given considerable control of the experimental situation since they manipulated the stimulator knob themselves and applied the electrode to their own tooth fillings. In addition they were trained in estimating intensities of painful stimuli for approximately one week prior to testing. In view of conditions and results discussed! in published studies on pain perception thresholds, it might be expected that if conditions had been favorable for enhancement of anxiety (anticipatory responses to expected unpleasant stimuli), Isbell and Frank would have obtained different results. The present investigation is an attempt to determine the extent to which anxiety and morphine alter pain intensity estimation. The experiment was designed to investigate the effect of controlled variations in the experimenter's treatment of the subject on estimation of pain intensities, while the number, the order, and the intensity of the stimuli were kept constant for all groups. If it could be

Cardiovascular and renal adjustments to a hypotensive agent (l'hydrazinophthalazine: Ciba BA-5968: apresoline).

Abstract: Since the work of Goldblatt, Lynch, Hanzal, and Summerville which related renal ischemia causally to hypertension (1), it has seemed logical to use renal vasodilators in the treatment of the syndrome. Yet the pyrogens are the only substances which heretofore have been demonstrated to increase consistently renal blood flow and these have not been found suitable for therapeutic use (2, 3). Chemical or hormonal compounds proposed as anti-hypertensive agents either exert a negligible effect on the renal circulation or reduce renal blood flow while lowering arterial pressure. These include the adrenergic blocking agent dibenamine (4, 5), the benzodioxanes (6), the ergot alkaloids (7), and the imidazolines (6, 8). Xanthine derivatives, of which aminophylline may be considered the prototype, induce renal hyperemia only in congestive cardiac failure (9, 10). The commonly used peripheral vasodilators-nicotinic acid, histamine, and the nitrites-similarly fail to augment renal blood (3, 11 ). l-Hydrazinophthalazine (Ciba BA-5968 or Apresoline) is the basic chemical compound and one of several substituted compounds which have in common the properties of (a) increasing renal blood flow and (b) reducing arterial pressure in both animals and man (12-16). It has been shown that this drug antagonizes the pressor action of epinephrine and to a lesser extent that of nor-epinephrine (14, 17-20). It abolishes the pressor effect brought about by centripetal vagus stimulation and thought due to serotonin (21), and it has an inhibitory effect against

Cerebral circulation and metabolism in sickle cell and other chronic anemias, with observations on the effects of oxygen inhalation.

Abstract: Sickle cell anemia may be associated with a variety of serious cerebral manifestations, such as hemiplegia, aphasia, convulsions, stupor or coma (1, 2). These symptoms are usually attributed to thromboses of the cerebral vessels produced by sickled erythrocytes, vascular stasis and degenerative changes in the small and medium-size arteries of the central nervous system (3, 4). In chronic anemias from various causes, such mental manifestations as drowsiness, irritability, and fainting are often seen. Psychoses have been observed in pernicious anemia and in chronic posthemorrhagic anemia (5). A diminution in cerebral oxygen consumption in patients with pernicious anemia has been reported and may be the basis for the alterations in the mental status seen in these patients (6). It seemed worth-while for these reasons to study the cerebral circulation and metabolism in such patients, and this report presents the findings in 10 patients with sickle cell disease and eight patients with other types of chronic anemia. In order to obtain insight into the pathogenesis of the abnormalities observed, the effects of inhalation of 85-100%o oxygen on cerebral functions were determined and the data thus obtained are also presented in this report.

The possible use of neutron-capturing isotopes such as boron10 in the treatment of neoplasms. ii. computation of the radiation energies and estimates of effects in normal and neoplastic brain

Abstract: The nuclei of the principal atoms found in normal living tissue have but little tendency to capture very slow (thermal) neutrons, whereas the nuclei of a certain few isotopes have a remarkable propensity for capture of thermal neutrons. Among the isotopes in the latter group, boron'0 (B10) attracted the attention of Kruger (1) and of Zahl, Cooper, and Dunning (2) as early as 1940 because the capture reaction yields a high energy alpha particle which dissipates all its energy in tissue within circa 14 a. The reaction may be written:

Studies of niacin requirement in man. I. Experimental pellagra in subjects on corn diets low in niacin and tryptophan.

Abstract: Early attempts to estimate human niacin requirement were based on calculations of the niacin content of pellagragenic and nonpellagragenic diets (1, 2). It was appreciated that the protein content of the diet was in some way related to niacin requirement. Recent studies showing that the amino acid tryptophan is converted in part to niacin compounds in man (3-5) may explain the above relationship, and also the pellagra preventive effect of foods which are low in niacin but rich in "good" protein. The present experiments were designed to study niacin requirement in man with diets of known tryptophan content. Estimation of minimum tryptophan requirement for nitrogen balance (6) permits formulation of diets containing little excess tryptophan which may be converted to niacin. The discovery of the major metabolites of niacin, namely Nl-methylnicotinamide (N'-Me) and the 6-pyridone of Nl-methylnicotinamide (pyridone), and the development of methods for the measurement of these compounds in urine, now permit more complete studies of niacin metabolism (7-11).

The rate of removal of radioactive iron from the plasma—an index of erythropoiesis

Abstract: Transport iron normally exists in the plasma as ferric beta-l-globulinate. Since in most individuals the greater part of the body iron is incorporated in the hemoglobin of the red blood cells, it is probable that changes in the production and destruction of these erythrocytes will be reflected in the turnover of plasma iron. Radioactive iron of high specific activity is particularly useful for a study of iron metabolism since it can be injected intravenously in tracer amounts without changing the steady state of the organism; the turnover of this radioiron will then mirror the metabolism of the iron in the body.