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Abstracts

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Abstract

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The distribution kinetics of triiodothyronine: studies of euthyroid subjects with decreased plasma thyroxine-binding globulin and patients with Graves' disease

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The kinetics of distribution of 3,3′,5-triiodo-L-thyronine (T3) have been studied employing both a single-injection and a continuous infusion of T3-131I. External monitoring of radioactivity in the liver during the infusion permitted estimation of the hepatic distribution volume (VH) and the one-way hepatic clearance (CH) of the hormone. Among 10 euthyroid control subjects, VH averaged 2.07 liters ±0.50 (SD), and the mean value for CH, 231 ml of plasma per min (±64). In three euthyroid men whose plasma showed decreased binding capacity by thyroxine-binding globulin (TBG) abnormally high VH and CH values were found, the increase in CH being proportional to the decrease in binding activity by plasma proteins. Among all 13 subjects, there was a high correlation (+ 0.86) between CH and the proportion of free hormone in plasma, measured in vitro.

Authors

Ralph R. Cavalieri, Martin Steinberg, Gilbert L. Searle

Acromegalic pneumonomegaly: lung growth in the adult

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Lung size was evaluated with pulmonary function tests in 10 patients with acromegaly, 1 pituitary giant, and 1 patient who had acromegaly but now has hypopituitarism. In the six acromegalic men all lung volumes were increased. The average values and per cent of predicted were total lung capacity 9.1 liters. 139%; functional residual capacity 5.2 liters, 145%; vital capacity 6.0 liters, 134%; and tissue volume 1.1 liters. There was no evidence of airflow obstruction or air trapping. Anatomic dead space was increased in proportion to the large lung volumes. Lung compliance was increased, averaging 0.43 liters/cm H2O, but lung elastic recoil was normal. These studies show that the lung is involved in the general visceromegaly of acromegaly and that lung size increases in acromegalic men as a result of actual lung growth. Despite the large lung volumes, diffusing capacity was normal suggesting that lung growth resulted from an increase in the size rather than from an increase in the number of alveoli. In contrast to the acromegalic men, lung volumes, anatomic dead space and tissue volume were normal in four acromegalic women, suggesting that sex hormones may modify the effect of growth hormone on the lung. Lung size was large in the pituitary giant but lung volumes were normal according to predicted values based on the patient's great height. Lung volumes were normal in the one male who had been acromegalic but who has been hypopituitary for 21 yr. The role of growth hormone in normal postnatal lung growth and in the maintainance of normal lung size remains to be defined.

Authors

Jerome S. Brody, Aron B. Fisher, Ayhan Gocmen, Arthur B. DuBois

Hypoxic ventilatory drive in normal man

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A technique is described which permits the inscription of the ventilatory response to isocapnic hypoxia in man as a continuous curve relating alveolar oxygen tension and minute ventilation. The adjustment of ventilation to changes in alveolar oxygen tension is complete in 18-23 sec and this is sufficiently rapid to justify the use of a non-steady-state method. Changes in alveolar carbon dioxide tension are prevented by addition of carbon dioxide to the inspired gas. The resulting [unk]VE-PAo2 curves are hyperbolic such that falling PAo2 produces only slight rises in [unk]VE until a critical PAo2 range of 50-60 mm Hg is reached. With further fall in PAo2, [unk]VE increases steeply and the slope of the curve approaches infinity at a tension of 30-40 mm Hg. For purposes of quantitation these curves are approximated by a simple hyperbolic function, the parameters of which are evaluated by a least squares fit of the data. The parameter A denotes curve shape such that the higher the value of A. the greater the increase in ventilation for a given decrease in PAo2 and hence the greater the hypoxic drive. Curves are highly reproducible for each subject and curves from different subjects are similar. In 10 normal subjects at resting PACo2, A = 180.2 ±14.5 (SEM). When PACo2 is adjusted to levels 5 mm Hg above and below control in six subjects A = 453.4 ±103 and 30.2 ±6.8 respectively. These latter values differed significantly from control (P < 0.05). These changes in curve shape provide a clear graphic description of interaction between hypercapnic and hypoxic ventilatory stimuli. At normal PACo2 the [unk]VE-PAo2 curve has an inflection zone located over the same Po2 range as the inflection in the oxygen-hemoglobin dissociation curve. This indicated that ventilation might be a linear function of arterial oxygen saturation or content. Studies in four subjects have demonstrated that ventilation is indeed related to arterial oxygen content in a linear fashion. These data suggest, but do not prove, that oxygen tension in chemoreceptor tissue as in part determined by circulatory oxygen delivery may be an important factor in controlling the ventilatory response to hypoxia.

Authors

John V. Weil, Edward Byrne-Quinn, Ingvar E. Sodal, W. Otto Friesen, Brian Underhill, Giles F. Filley, Robert F. Grover

Changes in serum and urinary calcium during phosphate depletion: studies on mechanisms

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The changes in serum calcium and the renal handling of this ion were evaluated during phosphate depletion. 96 renal clearance studies were carried out in 10 dogs before and after prolonged phosphate depletion (30-160 days) and after repletion. Depletion was produced by reducing phosphate intake and administering aluminum hydroxide gel while intakes of sodium, calcium, and magnesium were constant. With phosphate depletion, serum phosphorus fell to less than 1.0 mg/100 ml and diffusible serum calcium either remained unchanged or rose transiently. Glomerular filtration rate (GFR) fell by 15 to 53%. Despite the reduced filtered load of calcium, its fractional excretion increased in most experiments. This hypercalciuria was not dependent upon changes in sodium or magnesium excretion, or the urinary concentration of complexing anions, and persisted after sodium restriction. Phosphate repletion reversed the effects on GFR and calcium excretion. The intravenous infusion of small quantities of phosphate (0.04 mmole/min) into either intact or thyroparathyroidectomized (T-PTX), phosphate-depleted animals caused a significant reduction in fractional excretion of calcium, but the intrarenal infusion of 0.02 mmole/min of phosphate into one kidney failed to produce an ipsilateral effect. The administration of parathyroid extract reduced fractional calcium excretion, but the latter remained significantly elevated. After T-PTX, fractional calcium excretion did not increase in the phosphate-depleted animals. Furthermore, serum calcium was normal after T-PTX until serum phosphorus increased slightly, and only then did hypocalcemia develop. These observations indicate that (a) phosphate depletion produces hypercalciuria through a reduction in tubular reabsorption of calcium which is not due to changes in the tubular reabsorption of other ions; this effect is not reversed by the direct intrarenal infusion of phosphate; (b) a state of functional hypoparathyroidsm occurs during phosphate depletion which may, in part, cause reduced tubular reabsorption of calcium; (c) other extra renal mechanism(s), possibly related to events occurring in bone as a result of phosphate depletion, may have an effect on urinary calcium excretion; and (d) in the phosphatedepleted state, parathyroid hormone is not required for the maintenance of a normal level of serum calcium.

Authors

Jack W. Coburn, Shaul G. Massry

The interaction of 2,3-diphosphoglycerate with various human hemoglobins

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Oxygen equilibria were measured on a number of human hemoglobins, which had been “stripped” of organic phosphates and isolated by column chromatography. In the presence of 2 × 10-4 M 2,3-diphosphoglycerate (2,3-DPG), the P50 of hemoglobins A, A2, S, and C increased about twofold, signifying a substantial and equal decrease in oxygen affinity. Furthermore, hemoglobins Chesapeake and MMilwaukee-1 which have intrinsically high and low oxygen affinities, respectively, also showed a twofold increase in P50 in the presence of 2 × 10-4 M 2,3-DPG. In comparison to these, hemoglobins AIC and F were less reactive with 2,3-DPG while hemoglobin FI showed virtually no reactivity. The N-terminal amino of each β-chain of hemoglobin AIC is linked to a hexose. In hemoglobin FI the N-terminal amino of each γ-chain is acetylated. These results suggest that the N-terminal amino groups of the non-α-chains are involved in the binding of 2,3-DPG to hemoglobin.

Authors

H. Franklin Bunn, Robin W. Briehl

Diabetes mellitus and sexual ateliotic dwarfism: a comparative study

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The incidence of diabetic retinopathy was determined in 38 diabetics and 31 sexual ateliotic dwarfs deficient only in human growth hormone (HGH). The age and sex distribution were approximately the same in each group. The incidence and pattern of glucose intolerance were similar in diabetics and HGH-deficient dwarfs. The majority of diabetics (21 of 38) and HGH-deficient dwarfs (26 of 31) exhibited insulinopenia after glucose, mixed glucose-beef meals, and the infusion of l-arginine. A smaller number of HGH-deficient dwarfs (5 of 31) and diabetics (8 of 38) had normal or augmented absolute insulin responses to these same provocative stimuli. Hypercholesterolemia and hypertriglyceridemia occurred with greater frequency in both diabetics and HGH-deficient dwarfs than in normal controls. 8 of 21 diabetics and 6 of 21 sexual ateliotics exhibited significant hypertriglyceridemia. Five diabetics and six sexual ateliotics had significantly greater than normal serum cholesterol levels.

Authors

T. J. Merimee, S. E. Fineberg, V. A. McKusick, J. Hall

Gamma G globulin subgroup composition of the glomerular deposits in human renal diseases

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36 renal biopsies from patients with nephritis were studied for glomerular localization of the heavy chain subgroups of immunoglobulin G (IgG or γG). The deposition pattern of these subgroups was selective and did not reflect the normal serum concentration of these proteins. γG2, which comprises 18% of normal serum γG, was the predominant or unique subgroup deposited in five cases of lupus nephritis and four biopsies with other forms of nephritis associated with granular γG deposits. γG3, which normally makes up only 8% of the serum γG, was the dominant subgroup seen in one biopsy of lobular glomerulonephritis. Patients with linear γG deposits generally had a selective absence of γG3 and often had large amounts of γG4 (normally 3% of the serum γG) deposited. The deposition of complement components C1q, C4, and C3 was variable. One biopsy had only γG2 and no complement components in the deposits and had no neutrophile leukocyte infiltration. This latter observation correlates well with the poor ability of γG2 to fix complement in vitro. Similarly, deposits containing large amounts of γG4, which does not fix complement, also tended to have less inflammatory infiltrate than deposits devoid of this subgroup. The selective deposition of monotypic or restricted γG subgroups on the glomerulus supports the likelihood that the γG represents antibody. The nature of the subgroup involved in the deposit may represent one variable in the determination of the inflammatory and morphological picture that evolves in human glomerulonephritis.

Authors

Edmund J. Lewis, George J. Busch, Peter H. Schur

Immunoglobulin synthesis and total body tumor cell number in IgG multiple myeloma

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Studies of synthesis of IgG paraproteins were performed in 10 patients who had IgG myeloma in order to quantitate cellular immunosynthetic functions and derive estimates of the number of tumor cells present in such patients. Serial in vitro studies demonstrated constancy in the cellular rate of IgG paraprotein secretion for up to 8 months. Average molecular synthesis rates in different patients ranged from 12,500 to 85,000 molecules of IgG per minute per myeloma cell. Estimated total body tumor cell number ranged from 0.5 × 1012 to 3.1 × 1012 myeloma cells, and could be correlated with the degree of skeletal damage observed on roentgenograms (P = <0.01). Serial measurements of tumor cell number may prove useful in characterizing the growth rate and natural history of multiple myeloma. Myeloma is the first metastatic human malignancy in which quantitative measurements of the body's burden of malignant cells have been obtained.

Authors

Sydney E. Salmon, Beth A. Smith

Formation, mineralization, and resorption of bone in vitamin D—deficient rats

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Quantitative histologic methods have been devised to measure several processes dealing with formation and mineralization of matrix and bone resorption. In vitamin D-deficient rats, the total osteoblastic matrix formation rate was 20% less and the total osteoclastic bone resorption rate was 80% more than in pair-fed control rats. These changes were found to be primarily because of changes in the rates of matrix formation and of bone resorption per unit area of forming or resorbing surfaces rather than to changes in the areas of these surfaces. The rate of maturation of osteoid and the rate of initial mineralization both were reduced to half of normal in the vitamin D-deficient rats. These variables related to matrix formation and mineralization were significantly correlated with the concentration of calcium but not with the concentration of phosphate in serum. The occurrence of hypocalcemia is interpreted as the consequence, both of reduced calcium absorption and of inadequate resorptive response of bone cells to homeostatic stimuli, such that, although bone resorption was greater than normal, it did not adequately compensate for the reduced intestinal absorption.

Authors

D. Baylink, M. Stauffer, J. Wergedal, C. Rich

The effects of unsaturated dietary fats on absorption, excretion, synthesis, and distribution of cholesterol in man

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Cholesterol balance studies were carried out in 11 patients with various types of hyperlipoproteinemia to determine the mechanism by which unsaturated fats lower plasma cholesterol. Unsaturated fats produced no increase in fecal endogenous neutral steroids in 10 of 11 patients and no decrease in absorption of exogenous cholesterol in 5 patients who received cholesterol in the diet. In 8 of 11 patients no changes occurred in excretion of bile acids during the period on unsaturated fat when plasma cholesterol was declining. However, in 3 of 11 patients small but significant increases in bile acid excretion were found during this transitional period; in 2 others increases also occurred after plasma cholesterol had become constant at lower levels on unsaturated fat.

Authors

Scott M. Grundy, E. H. Ahrens Jr.

The effects of abnormal sympathetic nervous function upon the ventilatory response to hypoxia

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The ventilatory response to hypoxia was studied in two groups of subjects with abnormal sympathetic nervous control: (a) human subjects with familial dysautonomia (Riley-Day syndrome), and (b) unanesthetized goats treated with an alpha-adrenergic blocking agent (phenoxybenzamine). The ventilatory response to hypoxia was evaluated in two ways: (a) from the slope of the relationship between ventilation and alveolar PCo2 ([unk]VE-PACo2 slope) during the rebreathing of hypoxic and hyperoxic gases, and (b) from the change in ventilation produced when hypoxia was abruptly relieved.

Authors

N. H. Edelman, N. S. Cherniack, S. Lahiri, E. Richards, A. P. Fishman

The demonstration of alternating contractile state in pulsus alternans

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Pulsus alternans was induced in 11 anesthetized, open-chest dogs by rapid atrial pacing, and the left ventricular filling characteristics and length-tension-velocity relationship of alternating beats were compared. The end-diastolic circumferences (cire) of the strong beats were slightly, but significantly, increased over the weak beats (7.3 > 6.9 cm, P < 0.01), confirming that diastolic filling does alternate in pulsus alternans. This alternation in initial fiber length seemed to result from an alternation in the prior end-systolic length, rather than from an alternation in diastolic filling time or compliance. There was also no difference in end-diastolic tension as measured by an isometric strain gauge suggesting no difference in contractile element relaxation before weak and strong beats.

Authors

R. Joe Noble, Donald O. Nutter

Complement in overt and asymptomatic nephritis after skin infection

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In an ongoing study of streptococcal skin infection and acute glomerulonephritis (AGN) begun in 1964, C′3 determinations were done in 784 patients. There were 126 patients with acute poststreptococcal nephritis, 172 of their siblings, and 486 patients with uncomplicated impetigo from families without an index case of nephritis.

Authors

C. Warren Derrick, Mary Sue Reeves, Hugh C. Dillon Jr.

Cell proliferation in human melanoma

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The cytokinetics of subcutaneous metastases in five patients with melanoma was studied. Multiple simultaneous biopsies following pulse labeling with tritiated thymidine were performed in one patient. There was relatively uniform labeling and mitotic indices among these. Within the individual tumors, there was some variation in the labeling index with small clusters of tumor cells having significantly higher labeling indices than more sparsely infiltrating tumor cells. Repetitive biopsies following pulse labeling were performed in two patients. The per cent labeled mitosis curves were similar in the two patients. By computer analysis a median G2 period of 5.3 hr and an S period of 21 hr were obtained. The generation time (Te) was highly variable with a median of 3 days. This Te was consistent with that calculated from grain count studies in these patients. Two patients received either intermittent or continuous tritiated thymidine over a 10-20 day period. Analysis of the labeling index curve by computer fitting indicated a growth fraction of 20-30%. The growth fraction calculated by other indirect methods was consistent with the computer analysis. The potential tumor doubling time as calculated from the Te and growth fraction was much shorter than the actual doubling time indicating that cell loss was approximately 70% of the rate of cell production.

Authors

S. Shirakawa, J. K. Luce, I. Tannock, E. Frei III

Fluid reabsorption in Henle's loop and urinary excretion of sodium and water in normal rats and rats with chronic hypertension

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The function of the short loops of Henle was investigated by micropuncture technique in normal rats, in rats with spontaneous hypertension, and in the untouched kidney of rats with experimental renal hypertension. All animals received a standard infusion of 1.2 ml of isotonic saline per hr.

Authors

Klaus O. Stumpe, Hans D. Lowitz, Bruno Ochwadt

Lipolysis and lipogenesis from glucose in human fat cells of different sizes: Effects of insulin, epinephrine, and theophylline

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Lipogenesis from glucose and lipolysis in human omental and subcutaneous fat cells were studied as functions of adipose cell size and number in adult females. Since subcutaneous fat cells were larger than those prepared from the greater omentum, a comparison could be made of the metabolism of different sizes of cells within individual subjects. Rates per cell of glyceride-glycerol and glyceride-fatty acid synthesis from glucose were similar in omental and subcutaneous fat cells incubated in the presence or absence of insulin. However, subcutaneous fat cells exhibited higher rates of basal lipolysis than omental fat cells and these differences were maintained when lipolysis was stimulated with theophylline. Different rates of lipolysis were not demonstrable after incubations with epinephrine, indicating that subcutaneous fat cells were less responsive to this hormone than smaller omental fat cells. Correlation and partial correlation analysis showed that differences in basal and theophylline-stimulated lipolysis between fat cells prepared from different subjects and between omental and subcutaneous fat cells could be accounted for by differences in adipose cell volume. In subcutaneous fat cells highly significant intercorrelations were demonstrated between cell volume, basal lipolysis, and the basal conversion of glucose to glyceride-glycerol. There was no correlation between fat cell volume, age, or relative obesity and the effects of theophylline or insulin on lipolysis or lipogenesis from glucose in vitro when the data were expressed as percentage changes above basal values.

Authors

R. B. Goldrick, G. M. McLoughlin

Studies on the exaggerated natriuretic response to a saline infusion in the hypothyroid rat

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The exaggerated natriuresis of hypothyroid rats receiving a 5% saline infusion was studied to determine the mechanism and the site within the nephron responsible for this increase in sodium excretion. Sodium clearance (CNa) and fractional sodium excretion were both demonstrated to be greater in hypothyroid rats for any amount of sodium infused. The rate of increase in fractional sodium excretion in response to saline loading was 3.4 times greater in hypothyroid animals. At the conclusion of the diuresis some of the hypothyroid animals excreted greater than 45% of the filtered sodium load, while no control animal excreted more than 12% of the filtered sodium load.

Authors

Edward W. Holmes Jr., Vincent A. DiScala

A water-filled body plethysmograph for the measurement of pulmonary capillary blood flow during changes of intrathoracic pressure

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A water-filled body plethysmograph was constructed to measure gas exchange in man. As compared to an air-filled plethysmograph, its advantages were greater sensitivity, less thermal drift, and no change from adiabatic to isothermal conditions after a stepwise change of pressure. When five subjects were completely immersed within it and were breathing to the ambient atmosphere, they had a normal heart rate, oxygen consumption, CO2 output, and functional residual capacity. Pulmonary capillary blood flow ([unk]Qc) during and after Valsalva and Mueller maneuvers was calculated from measurements of N2O uptake. Control measurements of [unk]Qc were 2.58 liters/min per m2 at rest and 3.63 liters/min per m2 after moderate exercise. During the Valsalva maneuver at rest (intrapulmonary pressure: 24, SD 3.0, mm Hg), [unk]Qc decreased from a control of 2.58, SD 0.43, liters/min per m2 to 1.62, SD 0.26, liters/min per m2 with a decrease in pulmonary capillary stroke volume from a control of 42.4, SD 8.8, ml/stroke per m2 to 25.2, SD 5.5, ml/stroke per m2. After release of the Valsalva, there was an overshoot in [unk]Qc averaging +0.78, SD 0.41, liter/min per m2 accompanied by a significant increase in heart rate. Similar changes occurred during and after the Valsalva following moderate exercise. During the Mueller maneuver at rest and after exercise, [unk]Qc, heart rate, and central stroke volume did not change significantly.

Authors

Yoshikazu Kawakami, Harold A. Menkes, Arthur B. DuBois

Effect of acute hypoxia on vascular responsiveness in man: I. Responsiveness to lower body negative pressure and ice on the forehead. II. Responses to norepinephrine and angiotensin. III. Effect of hypoxia and hypocapnia

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An effect of hypoxemia on vascular responsiveness and blood pressure regulation has not been demonstrated in man. The response of forearm resistance vessels to several vasoconstrictor stimuli was compared during normoxia and acute hypoxia. Forearm vasoconstrictor responses to lower body negative pressure and to the application of ice to the forehead, which are neurogenic stimuli, were decreased during acute hypoxia. Lower body negative pressure caused a decrease in mean arterial pressure during hypoxia, but not during normoxia. Because norepinephrine is the neurotransmitter released during reflex vasoconstriction, we considered the possibility that decreased responsiveness to norepinephrine might be one mechanism for diminished responses to lower body negative pressure and ice on the forehead during hypoxia. Hypoxia decreased the response of forearm resistance vessels to infusions of norepinephrine and angiotensin into the brachial artery. In addition, the effectiveness of intravenous infusions of norepinephrine in elevating mean arterial pressure was decreased during hypoxia. Since exposure to acute hypoxia stimulates hyperventilation and hypocapnia, experiments were done to determine the contribution of hypocapnia during hypoxia to the decreased vasoconstriction. The results indicate that hypocapnia may diminish the vascular response to some stimuli, but the reduction in oxygen appears to be the primary mechanism for decreased vasoconstrictor responses during acute hypoxia.

Authors

Donald D. Heistad, Robert C. Wheeler

The effect of diphenylhydantoin on thyroxine metabolism in man

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The effect of 5,5′-diphenylhydantoin on thyroxine metabolism was examined in five normal volunteers. Intravenous injection of radiothyroxine was followed by a 10-12 day control and subsequent 9-14 day treatment periods. During oral administration of diphenylhydantoin, plasma thyroxine concentration decreased to about 80% of its pretreatment level and the plasma radiothyroxine disappearance rate increased a maximum of 20% over control estimates. These changes were a result of increases in both urinary and fecal excretion of radioisotope.

Authors

P. R. Larsen, A. J. Atkinson Jr., H. N. Wellman, R. E. Goldsmith

Catalase-dependent peroxidative metabolism in the alveolar macrophage during phagocytosis

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Evidence for the presence of peroxidative metabolism in rabbit alveolar macrophages (AM) has been obtained from the following observations: (a) catalase is present in high concentrations; (b) peroxidase activity could not be detected employing guaiacol as substrate; (c) the irreversible inhibition of AM catalase by aminotriazole served as a detection system for H2O2 and demonstrated increased intracellular H2O2 after phagocytosis; (d) formate oxidation, a marker of catalase-dependent peroxidations, occurs in resting AM and is increased by phagocytosis; (c) measurements of H2O2 accumulation in a dialysate of AM demonstrated twofold increase during phagocytosis; and (f) aminotriazole diminishes O2 utilization and 14CO2 production from labelled glucose and pyruvate. It is concluded that, while catalase-dependent H2O2 metabolism is not essential for particle entry, this pathway represents one of the metabolic pathways stimulated by particle entry in the AM.

Authors

J. Bernard L. Gee, Charles L. Vassallo, Paul Bell, James Kaskin, R. E. Basford, James B. Field

Effect of renal insufficiency on the active transport of calcium by the small intestine

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The intestinal absorption of calcium is often depressed in patients with chronic renal insufficiency. Furthermore, the malabsorption of calcium and the osteodystrophy which occur in association with chronic renal disease are often “resistant” to vitamin D; the basis for this resistance remains uncertain however. Recent studies by others have emphasized the role of an abnormality in the metabolism of vitamin D in accounting for the alterations in the calcium absorption and the apparent vitamin D-resistance which accompany the uremic syndrome.

Authors

Richard D. Baerg, Daniel V. Kimberg, Elaine Gershon

Biomedical research and national policy.

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Authors

Lloyd H. Smith Jr.

Characterization of human anti-glomerular basement membrane antibodies eluted from glomerulonephritic kidneys

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Authors