On the Uptake of Materials by the Intact Liver THE CONCENTRATIVE TRANSPORT OF RUBIDIUM-86

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Abstract

In this study we use the multiple indicator dilution technique to outline the kinetic mechanisms underlying the uptake of rubidium, a cation which, in the steady state, is concentrated by hepatic parenchymal cells. We inject a mixture of 51Cr-labeled red blood cells (a vascular reference substance), 22Na (which is confined to the extracellular space, the expected extravascular distribution space for rubidium, in the absence of cellular uptake), and 86Rb into the portal vein and obtain normalized outflow patterns, expressed as outflowing fractions of each injected mass per milliliter vs. time. The labeled red cell curve rises to the highest and earliest peak and decays rapidly. That for labeled sodium rises to a later and lower peak, and decays less rapidly. Its extrapolated recovery is equal to that for the red cells. The observed 86Rb curve consists of two parts: an early clearly defined peak of reduced area, related to the 22Na peak in timing; and a later tailing, obscured by recirculation, so that total outflow recovery cannot be defined (even though it would be expected to be the same). We model the concentrative uptake of 86Rb and find two corresponding outflow fractions: throughput material, which sweeps past the cell surface as a wave delayed with respect to the vascular reference (tracer which has not entered cells); and exchanging material (tracer which has entered cells and later returns to the circulation). We find that the outflow form of the rubidium curve, the presence of both a relatively clearly defined throughput component and a relatively prolonged low-in-magnitude tailing, is consequent to the concentrative character of the transport mechanism, to the presence of an influx rate constant many times the efflux rate constant. The modeling which we develop is general, and has potential application in situations where transport is nonconcentrative.

Authors

Carl A. Goresky, Glen G. Bach, Brita E. Nadeau

On the Uptake of Materials by the Intact Liver. THE TRANSPORT AND NET REMOVAL OF GALACTOSE

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D-galactose, a monosaccharide rapidly phosphorylated within liver cells, is irreversibly removed from the portal circulation. We have studied the kinetic relations between the hepatic cell entry process and the metabolic sequestration process, by means of the multiple indicator dilution technique. Labeled red blood cells (a vascular indicator), labeled sucrose (an extracellular reference), and labeled galactose were rapidly injected into the portal vein, and from rapidly sampled hepatic venous blood, normalized outflow-time patterns were secured. The labeled red cell curve rises to the highest and earliest peak, and decays rapidly; and that for labeled sucrose rises to a later and lower peak. Its extrapolated recovery is equivalent to that of the labeled red cells. At low blood galactose concentrations, the labeled galactose appears at the outflow with labeled sucrose, but is much reduced in magnitude, and exhibits a long tailing. Its outflow recovery is much reduced. At high blood galactose concentrations, the initial part of the profile increases towards that for labeled sucrose, the tailing becomes much larger in magnitude, and the outflow recovery becomes virtually complete.

Authors

Carl A. Goresky, Glen G. Bach, Brita E. Nadeau

Effects of Replacement Doses of Sodium-L-Thyroxine on the Peripheral Metabolism of Thyroxine and Triiodothyronine in Man

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Studies of the effect of L-thyroxine administration (0.3 mg daily for 7-9 wk) on the peripheral metabolism of 131I-labeled triiodothyronine (T3) and 125I-labeled thyroxine (T4) and on the concentration and binding of T4 and T3 in serum were carried out in 11 euthyroid female subjects. Administration of L-thyroxine led to consistent increases in serum T3 concentration (137 vs. 197 ng/100 ml), T3 distribution space (39.3 vs. 51.7 liters), T3 clearance rate (22.9 vs. 30.6 liters/day) and absolute T3 disposal rate (30 vs. 58 μg/day), but no change in apparent fractional turnover rate (60.3 vs. 60.6%/day). The proportion and absolute concentration of free T3 also increased during L-thyroxine administration. Increases in serum total T4 concentration (7.3 vs. 12.8 μg/100 ml) and in both the proportion and absolute concentration of free thyroxine also occurred. In five of the subjects, the kinetics of peripheral T4 turnover were simultaneously determined and a consistent increase in fractional turnover rate (9.7 vs. 14.2%/day), clearance rate (0.84 vs. 1.37 liters/day), and absolute disposal rate (64.2 vs. 185.0 μg/day) occurred during L-thyroxine administration. Despite these increases in the serum concentration and daily disposal rate of both T4 and T3, the patients were not clinically thyrotoxic. However, basal metabolic rate (BMR) values were marginally elevated and, as in frank thyrotoxicosis, T4-binding capacities of thyroxine-binding globulin (TBG) and thyroxine-binding prealbumin (TBPA) reduced, suggesting that subclinical thyrotoxicosis was present. Thus, the often recommended replacement dose of 0.3 mg L-thyroxine daily may be greater than that required to achieve the euthyroid state.

Authors

Lewis E. Braverman, Apostolos Vagenakis, Patricia Downs, Angela E. Foster, Kenneth Sterling, Sidney H. Ingbar

Evidence for Delayed Development of the Glucagon Receptor of Adenylate Cyclase in the Fetal and Neonatal Rat Heart

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The effects, in vivo, of epinephrine, glucagon, and dibutyryl cyclic adenosine 3′,5′-monophosphate (cyclic AMP) on the glycogen content of rat heart and liver and, in vitro, upon adenylate cyclase activity in homogenates of rat heart and liver were determined during the latter third of gestation and the neonatal period. Hepatic glycogen was depleted by epinephrine, glucagon, and dibutyryl cyclic adenosine 3′,5′-monophosphate, but myocardial glycogen was depleted only by epinephrine and dibutyryl cyclic AMP in the neonates. Hepatic adenylate cyclase activity was augmented by both epinephrine (10-5 M) and glucagon (10-5 M), and myocardial cyclase was increased only by epinephrine in tissue obtained from 16, 18, and 20 day fetal rats. Myocardial adenylate cyclase responsiveness to glucagon was present in tissue obtained from rats 4 wk of age and older. It is concluded that in contrast to hepatic adenylate cyclase, myocardial adenylate cyclase in the rat is not responsive to glucagon during gestation and that responsiveness to glucagon and the associated ability of glucagon to deplete myocardial glycogen do not develop until well after birth.

Authors

Charles M. Clark Jr., Bruce Beatty, Donald O. Allen

Thymus-Derived Rosette-Forming Cells in Various Human Disease States: Cancer, Lymphoma, Bacterial and Viral Infections, and Other Diseases

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Lymphocytes that bind in vitro to sheep erythrocytes in a rosette formation are thymus-derived. A modified technique that does not detect the total number of rosette-forming cells (RFC) was used to study normal subjects and various disease states. Of 100 healthy subjects, 95 had more than 15% RFC (mean 28.4±6.5%). We studied 104 patients with solid tumors, who were classified according to clinical status and stage of therapy. Of 19 newly diagnosed patients, 13 had less than 15% RFC. Of 44 untreated patients undergoing relapse, 32 had less than 15% RFC. In both categories, patients with metastases had fewer RFC than patients with localized disease. 11 patients were studied 2 wk after cessation of therapy; four of them showed less than 15% RFC. Only one of 30 patients in remission had less than 15% RFC. In seven patients followed for various periods of time, the numbers of RFC correlated generally with clinical status. 11 patients with chronic lymphatic leukemia had very low percentages of RFC. 21 of 21 patients with symptoms of viral upper respiratory diseases had less than 15% RFC. RFC returned to normal values between 5 days and 7 wk after disappearance of clinical symptoms. 20 patients with bacterial infections had normal numbers of RFC. Of 25 patients with miscellaneous nonimmunologically related diseases, two had low numbers of RFC. It appears that the percentage of RFC may be valuable in evaluating not only immunological defenses but also the status of patients with solid tumors, lymphomas, viral diseases and, perhaps, bacterial infections.

Authors

Joseph Wybran, H. Hugh Fudenberg

Antibody-Associated Lymphotoxin in Acute Infection

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Five pediatric patients who were known to be previously healthy acutely developed lymphopenia during various viral or mycoplasma infections. In one case, fatal generalized varicella occurred and in another, severe toxic epidermal necrolysis ensued.

Authors

Shih-Wen Huang, Doris B. Lattos, Donald B. Nelson, Kenneth Reeb, Richard Hong

Dynamics of Insulin Release and Microtubular-Microfilamentous System. I. EFFECT OF CYTOCHALASIN B

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In order to assess the participation of the microfilamentous cell web in the multiphasic response of the pancreatic beta cell, the effect of cytochalasin B upon both glucose- and sulfonylurea-induced insulin release was investigated in the perfused isolated pancreas. Cytochalasin B failed to affect the basal rate of insulin release, but enhanced the initial and later phases of insulin secretion in response to either glucose or gliclazide. In addition, cytochalasin B lowered the threshold concentration for the stimulant action of glucose upon insulin release. Ultrastructural studies supported the concept of a specific interaction of cytochalasin B with the microfilamentous cell web of the beta cell. It is concluded that the integrity of such a structure is equally important for both the initial and later secretory responses of the beta cell to various insulinotropic agents.

Authors

E. Van Obberghen, G. Somers, G. Devis, G. D. Vaughan, F. Malaisse-Lagae, L. Orci, W. J. Malaisse

Inhibition of Bone Matrix Formation, Mineralization, and Resorption in Thyroparathyroidectomized Rats

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In previous work we found that vitamin D-deficient and also calcium-deficient rats developed hypocalcemia and an impairment of bone formation and mineralization. The present study of thyroparathyroidectomized (TPTX) rats was undertaken to determine the effect of hypocalcemia without secondary hyperparathyroidism. TPTX rats fed a normal diet developed hypocalcemia and hyperphosphatemia in association with impairment of osteoblastic bone matrix formation and of mineralization of newly formed matrix. The serum calcium × phosphorus product was not decreased. The decreased formation was largely due to a reduction in matrix apposition indicating decreased synthetic activity of individual ostcoblasts. In contrast to the above results, when TPTX rats were fed a high-calcium diet to prevent hypocalcemia, no impairment of either formation or mineralization was found. From the results of these two experiments, it is reasonably certain that hypocalcemia was responsible for the inhibition of formation and mineralization. Moreover, based on the magnitude of the changes in serum calcium and bone parameters in TPTX rats, hypocalcemia could have accounted for the inhibition of formation and mineralization in calcium-deficient as well as vitamin D-deficient rats.

Authors

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

Evidence Suggesting Persistence of Nephritogenic Immunopathologic Mechanisms in Patients Receiving Renal Allografts

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Direct immunofluorescent (IF) examinations and elutions were performed on native kidneys and allografts of 24 patients undergoing renal transplantation. Immunoglobulins (Ig) were detected by IF on native kidneys of 12 of the 24; 11 of the 12 later had Ig localized to allograft glomeruli by direct IF. In addition, three other patients also developed Ig deposition on allograft glomeruli, although direct IF of native kidneys was negative. Elution studies indicated: (a) that linear Ig deposition on allograft glomeruli was the result of antiglomerular basement membrane (GBM) antibodies, (b) Ig localizing to allograft glomeruli in many of these patients was the result of persistent immunopathogenetic mechanisms existing at the time of allograft placement, and (c) occasionally, kidneys negative for Ig localization by direct IF contain elutable nephritogenic antibodies.

Authors

J. J. McPhaul Jr., A. L. Thompson Jr., Robert E. Lordon, G. Klebanoff, A. B. Cosimi, R. DeLemos, R. B. Smith

The Relationship Between L-Chain Synthesis and γ-Globulin Production

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The simultaneous administration of labeled human γG globulin and L-chains to subjects has allowed examination of the metabolic relationship between a component part and the whole immunoglobulin molecule. Studies were carried out in a series of control subjects and in a group of patients where substandard production of γ-globulin was anticipated, i.e., patients with the nephrotic syndrome on chronic Imuran therapy and patients with uremia. Full expression of the plasma decay curve was obtained for both substances, that for L-chain requiring only 4-5 days except in uremic subjects and that for γ-globulin requiring up to 30-40 days. Urinary excretion of inorganic iodide was also quantitated for 20-30 days. Equilibrium of the extravascular, vascular, and urinary radioactivity from the labeled γG globulin was usually not seen during this time interval suggesting more than one site of catabolism of the protein.

Authors

Christine Waterhouse, George Abraham, John Vaughan

Plasma Lipoproteins in Familial Lecithin:Cholesterol Acyltransferase Deficiency FURTHER STUDIES OF VERY LOW AND LOW DENSITY LIPOPROTEIN ABNORMALITIES

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Plasma lipoproteins of d<1.006 g/ml, d 1.006-1.019 g/ml, and d 1.019-1.063 g/ml from patients with familial lecithin:cholesterol acyltransferase deficiency yielded abnormal subfractions upon being separately filtered through 2% agarose gel. A subfraction that emerged with the void volume and contained unusually large amounts of unesterified cholesterol and phosphatidylcholine was present in each lipoprotein group, and in each group this subfraction was less prominent in the nonlipemic plasma of one patient than in the lipemic plasma of other patients. A subfraction containing smaller lipoproteins also was present in each lipoprotein group. These lipoproteins were of the same size as normal lipoproteins of the corresponding density, but contained abnormally small amounts of cholesteryl ester. The lipoproteins of 1.019-1.063 g/ml contained abnormal components of intermediate molecular weight as well as large and small abnormal components similar to those described previously. The intermediate components were more prominent in the nonlipemic plasma but were easily recognized in the hyperlipemic plasma as a peak of Sf 20-30 in the analytical ultracentrifuge. Also they could be recognized, upon electron microscopy of the lipoproteins of d 1.019-1.063 g/ml, as particles 340-1000 Å in diameter.

Authors

John A. Glomset, Alex V. Nichols, Kaare R. Norum, Weiling King, Trudy Forte

The Effect of Chronic Sodium Loading and Sodium Restriction on Plasma Prostaglandin A, E and F Concentrations in Normal Humans

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It has been suggested that prostaglandins may be involved in the control of sodium homeostasis. Prostaglandin A and prostaglandin E have been shown to increase renal blood flow and urinary sodium excretion and prostaglandin A has been shown to stimulate aldosterone release. The purpose of this study was to determine the effect of chronic sodium loading and sodium restriction on plasma prostaglandin A, E, and F concentrations.

Authors

Randall M. Zusman, David Spector, Burton V. Caldwell, Leon Speroff, George Schneider, Patrick J. Mulrow

Assessment of Thyrotropin-Releasing Hormone and Thyrotropin Reserve in Man

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Endogenous thyrotropin-releasing hormone (TRH) reserve and pituitary thyrotropin (TSH) reserve were assessed in four normal subjects, three patients post-cryohypophysectomy, one patient with a hypothalamic lesion secondary to trauma, and four patients with Sheehan's syndrome. TSH reserve was determined by the immunoassayable TSH response to 500 μg TRH given i.v. (TRH stimulation test). TRH reserve was assessed by the rebound response in thyroidal iodine release (TIR) following withdrawal of pharmacologic doses of prednisolone (glucocorticoid withdrawal test). When compared with normals, the post-cryohypophysectomy patients demonstrated parallel impairment of TRH stimulation and glucocorticoid withdrawal testing. The patient with the hypothalamic lesion and the four patients with Sheehan's syndrome all had normal TRH stimulation tests, indicating adequate TSH reserve capacity, yet had abnormal glucocorticoid withdrawal tests, indicative of impairment in endogenous TRH reserve or neurohumoral transport. Three of the patients (hypothalamic injury and two Sheehan's) with impaired TRH reserve were euthyroid.

Authors

Peter A. Singer, John T. Nicoloff

Responsiveness of Growth Hormone-Deficient Children to Human Growth Hormone EFFECT OF REPLACEMENT THERAPY FOR ONE YEAR

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Previous studies have shown that growth hormone (GH)-deficient children are more responsive to exogenous human growth hormone (HGH) than non-GH-deficient children. In six GH-deficient children, velocity of linear growth was less than 2.5 cm/yr. By the metabolic balance study technique, anabolic responses (increments in elemental balances) were measured to a 7 day course of 0.0532 U HGH/kg body weight (BW)3/4 per day (dose B) and to 0.168 U/kg BW3/4 per day (dose C). They were then treated for 1 yr with HGH at a dose intermediate between B and C. Velocity of linear growth accelerated to 15-25 cm/yr for the first 4-7 mo, then declined to 0-8 cm/yr. At 12 mo, responsiveness to doses B and C was measured again; the responses were only 20-60% as great as before treatment. After 3 mo without HGH treatment, responsiveness to the anabolic effects of doses B and C returned to the magnitudes observed before treatment. A low titer of plasma antibodies to HGH was detected in two of the six children at the end of the year's treatment; these titers showed little change after 3 mo without HGH. Thus the hyperresponsiveness of GH-deficient subjects to exogenous HGH, compared to non-GH-deficient individuals, declines during long-term HGH treatment and is restored by 3 mo interruption of treatment. These changes in peripheral responsiveness may be related to the decline in velocity of linear growth which occurs after 4-7 mo of continuous treatment.

Authors

Daniel Rudman, Joseph H. Patterson, Donna L. Gibbas

Metabolism of Proinsulin, Insulin, and C-Peptide in the Rat

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The renal extraction and excretion of bovine proinsulin, insulin, and C-peptide and the contribution of the kidney to their total metabolic clearance rate (MCR) were studied in the rat. Metabolic clearance rates were measured by the constant infusion technique and plasma and urine concentrations of each polypeptide were determined by radioimmunoassay.

Authors

Adrian I. Katz, Arthur H. Rubenstein

Suppression of Urinary and Plasma Follicle-Stimulating Hormone by Exogenous Estrogens in Prepubertal and Pubertal Children

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Clomiphene citrate, an “anti-estrogen” with mild estrogenic properties, inhibits rather than stimulates gonadotropin excretion in prepubertal and early pubertal children. These and other data suggest that the sensitivity of the hypothalamic-pituitary “gonadostat” decreases at the onset of puberty. To test this hypothesis further, the daily excretion of urinary follicle-stimulating hormone (FSH) and luteinizing hormone (LH) was determined in 19 children (5 “short normals” and 14 with isolated human growth hormone (HGH) deficiency) who were given ethinyl estradiol (EE) 1.4-14.7 μg/m2 per day (2-10 μg/day) for 4 to 7 days. In addition, plasma and urinary gonadotropins and plasma estrogens were serially determined in two prepubertal females(with isolated HGH deficiency) given two injections (24 h apart) of estradiol benzoate, 10 μg/kg. FSH and LH concentrations in plasma and kaolin-acetone urinary concentrates and plasma 17β-estradiol (E2) and estrone (E1) were measured by radioimmunoassays. 2-3 μg/m2 per day of EE significantly suppressed urinary FSH (and LH when detected in the control period) in two out of six prepubertal children, while all doses >5 μg/m2 per day suppressed urinary gonadotropins to undetectable levels in eight prepubertal subjects. In early to midpubertal subjects. 2-10 μg/m2 per day of EE produced a slight suppression of urinary FSH, but failed to suppress to undetectable levels. Two subjects in late puberty (stage 4) did not suppress their urinary FSH while on 7 and 8.3 μg/m2 per day. In both subjects treated with estradiol benzoate, plasma FSH promptly decreased after the first injection. Urinary FSH was suppressed to <0.1 IU/day on day 2 and urinary and plasma gonadotropins remained suppressed for the duration of the study (3 days). Plasma E2 and E1 rose from prepubertal values to peak concentrations of 150 to 250 pg/ml (E2), and 50 and 100 pg/ml (E1) at approximately 36 h. We conclude that the hypothalamic-pituitary-gonadal axis is operative in the prepubertal child and that the sensitivity of the hypothalamic-pituitary center(s) which control the secretion of FSH and LH decreases at the onset of puberty in man.

Authors

R. P. Kelch, S. L. Kaplan, M. M. Grumbach

Mechanisms of Immune Lysis of Red Blood Cells In Vitro I. PAROXYSMAL NOCTURNAL HEMOGLOBINURIA CELLS

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Abstract

The effect of five different reactions which activate complement (antibody activation, reduction in ionic strength, acidification, cobra venom factor (CoF) activation, and inulin activation) upon normal and PNH cells was investigated, using normal serum and serum devoid of the fourth component of complement (C4) activity from patients with hereditary angioneurotic edema (HANE) as a source of complement.

Authors

Gerald L. Logue, Wendell F. Rosse, Judith P. Adams

Abnormal Vascular Responses to Exercise in Patients with Aortic Stenosis

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We tested the hypothesis that the normal forearm vasoconstrictor response to leg exercise is inhibited or reversed in patients with aortic stenosis, possibly because of activation of left ventricular baroreceptors. Forearm vascular responses to supine leg exercise were measured in 10 patients with aortic stenosis and in 2 control groups of 6 patients with mitral stenosis and 5 patients without valvular heart disease.

Authors

Allyn L. Mark, J. Michael Kioschos, Francois M. Abboud, Donald D. Heistad, Phillip G. Schmid

Reflex Vascular Responses to Left Ventricular Outflow Obstruction and Activation of Ventricular Baroreceptors in Dogs

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Reflex vascular responses to acute left ventricular outflow obstruction were studied in anesthetized dogs. The studies were done to compare the effects of activation of ventricular baroreceptors on vascular resistance in skeletal muscle (gracilis muscle) and skin (hindpaw); to identify afferent and efferent pathways which mediate the reflex vasodilatation; and to assess the relative contribution of ventricular baroreceptors and baroreceptors in left atrium and pulmonary vessels in responses to left ventricular outflow obstruction. The gracilis artery and the cranial tibial artery to the paw were perfused separately at constant flow. Changes in perfusion pressure to each bed reflected changes in vascular resistance. Outflow obstruction was produced by inflating a balloon in the left ventricular outflow tract for 15 s while pressures in the left ventricle and aortic arch were measured.

Authors

Allyn L. Mark, Francois M. Abboud, Phillip G. Schmid, Donald D. Heistad

Marrow Cell Egress. THE CENTRAL INTERACTION OF BARRIER PORE SIZE AND CELL MATURATION

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Release of marrow cells may be determined primarily by the restrictive barrier that separates marrow hematopoietic cords from sinusoids, and by the ability of the cell to negotiate the barrier pores which are of smaller diameter than the cell. This critical interrelationship may be further modulated by humoral agents (releasing factors).

Authors

Gerald F. Giordano, Marshall A. Lichtman

Specific Biologic Effects of Intestinal Glucagon-Like Materials

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It has been demonstrated that gastrointestinal extracts contain substances which react immunologically with antibodies prepared to pancreatic glucagon. These extracts have been termed intestinal GLI for glucagon-like immunoreactivity, or enteroglucagon. To determine whether GLI has specific biological effects, studies were designed using the criterion of effect with antiglucagon antibodies. These antibodies did not cross-react with either secretin or pancreozymin.

Authors

Raul A. Gutman, Gloria Fink, Nancy Voyles, Helena Selawry, Juan C. Penhos, Albert Lepp, Lillian Recant

Purification and Biophysical Characterization of Hepatitis B Antigen

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Hepatitis B antigen (HB Ag) has been purified from serum by pepsin digestion and equilibrium sedimentation. The sedimentation coefficient, density, particle size, and electrophoretic mobility have been determined before and after purification and found to be unaltered. In addition, the diffusion constant and molecular weight of purified HB Ag have been documented.

Authors

Chung Yong Kim, Jeremiah G. Tilles

Extent of Regulation of the Heart's Contractile State in the Conscious Dog by Alteration in the Frequency of Contraction

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The effects of alterations in the frequency of contraction over the range from 94 to 220/min on left ventricular pressure, diameter, and dP/dt were studied in 10 dogs instrumented with ultrasonic diameter ganges and miniature pressure gauges. The same dogs were studied on separate days in the conscious state, after general anesthesia with pentobarbital Na, 30 mg/kg, and in the conscious state after pretreatment with propranolol, 3 mg/kg. End diastolic diameter was maintained constant during alterations in frequency by infusing saline intravenously. The maximum increases in peak dP/dt and dP/dt/P in the conscious state were 14 and 10%, respectively. After anesthesia, raising the frequency of contraction from 122 to 220/min caused maximum increases in peak dP/dt and dP/dt/P of 36 and 30%, respectively. In the conscious state after cardiac depression by propranolol, the maximum increases in peak dP/dt and dP/dt/P were 23 and 23%, respectively. Thus, increasing the frequency of contraction of the normal heart of the conscious dog causes only a slight inotropic effect, but this effect is significantly greater in the presence of myocardial depression produced by anesthesia with pentobarbital Na or in the conscious animal after a myocardial-depressing dose of propranolol.

Authors

Charles B. Higgins, Stephen F. Vatner, Dean Franklin, Eugene Braunwald

Serum Triiodothyronine and Thyroxine in the Neonate and the Acute Increases in These Hormones Following Delivery

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Low triiodothyronine (T3) and high normal thyroxine (T4) concentrations are present in cord sera from full term infants. To examine this phenomenon further, radioimmunoassay of T3 and T4 was carried out in paired maternal and cord sera as well as capillary sera from neonates at different intervals after delivery. Free T3 and free T4 concentrations were also estiamted in cord and maternal sera by equilibrium dialysis. In 12 paired specimens, the T3 concentration in cord sera was significantly lower than the maternal level (51±4 vs. 161±11 ng/100 ml, mean ±SE). Mean free T3 concentration was also lower in the cord samples (0.15±0.02 vs. 0.31±0.04 ng/100 ml). whereas total and free T4 concentrations were not significantly different. Umbilical vein and artery samples from 11 neonates did not differ significantly in their T3 and T4 concentrations. In seven infants the mean T3 concentration increased from 51±3 ng/100 ml at delivery to 79±13 at 15 min and 191±16 at 90 min. In four other infants the mean T3 concentration at 24 and 48 h was not significantly different from the 90 min value of the previous group. Less pronounced changes were observed for T4 which increased from 12.3±2.0 μg/100 ml (mean ±SE) at delivery to 14.1±1.9 at 90 min and appeared to have reached a plateau at approximately twice the cord value by 24-48 h after delivery.

Authors

J. Abuid, D. A. Stinson, P. R. Larsen

Chemotactic Factor Inactivator in Normal Human Serum

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Normal human serum contains an inactivator of chemotactic factors for neutrophilic leukocytes. The chemotactic factor inactivator (CF-I) remains soluble when serum is fractionated with ammonium sulfate (at 45% saturation), directly and irreversibly inactivates chemotactic factors, and it has a broad spectrum of activity as indicated by its inactivation of the chemotactic fragments of human C3 and C5 (third and fifth components of complement), C5̅6̅7̅, and the bacterial chemotactic factor derived from Escherichia coli. CF-I appears as a biphasic activity according to preparative techniques of sucrose density ultracentrifugation, electrophoresis, and gel filtration. Studies on the interaction of CF-I with the radiotagged C5 chemotactic fragment fail to reveal evidence for irreversible binding as the basis for inactivation. CF-I varies from the anaphylatoxin inactivator in several physical-chemical respects, but evidence does not permit a conclusive statement about the relationship of the two inactivators. CF-I may function as a regulator of inflammatory responses.

Authors

Jeffrey L. Berenberg, Peter A. Ward

The Complement System in Bullous Pemphigoid. I. COMPLEMENT AND COMPONENT LEVELS IN SERA AND BLISTER FLUIDS

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Compared with other serum and blister fluid proteins, total hemolytic complement was reduced in the blister fluid of six serologically positive bullous pemphigold patients while four serologically negative cases had blister fluid complement levels closely approaching the serum levels. Except for pemphigus vulgaris blisters. blister fluids from most patients with other bullous diseases and experimentally induced blisters had blister fluid complement levels more closely approaching the serum levels. With the exception of the two terminal components. C8 and C9, individual components of the complement sequence were also reduced in the blister fluids of the six bullous pemphigold patients with circulating basement membrane zone antibodies. On the other hand, transferrin and IgG levels of these same six serologically positive blister fluids closely approached the corresponding serum levels. Conversion of C3 proactivator was also demonstrable in the serologically positive bullous pemphigoid blister fluids, but not in the corresponding sera. Our studies, therefore, are suggestive of local activation of the complement sequence, by both the classical and alternate pathways, in blisters of serologically positive bullous pemphigold patients.

Authors

R. E. Jordon, N. K. Day, W. M. Sams Jr., R. A. Good

Indicator Dilution Measurements of Lung Volumes and Alveolar Air Exchange During Breathing

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A new triple tracer indicator dilution technique has been used to measure alveolar ventilation as well as air and tissue volumes in the lungs of experimental animals and man. The tracers indocyanine green, [121I]antipyrine and xenon-133 were rapidly injected into the right atrium, while sampling was carried out from a peripheral artery.

Authors

Herbert B. Hechtman, Michael H. Reid, Barry C. Dorn, Richard D. Weisel

Effect of Glycine-Conjugated Bile Acids with and without Lecithin on Water and Glucose Absorption in Perfused Human Jejunum

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Perfusion studies were performed in healthy volunteers to test whether the secretory effect of conjugated bile acids, previously shown for the colon, was also present in the jejunum. A perfusion system with a proximal occlusive balloon (and continuous aspiration of duodenal secretions) was used; isotonic test solutions contained glycine-conjugated bile acids with or without lecithin. Fluid movement was measured by changes in the concentration of polyethylene glycol (PEG, mol wt 4,000). Conjugated dihydroxy bile acids inhibited electrolyte and fluid absorption and, at higher concentrations, evoked secretion of an isotonic fluid. Glucose absorption continued, despite fluid secretion, but its rate decreased. The secretory effects of bile acids were abolished by the addition of lecithin to the bile acid solutions. A trihydroxy bile acid (cholylglycine) had no effect on jejunal absorption. Small amounts (6-9%) of conjugated bile acids were absorbed in the jejunum; lecithin was well absorbed (72-90%). The results indicate that dihydroxy bile acids influence salt and water transport in the human jejunum but that this effect may be abolished when a polar lipid such as lecithin is present. We speculate that this effect of bile acids may modify fluid movement in the small intestine postprandially after fat absorption has occurred.

Authors

David L. Wingate, Sidney F. Phillips, Alan F. Hofmann

Abnormal Fatty Acid Metabolism in Peripheral Nerves of Patients with Pernicious Anemia

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Abstract

Fatty acid synthesis from radiopropionate was evaluated in sural nerve biopsy slices from five normal controls and nine patients with pernicious anemia. The nerves were incubated in [14C]propionate, the lipids were extracted, and the fatty acid methyl esters were chromatographed by gas-liquid chromatography. In the normal nerves the radiolabel was found primarily in short chain (C12 and C14) fatty acids. The nerves from pernicious anemia patients showed two fatty acids peaks that were not discernible in the normal nerves, and these fatty acids had retention times intermediate to those of myristic (C14·0) and palmitic (C16·0) acids and palmitoleic (C16·1) and stearic (C18·0) acids, respectively. These two peaks (a C15 and C17 fatty acid) contained the bulk of the radioactivity recovered in the fatty acid fraction after incubation with [14C]propionate. Catalytic reduction and rechromatography failed to alter the retention time of these compounds suggesting that they are not unsaturated fatty acids. The nerves from the pernicious anemia patients had a decrease in the mean content of normal fatty acids when compared with the nerves from control patients as well as a decrease in the mean synthesis of normal fatty acids as estimated by isotope incorporation after incubation with [14C]propionate or 3H2O. Analysis of myelin isolated from the nerves indicated that the changes at least in part were in that fraction.

Authors

Eugene P. Frenkel

Glucagon Release Induced by Pancreatic Nerve Stimulation in the Dog

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Abstract

A direct neural role in the regulation of immunoreactive glucagon (IRG) secretion has been investigated during stimulation of mixed autonomic nerves to the pancreas in anesthetized dogs. The responses were evaluated by measurement of blood flow and hormone concentration in the venous effluent from the stimulated region of pancreas.

Authors

Errol B. Marliss, Lucien Girardier, Josiane Seydoux, Claes B. Wollheim, Yasunori Kanazawa, Lelio Orci, Albert E. Renold, Daniel Porte Jr.

Cerebrospinal Fluid and Ependymal Neurophysin

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Abstract

Neurophysins are “carrier proteins” associated with vasopressin and oxytocin in the neurohypophyseal system. The release of these hormone associated proteins may serve as an indicator of posterior pituitary function. This report describes the measurement of neurophysin in human and monkey plasma and cerebrospinal fluid (CSF) by radioimmunoassay. Tissue neurophysin is also localized in monkey brain by the immunoperoxidase technique. CSF from 68 patients and five monkeys had easily measurable neurophysin in every sample. The concentration of neurophysin in CSF and in plasma of man is 5.4±0.30 ng/ml (mean and SEM) and 0.69±0.04, respectively. The two means were significantly different (P < 0.001). In paired plasma and CSF specimens which were obtained simultaneously from each of 13 human and five monkey donors, the concentrations of neurophysin in CSF were greater than those of plasma in every case (paired t test, P < 0.001). Neurophysin administered intravenously to dogs did not enter CSF. Using the immunoperoxidase technique, we found neurophysin not only in the supraoptic and paraventricular nuclei, their tracts, and the posterior pituitary, but also in the specialized ependymal tanycytes of the infundibular recess of the third ventricle and in the external layer of the median eminence where capillaries drain into hypophyseal portal vessels. Neurophysin may pass from CSF to portal vessels via tanycytes in a manner similar to that postulated for releasing factors.

Authors

Alan G. Robinson, Earl A. Zimmerman

Seasonal Changes in IgE Antibodies and Their Relationship to IgG Antibodies during Immunotherapy for Ragweed Hay Fever

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Abstract

Seasonal changes in IgE antibodies and their relationship to IgG antibodies were studied in 52 patients with ragweed hay fever and 10 normal controls. Allergic patients received either no immunotherapy, preseasonal immunotherapy, or high dose perennial immunotherapy with aqueous-mixed ragweed extract. Serums were collected before, during, just after, and 4 mo after the ragweed pollination season. IgE antibodies to ragweed antigen E (AgE) were measured using the radioallergosorbent test, and IgG antibodies were measured by radioimmunoprecipitation.

Authors

John W. Yunginger, Gerald J. Gleich

Structural Identity of Bence Jones and Amyloid Fibril Proteins in a Patient with Plasma Cell Dyscrasia and Amyloidosis

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Abstract

The partial amino acid sequence of the amyloid fibril protein isolated from the small intestine of a patient with plasma cell dyscrasia and associated amyloidosis has been determined and compared with the sequence of the κ-type Bence Jones protein isolated from the urine of the same patient. Identical sequences were observed for the 27 amino-terminal residues that could be compared. The C-terminal tryptic peptide of the amyloid protein was identical with that of the Bence Jones protein. Apparent molecular weights and amino acid compositions of the Bence Jones and amyloid proteins were similar. It appears, therefore, that the predominant protein present in the amyloid deposits in this patient was an intact κ-type light polypeptide chain that was identical with the urinary Bence Jones protein.

Authors

William D. Terry, David L. Page, Shigeru Kimura, Takashi Isobe, Elliott F. Osserman, George G. Glenner

Release of Serotonin from Human Platelets Induced by Aggregated Immunoglobulins of Different Classes and Subclasses

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Abstract

The ability of human myeloma proteins of different classes and subclasses and of macroglobulins (all aggregated with bis-diazotized benzidine or heat) to aggregate washed human platelets and release [3H]-serotonin from the platelets was investigated and compared with the activity of normal IgG and tetanus-antitetanus IgG antigen-antibody complexes. Aggregated IgG1, IgG2, IgG3, IgG4, and normal IgG complexes all aggregated platelets and caused release of serotonin to similar extents. In contrast, IgA1, IgA2, IgD, and IgE myeloma proteins as well as IgM macroglobulins were completely inactive in this respect. Approximately 50% of the actvity remained in aggregated, mildly reduced and alkylated IgG myeloma proteins and their Fc fragments, whereas aggregated F(ab′)2 fragments were completely inactive. Addition of fresh serum inhibited the release of serotonin caused by aggregated IgG1 and IgG3 proteins and normal IgG antigen-antibody complexes by about 50% but had no effect upon the release of serotonin obtained with IgG2 and IgG4 proteins. This inhibition appeared to be mediated by complement. The release of serotonin was not accompanied by liberation of the cytoplasmic enzyme lactic dehydrogenase, indicating that no significant lysis of the platelets occurred. Addition of neutrophils did not enhance the serotonin release.

Authors

Peter M. Henson, Hans L. Spiegelberg

The Hormonal Regulation of Pyloric Sphincter Function

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Abstract

The purpose of this study was to evaluate the hormonal control of pyloric sphincter function. Studies were performed on both pyloric circular muscle, in vitro, and the human pylorus, in vivo. Full dose-response curves to gastrin I, cholecystokinin, and secretin were constructed for the pyloric muscle of the opossum studied at its length of optimal tension development, Lo. Both cholecystokinin and secretin were potent agonists on the muscle but gastrin I gave no increase in muscle tension. The combination of cholecystokinin and secretin was additive at submaximal concentrations but potentiation of the maximal responses was not observed. Gastrin I produced a surmountable, competitive-like antagonism to the effect of cholecystokinin on the pyloric muscle. The octapeptide of cholecystokinin was a more potent agonist than the whole molecule of cholecystokinin on the pyloric muscle. In man, the pyloric pressure rose significantly during intravenous infusion of either cholecystokinin or secretin. The combination of maximal doses of both hormones did not show significant potentiation. Gastrin I did not significantly increase pyloric pressure but did antagonize the pyloric response to duodenal acidification. These studies suggest that: (a) Both secretin and cholecystokinin augment pyloric sphincter pressure while gastrin I is an antagonist inhibiting their effects. (b) The hormonal responses of pyloric sphincter circular muscle, in vitro, can be correlated with human sphincter function, in vivo.

Authors

Robert S. Fisher, William Lipshutz, Sidney Cohen

Heterogeneity of 5′-Nucleotidase Activity in Lymphocytes in Chronic Lymphocytic Leukemia

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Abstract

The specific activity of 5′-nucleotidase was determined in lymphocyte plasma membranes from 14 normal subjects and 10 patients with chronic lymphocytic leukemia (CLL). Whereas the enzyme was present in the preparation from normal lymphocytes, in 7 out of 10 CLL patients the membranes had markedly decreased or no detectable 5′-nucleotidase activity. The lack of this activity from the lymphocytes of most patients with CLL constitutes an alteration in a plasma membrane enzyme from the normal cell. The presence of the enzyme in the lymphocytes of some patients with CLL and its decrease in others provide further evidence for biochemical heterogeneity among patients with this disorder.

Authors

John Lopes, Dorothea Zucker-Franklin, Robert Silber

Myelin from human peripheral nerves. Quantitative and qualitative studies in two age groups

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Abstract

Authors