ATLANTIC CITY MEETINGS 1968

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Chronic hemolytic anemia due to cold agglutinins: II. The role of C′ in red cell destruction

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The sera of four patients with chronic hemolytic anemia due to cold agglutinins deposited C′ globulins on normal red cells at 37°C. The circulating cells of the patients were heavily coated with C′ complex and were relatively resistant to C′ hemolysis by cold agglutinin. Such red cells were removed from the patients' circulation at an exponential rate with 51Cr t½ that varied from 7 to 19 days. Normal red cells were removed rapidly by hepatic sequestration during the first hours in the patients' circulation. Thereafter, a slower rate of abnormal destruction occurred which was associated with the accumulation of C′ complexes on the red cell and the development of resistance to C′ hemolysis by cold agglutinin. Normal red cells coated with sufficient C′ complex by action of cold agglutinins in vitro to produce resistance to C′ hemolysis by cold agglutinins demonstrated varying degrees of improved survival during the first hours in the circulation of three of the patients.

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Robert S. Evans, Elizabeth Turner, Margaret Bingham, Richard Woods

Observations on the mechanisms of glucosuria during glucose loads in normal and nondiabetic subjects

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The study of 14 normal young men by glucose titration procedures has defined the magnitude of splay in this population, differing from previously reported data in its unexpected deviation from the line of theoretic unity high on the titration curve. Compared to these normal subjects, a group of glucosuric men could be divided into two subclasses, those with normal maximal rate of glucose reabsorption (TmG) and those with subnormal TmG, both with comparably abnormal splay. Most consistent glucosurics fall into the latter group. Nephritic patients studied were not such a homogeneous group in terms of age and sex, but did manifest an abnormal splay during their titration curves in most cases. They also demonstrated a greater than normal reabsorptive rate of glucose per unit measured glomerular filtration rate. It is concluded that renal glucosuria must be defined not only in terms of the concept of TmG but also by deviation of the glucose titration curve expressing an unusual degree of splay. The latter is presumed, as has been suggested by others, to be a characteristic of nonhomogeneity of glucose handling units in the kidney. This seems subject to exaggeration in the adaptations which accompany chronic renal disease.

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John J. McPhaul Jr., John J. Simonaitis

Effects of diet on hepatic triglyceride synthesis

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The effects of diet on the rate of triglyceride synthesis by rat liver homogenates was measured. Changes in triglyceride synthesis were correlated with the level of activity of L-α-glycerophosphate acyltransferase, the enzyme catalyzing the first specific reaction in hepatic glycerolipid synthesis.

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Harold J. Fallon, E. Leon Kemp

Effect of thyroid-suppressive doses of triiodothyronine on thyroxine turnover and on the free thyroxine fraction

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The relationship between free thyroxine concentration and thyroxine turnover was studied during thyroid suppression with triiodothyronine. Although there was some increase in the proportion of serum thyroxine bound to thyroxine-binding globulin, the ratio of ultrafilterable to protein-bound hormone was not significantly affected. The fractional disappearance rate of thyroxine increased from an average control value of 11.47%/day to 14.72%/day. Because of contraction of the thyroxine distribution space the clearance of thyroxine was less markedly affected, increasing from 1.37 to 1.56 liters/day. Since the ratio of thyroxine turnover to free thyroxine concentration, i.e., the free thyroxine clearance, increased proportionately (4.79-5.55 liters × 103/day) we conclude that triiodothyronine stimulates thyroxine clearance by a mechanism that is independent of effects on free thyroxine concentration.

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George C. Schussler, Vernon K. Vance

Elevated serum human growth hormone and decreased serum insulin in prediabetic males after intravenous tolbutamide and glucose

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Serum human growth hormone (HGH), serum immunoreactive insulin (IRI), plasma free fatty acids, and blood glucose were measured during intravenous glucose and intravenous tolbutamide tolerance tests in 13 normal and 13 prediabetic (offspring of two diabetic parents) males, closely matched for weight and age. Only prediabetics with normal glucose tolerance during oral, intravenous, and cortisone-primed glucose tolerance tests were evaluated.

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G. Boden, J. S. Soeldner, R. E. Gleason, A. Marble

An extrarenal mechanism of potassium adaptation

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Rats fed a diet high in potassium for several days survive an acute load of potassium that is lethal to animals on a regular diet. Previous data suggested that this survival occurred because of enhanced kaluresis.

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Edward A. Alexander, Norman G. Levinsky

Phospholipid exchange between plasma and erythrocytes in man and the dog

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The turnover of the four major erythrocyte phospholipids has been studied with 32P, both in vivo and in vitro, in man and the dog. Phosphatidyl serine and phosphatidyl ethanolamine appeared to be stable erythrocyte lipids in both species. Turnover of the phosphate moiety of lecithin and sphingomyelin in the circulating erythrocytes of these two species seems entirely due to an exchange of the whole molecule with the corresponding plasma compound. Exchangeable and nonexchangeable pools of these two cellular lipids were found. In man about 60% of erythrocyte lecithin is exchangeable. The 12 hr fractional turnover of this pool is approximately 13%. Only 30% of the sphingomyelin in human cells appeared exchangeable; this portion had a 12 hr fractional turnover of about 14%. Similar results were obtained in the dog except that in this species about 75% of the erythrocyte sphingomyelin was exchangeable. Inorganic 32P was not incorporated into any of the four major phospholipids in either species. The present findings aid in estimating quantitatively the effect of plasmaerythrocyte lipid exchange on red blood cell phospholipids.

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Claude F. Reed

Demonstration of a hormonal inhibitor of proximal tubular reabsorption during expansion of extracellular volume with isotonic saline

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Evidence for the elaboration of a hormonal inhibitor of renal tubular reabsorption in response to expansion of extracellular fluid volume was obtained by examining the effects of plasma from rats and dogs undergoing saline diuresis on the rate of proximal tubular reabsorption measured both directly by micropuncture techniques and indirectly by clearance techniques.

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Floyd C. Rector Jr., Manuel Martinez-Maldonado, Neil A. Kurtzman, Jack C. Sellman, Fred Oerther, Donald W. Seldin

Functional correlates of compensatory renal hypertrophy

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The functional correlates of compensatory renal hypertrophy were studied by micropuncture techniques in rats after the removal of one kidney. The glomerular filtration rate increased to roughly the same extent in the whole kidney and in individual surface nephrons, resulting in a greater amount of sodium delivered to the tubules for reabsorption. The fraction of the glomerular filtrate absorbed [determined from the tubular fluid-to-plasma ratio (TF/P) for inulin] remained unchanged in both proximal and distal portions of the nephron. The way in which the tubules adjusted to nephrectomy, however, differed in proximal and distal convolutions. After nephrectomy, the reabsorptive half-time, indicated by the rate of shrinkage of a droplet of saline in a tubule blocked with oil, was unchanged in the proximal tubule but significantly shortened in the distal convoluted tubule. Nevertheless, steady-state concentrations of sodium in an isolated raffinose droplet in the distal as well as the proximal tubule were the same in hypertrophied kidneys as in control animals. Possible reasons for this paradox are discussed.

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John P. Hayslett, Michael Kashgarian, Franklin H. Epstein

Longitudinal distribution of vascular resistance in the pulmonary arteries, capillaries, and veins

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A new method has been described for measuring the pressure and resistance to blood flow in the pulmonary arteries, capillaries, and veins. Studies were performed in dog isolated lung lobes perfused at constant flow with blood from a donor dog. Pulmonary artery and vein volume and total lobar blood volume were measured by the ether plethysmograph and dyedilution techniques. The longitudinal distribution of vascular resistance was determined by analyzing the decrease in perfusion pressure caused by a bolus of low viscosity liquid introduced into the vascular inflow of the lobe.

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Jerome S. Brody, Edward J. Stemmler, Arthur B. DuBois

Differential reactivity in the pulmonary circulation

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A new method for relating regional intravascular resistance to pulmonary arterial, capillary, and venous pressure and volume was used to evaluate local differences of reactivity in the pulmonary blood vessels in the isolated lung lobe of the dog.

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Jerome S. Brody, Edward J. Stemmler

Bile salts and cholesterol in the pathogenesis of target cells in obstructive jaundice

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Free cholesterol is in rapid equilibrium between serum lipoproteins and red cells. The level of red cell cholesterol is influenced by bile salts, which shift the serum/cell partition of free cholesterol to the cell phase and which inhibit the cholesterol-esterifying mechanism. During incubation in normal serum possessing an active cholesterol-esterifying mechanism, red cells lose cholesterol and surface area and thereby become more spheroidal and less resistant to osmotic lysis. When exposed to serum from patients with obstructive jaundice or to normal serum with added bile salts, red cells accumulate cholesterol and increase their surface area, thereby acquiring a flattened shape and an increased resistance to osmotic lysis. The described gains and losses of red cell cholesterol and surface area do not involve metabolic injury and occur with no significant change in phospholipid content.

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Richard A. Cooper, James H. Jandl

Renal tubular transport of proline, hydroxyproline, and glycine: III. Genetic basis for more than one mode of transport in human kidney

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Impaired renal tubular transport of proline, hydroxyproline, and glycine was inherited as an autosomal recessive trait in two Ashkenazi-Jewish pedigrees and one French-Canadian family; the heterozygotes for the trait exhibited hyperglycinuria only. Intestinal transport of imino acids and glycine was not impaired in homozygotes. It is possible that more than one mutant allele may occur at a locus controlling tubular transport of the imino acids and glycine, since one subject with the imino-glycinuric phenotype had one parent who was not hyperglycinuric.

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Charles R. Scriver

Studies on the in vitro behavior of agammaglobulinemic lymphocytes

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Circulating lymphocytes from patients with congenital X-linked agammaglobulinemia, sporadic congenital agammaglobulinemia, and acquired agammaglobulinemia have been cultured in vitro. They have been shown to proliferate in a normal manner under stimulus of phytohemagglutinin and antigens to which the patient was sensitized. Agammaglobulinemic cells have been shown to synthesize protein at a rate similar to that of normal cells, and the character of the extracellular protein produced is also similar. Agammaglobulinemic lymphocytes have been found to produce a small quantity of immunoglobulin G, similar to that found in normal cell cultures. The quantity of immunoglobulin produced may be increased by exposure of the cells to phytohemagglutinin. From these data, it appears that the basic lesion responsible for agammaglobulinemia is not a deficiency in lymphocyte-mediated antigen recognition or cellular proliferation. It would also appear that the basic deficiency in these disorders does not involve the structural or regulatory genes necessary for the synthesis of immunoglobulins. By exclusion, the pathogenesis of the deficiency would appear to involve cells other than circulating lymphocytes.

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S. R. Cooperband, F. S. Rosen, S. Kibrick

Mixing in the right ventricle and pulmonary artery in man: evaluation of ventricular volume measurements from indicator washout curves

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To assess the mixing characteristics of the right ventricle and pulmonary artery, radioiodinated 131I serum albumin and indocyanine green dye were injected simultaneously in 16 subjects. One indicator was injected into the atrium and the other into the ventricle, or both were injected at different sites in the ventricle. Washout curves were obtained by rapid catheter sampling alternately just above or just below the pulmonic valve. The washout of radioisotope was also recorded with a precordial scintillation detection probe.

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Attilio Maseri, Yale Enson

Hemoglobin synthesis in β-thalassemia: the properties of the free α-chains

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The decrease in hemoglobin A (HbA, α2β2) synthesis in the erythroid cells of patients with β-thalassemia is due to a selective defect in β-chain synthesis. Since α-chains continue to be formed at a normal rate in these cells, this results in a marked relative excess of α-chain synthesis over β- and γ-chain synthesis. The α-chains uncombined with β- or β-like-chains (δ, γ) will be referred to as free α-chains. The experiments presented in this paper show that these free α-chains are capable of combining with β-chains to form HbA and are, therefore, structurally normal. Alternatively, in the absence of added β-chains, α-chains aggregates of various sizes are formed.

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Arthur Bank

Myocardial mechanics in aortic and mitral valvular regurgitation: the concept of instantaneous impedance as a determinant of the performance of the intact heart

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The effects on myocardial mechanics of acute, artificial aortic and mitral regurgitation were studied in the dog to determine the manner in which the changes in load induced by valvular regurgitation alter ventricular performance. With mitral and aortic regurgitant volumes of approximately the same magnitude as the forward stroke volume, immediate increases occurred in total stroke volume, left ventricular enddiastolic pressure, and peak ejection velocity, whereas contractility remained unchanged. Although calculated myocardial fiber tension rose, the rate of decline of tension during ejection was accelerated with regurgitation due to the more rapid decrease in ventricular size. Average tension therefore decreased relative to average pressure. As a consequence of the increased fiber length and this unloading, contractile element velocity, work, and power were increased. Despite unchanged contractility of the myocardium, the ejection fraction rose with both aortic and mitral regurgitation.

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Charles W. Urschel, James W. Covell, Edmund H. Sonnenblick, John Ross Jr., Eugene Braunwald

The mechanisms of sodium absorption in the human small intestine

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The present studies were designed to characterize sodium transport in the jejunum and ileum of humans with respect to the effects of water flow, sodium concentration, addition of glucose and galactose, and variations in aniomic composition of luminal fluid. In the ileum, sodium absorption occurred against very steep electrochemical gradients (110 mEq/liter, 5-15 mv), was unaffected by the rate or direction of water flow, and was not stimulated by addition of glucose, galactose, or bicarbonate. These findings led to the conclusion that there is an efficiently active sodium transport across a membrane that is relatively impermeable to sodium. In contrast, jejunal sodium (chloride) absorption can take place against only the modest concentration gradient of 13 mEq/liter, was dramatically influenced by water movement, and was stimulated by addition of glucose, galactose, and bicarbonate. The stimulatory effect of glucose and galactose was evident even when net water movement was inhibited to zero by mannitol. These observations led to the conclusion that a small fraction of jejunal sodium absorption was mediated by active transport coupled either to active absorption of bicarbonate or active secretion of hydrogen ions. The major part of sodium absorption, i.e. sodium chloride absorption, appeared to be mediated by a process of bulk flow of solution along osmotic pressure gradients. The stimulatory effect of glucose and galactose, even at zero water flow, was explained by a model in which the active transport of monosaccharide generates a local osmotic force for the absorption of solution (NaCl and water) from the jejunal lumen, which, in the presence of mannitol, is counterbalanced by a reverse flow of pure solvent (H2O) through a parallel set of channels which are impermeable to sodium. Support for the model was obtained by the demonstration that glucose and bicarbonate stimulated the absorption of the nonactively transported solute urea even when net water flow was maintained at zero by addition of mannitol to luminal contents.

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John S. Fordtran, Floyd C. Rector Jr., Norman W. Carter

Platelet factor 3 in normal subjects and patients with renal failure

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Two tests were used to differentiate abnormalities in release of platelet factor 3 (PF3) from quantitative deficiencies of this factor in normal subjects and in patients with renal failure. The first test was an assay which determined availability of PF3 (PF3-A time) and involved the use of a mixture of patient's platelet-rich plasma (PRP) and normal platelet-poor plasma (PPP) in a fixed ratio (1:8). The second test was similar but used “frozen and thawed” platelets to obtain a quantitative estimate of PF3 (PF3-F time). An abnormal PF3-A time was found in approximately three-quarters of 55 patients with renal insufficiency; 43 of these had chronic and 12 had acute renal failure. This abnormality was present both in patients with and without hemorrhagic manifestations, although it was slightly more common in bleeders. The PF3-F test was abnormal in approximately one-third of the bleeding patients and one-quarter of the non-bleeders. The PF3-A time returned to normal or was significantly shortened 24-48 hr after peritoneal or hemodialysis. Studies on patients who were not dialyzed showed no statistically significant correlations between the PF3-A time and either the serum urea nitrogen, creatinine, calcium, or phosphorus. Furthermore, the PF3-A time was not affected by guanidinosuccinic or guanidinoacetic acids. We therefore conclude that the demonstrable platelet abnormality in patients with uremia is produced by an unknown dialyzable material.

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S. Frederick Rabiner, Otto Hrodek

Identification of a macromolecular factor in the ileum which binds intrinsic factor and immunologic identification of intrinsic factor in ileal extracts

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The precipitate which resulted when 57CoB12 bound to normal human gastric juice was subjected to a 15% concentration of Na2SO4 contained virtually no radioactivity. However, after in vivo incubation of the gastric juice-57CoB12 mixture in the distal ileum of the guinea pig, the dialyzed extract of the washed mucosa contained a fraction of 57CoB12 which was precipitated at 15% Na2SO4. In addition, in vitro incubation of gastric juice-57CoB12 with an extract of the ileal mucosa or brush border membranes also resulted in the formation of a 15% Na2SO4-insoluble fraction which contained 57CoB12. The formation of this 57CoB12-containing insoluble fraction did not occur or was diminished by (a) addition of an excess of B12-free normal human gastric juice. (b) reducing the incubation pH to 2, (c) incubating the mixture at 4°C, (d) pretreating the ileal extract at 56°C for 30 min, (e) incubating the reaction in sodium EDTA but not calcium EDTA, (f) incubating gastric juice-57CoB12 with an extract of jejunal mucosa. Sephadex gel filtration was used to demonstrate that the factor in the ileal extract which reacted with the gastric juice-57CoB12 filtered through G-100 and G-200 columns in the excluded volume.

Authors

Sheldon P. Rothenberg

The characterization of soluble amyloid prepared in water

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Amyloid was extracted from the spleen of a patient with primary amyloidosis by homogenizing it at high speed with water after preliminary treatments, first to remove proteins soluble in saline, and then to remove salts. The extracts containing amyloid appeared to be clear at concentrations up to 6 mg/ml of protein. The material gave little sediment on being centrifuged up to 20,000 g for 1 hr, but the protein was sedimented at 100,000 g in 1 hr. The amyloid could be precipitated from the extracts by addition of NaCl to 0.0075 mole/liter or of CaCl2 to 0.0025 mole/liter. The protein-bound Congo red formed a red precipitate and this property was used to estimate recovery and purity of amyloid during extraction.

Authors

M. Pras, M. Schubert, D. Zucker-Franklin, A. Rimon, E. C. Franklin

Circadian periodicity of tryptophan metabolism

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Rhythmicity of tryptophan metabolism via the kynurenine pathway has been demonstrated in man. Normal subjects given 3 g of tryptophan at 0900 hours excreted almost three times the quantity of kynurenine, kynurenic acid, and xanthurenic acid than did subjects given the same dose at 2100 hours. Other metabolites of the kynurenine pathway varied in the same fashion but with lesser magnitude. In contrast, indican, a tryptophan metabolite not in the kynurenine pathway, varied inversely with the other metabolites measured. The data suggest that the liver enzyme tryptophan pyrrolase has a circadian rhythm in man similar to that already described in mice in a previous study.

Authors

Morton I. Rapoport, William R. Beisel

In vivo lability of glucose-6-phosphate dehydrogenase in Gd^A- and Gd^{mediterranean} deficiency

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A decreased level of glucose-6-phosphate dehydrogenase might result from decreased rate of synthesis, synthesis of an enzyme of lower catalytic efficiency, increased lability, or a combined mechanism. To test the hypothesis of increased lability, the rate of decline of the enzyme in vivo was measured in three groups of individuals, controls, Gd(—),A-males, and Gd(—), Mediterranean males, by the slope of decline of activity in fractions containing erythrocytes of progressively increasing mean age. These fractions were obtained by ultracentrifugation on a discontinuous density gradient of erythrocyte suspensions free of contaminating platelets and leukocytes.

Authors

Sergio Piomelli, Laurence M. Corash, Deatra D. Davenport, Janet Miraglia, Edward L. Amorosi

Concentration dependence of active potassium transport in the human red blood cell in the presence of inhibitors

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The active potassium influx in the human red blood cell is inhibited by strophanthidin, ethacrynic acid, and MK-870 (a new diuretic), and the degree of inhibition is greater at low concentrations of extracellular potassium than at high. In the case of ethacrynic acid, potassium appears to diminish the rate of combination of the drug with the transport system. The kinetic behavior of the active potassium influx in the presence of the inhibitors strophanthidin and ethacrynic acid is consistent with a model in which the binding of potassium at one of the potassium-sensitive sites in the transport system reduces the affinity of the system for the drug, and binding of a second potassium ion further reduces the affinity. It is not possible to distinguish between the sites on the basis of the studies presented here.

Authors

John R. Sachs, Louis G. Welt

A comparison of the effects of vasodilator stimuli on peripheral resistance vessels in normal subjects and in patients with congestive heart failure

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The objective of this investigation was to characterize the mechanism of peripheral vasoconstriction observed in heart failure and to determine whether it can be attributed to the augmented sympathetic nervous activity, characteristic of this state. The response of the resistance bed in the forearm after release of inflow occlusion (reactive hyperemia), to hand exercise, and to local heating and the response of the calf resistance vessels to arterial occlusion and intra-arterial sodium nitrite and phentolamine were studied in 23 patients with congestive heart failure and 21 normal subjects. In the normal subjects, reactive hyperemia blood flow after varying periods of arterial occlusion greatly exceeded the values observed in patients with heart failure. Local anesthetic blockade and intra-arterial phentolamine did not significantly alter the reactive hyperemia response in heart failure patients, militating against the possibility that increased sympathetic vasoconstrictor activity is responsible for the reduction of this response. Following compensation, the reactive hyperemia response returned toward normal. The striking elevations of the forearm blood flow observed after hand exercise and heating of the forearm in normal subjects were also markedly attenuated in patients with heart failure. Following intra-arterial phentolamine and/or sodium nitrite, peak calf blood flow was still significantly reduced in heart failure.

Authors

Robert Zelis, Dean T. Mason, Eugene Braunwald

Estimation of Thyroxine Distribution in Man

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