The Mechanism of Appearance of Immunoglobulin A in Nasal Secretions in Man

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Abstract

Experiments were done to investigate mechanisms of appearance of both 7 S and 11 S IgA in nasal secretions. Three IgA preparations, (a) 11 S IgA from nasal secretions, (b) 7 S IgA from homologous serum, and (c) 7 S IgA from autologous serum, were isolated, labeled, and injected intravenously into volunteers. The rate of disappearance from plasma and the extent and nature of their appearance in nasal secretions were examined in detail. After intravenous injection, 11 S IgA from nasal secretions disappeared rapidly from plasma. However, only negligible amounts of 11 S IgA were detected in nasal secretion, which suggested that rapid selective secretion of circulating 11 S IgA does not occur as a mechanism of IgA accumulation in nasal secretions. Both the homologous and autologous 7 S IgA preparations disappeared from plasma at a normal rate, and both appeared in nasal secretions unchanged in sedimentation behavior. The specific activity of IgA in nasal secretions, when related to the total IgA concentration, was about 30-fold less than that in serum. When related to only the 7 S IgA concentration of nasal secretions, the specific activity was about one-half that of serum. These studies are consistent with the following hypotheses: (a) circulating 7 S IgA is a source of part of the 7 S IgA found in nasal secretions. The remainder of the nasal secretion 7 S IgA may be synthesized locally in the tissues of the upper respiratory tract; (b) 11 S IgA in nasal secretions is not assembled from serum 7 S IgA components; and (c) 11 S IgA in nasal secretions is synthesized de novo in the tissues of the upper respiratory tract.

Authors

William T. Butler, Roger D. Rossen, Thomas A. Waldmann

Systemic and Renal Hemodynamics in Oliguric Hepatic Failure: Effect of Volume Expansion

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Systemic and renal hemodynamics were studied by indicator dilution techniques before and after infusion of 500 ml of dextran 40 in 21 patients with renal failure developing in the course of decompensated cirrhosis.

Authors

Felix E. Tristani, Jay N. Cohn

Metabolism of Vitamin D₃-³H in Vitamin D-Resistant Rickets and Familial Hypophosphatemia

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The fate of an intravenous dose of tritiated vitamin D3 was studied in seven normal subjects, four children with vitamin D-resistant rickets, and four adults with a familial history of vitamin D-resistant rickets and persistent hypophosphatemia. An abnormal metabolism of vitamin D in vitamin D-resistant rickets was defined and characterized by a decrease in the plasma fractional turnover rate, a marked increase in plasma water-soluble metabolites, and a relative decrease in the conversion of vitamin D to a polar, biologically active metabolite. Alterations in vitamin D metabolism in the adults with persistent hypophosphatemia were similar but less severe than those of affected children with vitamin D-resistant rickets. It is tentatively concluded that the abnormalities in vitamin D metabolism documented in patients with vitamin D-resistant rickets and familial hypophosphatemia may account for the observed osseous and biochemical changes.

Authors

Louis V. Avioli, T. Franklin Williams, Judith Lund, Hector F. DeLuca

A Study of the Mechanisms by Which Adrenocorticotropic Hormone Maintains Adrenal Steroidogenic Responsiveness

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Following hypophysectomy in the rat, there was a progressive decline in the rate of adrenal protein synthesis in vivo during the ensuing 24-48 hr, and an accompanying decrease in the acute corticosterone secretory response to an intravenous injection of ACTH. There was a similar decrease in the in vitro conversion of Δ5-pregnenolone, progesterone, and deoxycorticosterone to corticosterone. These in vivo and in vitro effects of hypophysectomy could be reversed by the administration of depot ACTH for an additional 7 hr period. However, if cycloheximide, an inhibitor of protein synthesis, was administered concomitantly with the depot ACTH, then the restorative actions of ACTH on the steroid biosynthetic pathway were prevented. These experiments suggest that ACTH maintains not only the general structure of the adrenal cortex, but also the level of the steroid biosynthetic mechanism, through its effects on adrenal protein synthesis.

Authors

Robert L. Ney, Richard N. Dexter, Warren W. Davis, Leonard D. Garren

Follicle-Stimulating Hormone (FSH) and Luteinizing Hormone (LH) in the Urine of Prepubertal Children

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Abstract

Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) have been measured by specific bioassays in pooled urine samples from prepubertal children, aged 2-6 yr, and from male adults. For children the mean urinary excretion of FSH was 2.2 U 2nd International Reference Preparation (2nd IRP) per liter and the mean urinary excretion of LH was 0.44 U 2nd IRP per liter. For adults the mean FSH excretion was 5.6 U 2nd IRP per liter and the mean LH excretion was 4.7 U 2nd IRP per liter. Our data show a 2.5-fold increase of FSH, a 10.7-fold increase of LH, and a consequent decrease in the FSH: LH ratio from 5 to 1 between childhood and adulthood. FSH and LH in urine from three patients with gonadal abnormalities have also been studied. The results from normal children, adults, and abnormal patients form a spectrum and reveal that sexual maturity is accompanied by a marked increase in the excretion of LH with relatively smaller increases in FSH.

Authors

Arleen B. Rifkind, Howard E. Kulin, Griff T. Ross

Effect of Chloroquine on Morphology of Cytoplasmic Granules in Maturing Human Leukocytes—an Ultrastructural Study

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Abstract

Bone marrow and peripheral blood from patients who had received chloroquine phosphate were studied to determine the effect of this drug on the ultrastructure of cytoplasmic granules in leukocytes. Neutrophils from approximately one-half of the patients who were treated developed abnormal cytoplasmic granules. Vacuolar, lamellar, and particulate components within abnormal, large granules were present in myelocytes from certain patients who received chloroquine therapy. Mature neutrophils and lymphocytes from these patients showed variable numbers of large, membrane-bounded structures containing myelin figures. Cytoplasmic granules in eosinophilic myelocytes from patients treated with chloroquine did not contain the usual crystalloid structure, but instead contained small whorls of osmiophilic material. The granules in abnormal mature eosinophils were replaced by large vacuoles which contained amorphous material. The abnormal granules seen in these various white cells after chloroquine therapy may either reflect defective granule formation or autophagy.

Authors

Martha Fedorko

Neutrophil Kinetics in Acute Infection

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Abstract

Neutrophil kinetics of acute experimental infection were studied with diisopropylfluorophosphate-32P labeling in 31 dogs inoculated intrabronchially with pneumococci. In vitro neutrophil labeling indicated a rapid transit time through the blood in early infections, with an elevated marginal granulocyte pool sometimes preceding an elevation of the circulating granulocyte pool. 13 hr after infection, the circulating and total blood granulocyte pools were increased but the rate of neutrophil transit through the blood was normal. During the recovery from infection there was a marked prolongation of neutrophil blood transit time, suggesting virtually complete cessation of bone marrow release of neutrophils into the blood. Labeling of neutrophils in vivo indicated an increased rate of emptying of the bone marrow storage pool proportional to the severity of infection as measured by the fever index. The change in the blood ratio of nonsegmented to segmented neutrophils was a much more accurate index of the severity of infection than the blood granulocyte concentration, correlating significantly with the fever index.

Authors

J. C. Marsh, D. R. Boggs, G. E. Cartwright, M. M. Wintrobe

Plasma Insulin Responses to Oral and Intravenous Glucose: Studies in Normal and Diabetic Subjects

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The plasma insulin responses of normal weight and obese, diabetic, and nondiabetic subjects to intravenous glucose was only 30-40% of that seen after oral glucose, indicating that alimentary mechanism(s) in addition to the arterial blood sugar concentration regulate insulin secretion. Observations made in subjects with diverted portal circulation indicate that the alimentary insulinogenic mechanism is located in the intestinal tract. The insulinogenic potency of the alimentary and glycemic stimuli expressed in terms of insulin secretion per gram of glucose were remarkably similar within each group of individuals. Between these groups, however, there were considerable differences. Obesity, with or without associated diabetes, was associated with a true hypersecretory responsiveness, whereas diabetes was characterized, with or without obesity, by a marked impairment in insulin secretion. The experimental design used in these studies permitted quantitation of the magnitude of the glycemic component of an oral glucose load. As a consequence of impaired insulin secretion, a greater than normal proportion of the oral glucose load escapes initial hepatic extraction in the maturity-onset diabetic and enters the peripheral circulation. Therefore, in the noninsulin-requiring maturity-onset diabetic, the glycemic insulinogenic stimulus for a given oral glucose load is significantly greater than in normal subjects and accounts for the excessive plasma insulin responses observed late in the course of an oral glucose tolerance test.

Authors

Michael J. Perley, David M. Kipnis

Demonstration of a Role of Physical Factors as Determinants of the Natriuretic Response to Volume Expansion

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The importance of plasma protein concentration, renal vascular resistance, and arterial pressure as mediators of the natriuretic response to volume expansion was investigated in anesthetized dogs.

Authors

Joseph A. Martino, Laurence E. Earley

Studies of the Metabolism and Distribution of Fibrinogen in Patients with Hemophilia A

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Using autologous 131I-fibrinogen, we made studies of the metabolism and distribution of fibrinogen in 10 patients with hemophilia A. In two patients simultaneous studies of autologous 131I-fibrinogen and homologous 125I-fibrinogen prepared from healthy donors' plasma were carried out. The average value for the plasma volume was 42.1 ± 8.8 ml/kg; for the plasma fibrinogen concentration, 349 ± 90 mg/100 ml; for the intravascular fibrinogen, 144 ± 32 mg/kg; for the interstitial fibrinogen, 30 ± 11 mg/kg; for the slower half-life of 131I-fibrinogen, 2.34 ± 0.17 days; for the transcapillary transfer rate of fibrinogen, 109 ± 37 mg/kg per day; and for the catabolic and synthetic rates of fibrinogen, 51.7 ± 13.1 mg/kg per day. Comparison of these results with those of the previous study in healthy male subjects showed that in patients with hemophilia A the catabolic and synthetic rates of fibrinogen are markedly increased, whereas the plasma fibrinogen concentration, intravascular and interstitial fibrinogen, and the transcapillary transfer rate of fibrinogen are not significantly different. The simultaneous studies of autologous 131I-fibrinogen and normal homologous 125I-fibrinogen in two subjects revealed that the two preparations behaved very similarly. Based on these findings, we concluded that our present findings are not due to the qualitative difference between the hemophilia A and normal fibrinogens, but that they are due to the difference in the host condition with respect to the fibrinogen metabolism, which is either an increased rate of direct breakdown of fibrinogen or an increased rate of fibrinogen breakdown after fibrin formation, or both.

Authors

Y. Takeda, Alan Y. Chen

Carbon Monoxide Production Associated with Ineffective Erythropoiesis

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The rate of endogenous carbon monoxide production (˙Vco), determined by the closed rebreathing system technique, was elevated above the normal range in four of five patients studied with ineffective erythropoiesis (four patients with primary refractory anemia, one with thalassemia). The mean molar ratio of ˙Vco to ˙Vheme (rate of circulating heme catabolism, determined from 51Cr red cell survival curves) was 3.0 ± 0.6 (SE), indicating that most of the CO originated from sources other than circulating erythrocyte hemoglobin, in contrast to previous findings in patients with hemolytic anemia, where ˙Vco paralleled ˙Vheme closely.

Authors

Peter White, Ronald F. Coburn, William J. Williams, Manfred I. Goldwein, Mary L. Rother, Brenda C. Shafer

The Role of Sodium-Potassium—Activated Adenosine Triphosphatase in the Reabsorption of Sodium by the Kidney

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In order to evaluate the possible role of sodium- and potassium-activated adenosine triphosphatase in the active transport of sodium by the renal tubules, we examined the effect of large changes in the tubular reabsorptive load of sodium on the Na-K-ATPase activity of rat kidney homogenates. Glomerular filtration and tubular reabsorption of sodium per gram of kidney tissue increased progressively after contralateral uninephrectomy. This was paralleled by an increase in Na-K-ATPase per milligram of protein in a microsomal fraction of kidney cortex. The importance of this change is underlined by the absence of simultaneous increases in other microsomal enzymes such as glucose-6-phosphatase and Mg++-dependent ATPase, or in succinic dehydrogenase or glutaminase. Similar increases in Na-K-ATPase were observed when the net tubular reabsorption of sodium was increased by feeding the animals a high-protein diet or after injection of methylprednisolone. On the other hand, Na-K-ATPase was lowered when tubular transport of sodium was reduced by bilateral adrenalectomy. The results of these experiments show that renal Na-K-ATPase changes in an adaptive way when renal reabsorption of sodium is chronically increased or diminished and support the hypothesis that this enzyme system is involved in the process by which sodium is actively transported across the renal tubule.

Authors

Adrian I. Katz, Franklin H. Epstein

Tyrosine Metabolism in Patients with Liver Disease

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Plasma levels of tyrosine were assayed in the fasting state and after oral administration of either tyrosine (tyrosine tolerance test) or phenylalanine (phenlyalanine conversion test) in normal subjects and in patients with hepatitis, biliary obstruction, or cirrhosis. Fasting tyrosine levels tended to be slightly increased in patients with hepatitis and biliary obstruction and markedly increased in patients with cirrhosis.

Authors

Robert J. Levine, Harold O. Conn

Studies of the In Vivo Behavior of Human C′3 in Normal Subjects and Patients

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The metabolic behavior of C′3 labeled with radioactive iodine was investigated in 10 normal subjects and in 20 patients with diseases in which complement is thought to play a pathophysiological role. The mean fractional catabolic rate of C′3 in normal subjects was 2.3 ± 1.0% of the plasma pool per hr, whereas the fractional catabolic rate of C′3i, the inactive conversion product of C′3 produced by complement activation, was at least five times as great.

Authors

Chester A. Alper, Fred S. Rosen

Absorption of Bile Pigments by the Gall Bladder

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A technique is described for preparation in the guinea pig of an in situ, isolated, vascularized gall bladder that exhibits normal absorptive functions. Absorption of labeled bile pigments from the gall bladder was determined by the subsequent excretion of radioactivity in hepatic bile.

Authors

J. Donald Ostrow

Uneven Distribution of Maternal and Fetal Placental Blood Flow, as Demonstrated Using Macroaggregates, and Its Response to Hypoxia

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A technique is described for studying the distribution of blood flow to the maternal and fetal placental vessels in sheep and dogs with radioactive labeled macroaggregates of albumin.

Authors

Gordon G. Power, Lawrence D. Longo, Henry N. Wagner Jr., David E. Kuhl, Robert E. Forster II.

Use of ¹²⁵I- and ⁵¹Cr-Labeled Albumin for the Measurement of Gastrointestinal and Total Albumin Catabolism

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A method for the simultaneous measurement of gastrointestinal protein loss and total albumin turnover entailing the use of a combination of 125iodine- and 51chromium-labeled albumin is described. Albumin turnover was calculated by the measurement of albumin-125I plasma decay and cumulative urinary excretion, and the results obtained agreed closely with previous studies utilizing albumin-131I. Gastrointestinal catabolism was calculated from the rate of fecal excretion of 51Cr and the specific activity of plasma albumin-51Cr, and these data were related to the calculated albumin turnover results. During the period of 6-14 days after administration, the ratio of specific activties of albumin-125I and -51Cr in plasma and in extravascular spaces or gastric and biliary secretions remained almost identical. Fecal excretion of 51Cr was also quite stable at this time. In six normal subjects gastrointestinal catabolism accounted for less than 10% of total albumin catabolism. Excessive gastrointestinal protein losses did not contribute to the low serum albumin in three patients with cirrhosis or in two adults with the nephrotic syndrome. Multiple mechanisms leading to hypoalbuminemia were demonstrated in other subjects with a variety of gastrointestinal disorders.

Authors

Robert M. Kerr, John J. Du Bois, Peter R. Holt

Membrane Lipid Depletion in Hyperpermeable Red Blood Cells: Its Role in the Genesis of Spherocytes in Hereditary Spherocytosis

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Hereditary spherocytosis (HS) red cells lose membrane lipids excessively during incubation in vitro. Individual phosphatides as well as cholesterol are lost in proportion to their content in membranes, suggesting that fragments of membrane are removed. Supplementation of HS red cells with glucose during incubation has no consistent protective effect, whereas diminishing the excessive sodium flux through these cells by suspending them in either sodium-free or hypertonic media prevents membrane fragmentation. The characteristic excessive increase in osmotic fragility which occurs in incubated HS red cells results both from inordinate accumulation of intracellular sodium ions which produces osmotic swelling, and from depletion of surface material which generates microspherocytosis. Inhibiting both of these processes by incubating HS red cells in sodium-free media completely prevents increases in osmotic fragility despite prolonged incubation.

Authors

Harry S. Jacob

Splanchnic Extraction and Interconversion of Testosterone and Androstenedione in Man

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A constant infusion of 3H-testosterone and 14C-androstenedione was administered to four human subjects, two males and two females, until the concentrations of radioactive testosterone and androstenedione in systemic plasma became constant. At that time the concentrations of radioactive testosterone and androstenedione in hepatic vein plasma were determined. Splanchnic extraction of testosterone and androstenedione and the contribution of the splanchnic system to the blood interconversion of testosterone and androstenedione were calculated.

Authors

Marco A. Rivarola, Robert T. Singleton, Claude J. Migeon

Stimulation of Aldosterone Biosynthesis in Adrenal Mitochondria by Sodium Depletion

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The effect of various factors on the conversion of corticosterone to aldosterone was studied in an isolated mitochondrial system from rat adrenal glands. The adrenal mitochondrial fraction from rats on a low sodium diet has a greater capacity for converting corticosterone to aldosterone than mitochondria from rats fed a normal diet. After 1 day on a low sodium diet the amount converted was 162% and after the 2nd and 4th day the amounts converted were 239 and 242%, respectively, compared to a value of 100% for the control rats. Sodium and(or) potassium added in vitro did not affect the conversion of corticosterone to aldosterone.

Authors

Elisa T. Marusic, Patrick J. Mulrow

The Effects of Angiotensin II on Renal Water and Electrolyte Excretion in Normal and Caval Dogs

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The effects of intravenous administration of angiotensin II on renal water and electrolyte excretion were examined during hydropenia, water diuresis, and hypotonic saline diuresis in anesthetized normal dogs and dogs with thoracic inferior vena cava constriction and ascites (caval dogs). The effects of unilateral renal artery infusion of a subpressor dose were also examined.

Authors

Jerome G. Porush, George J. Kaloyanides, Roy J. Cacciaguida, Stanley M. Rosen

Plasma Volume in Cirrhosis of the Liver: Its Relation of Portal Hypertension, Ascites, and Renal Failure

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Abstract

Authors