Cholesterol Metabolism in Human Obesity

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Abstract

An experiment was undertaken to test whether in severe obesity cholesterol production rates obtained by isotope kinetic analysis (two-pool compartmental analysis) are comparable to those measured by chemical sterol balance techniques. Eight severely obese but normocholesterolemic patients were studied by the balance method, and five of these eight were studied by compartmental analysis. Cholesterol turnover was 10% higher by compartmental analysis.

Authors

Paul J. Nestel, Paul H. Schreibman, E. H. Ahrens Jr.

Immunological Studies of Coagulation Factor XIII

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Abstract

Human fibrin-stabilizing factor (Factor XIII) has been studied immunologically by the preparation of specific anti-Factor XIII antiserum in rabbits. On immunodiffusion it was found that normal plasma produced two precipitin lines. One of the precipitin lines was identical with that present in soluble platelet extract (the α-component), the other with that present in normal serum (β-component). Plasma and serum of patients with congenital Factor XIII deficiency contained only the β-component. By adsorption it was possible to prepare a second antiserum with solely anti-α-activity that did not react with the serum or plasma of XIII-deficient patients. Both antisera neutralized the clot-stabilizing activity of normal plasma. The action of thrombin on fibrinogen-free plasma or platelet extract abolished the immunoprecipitin α-line but did not reduce the capacity to neutralize antibody as measured by clot stabilization.

Authors

E. D. Israels, F. Paraskevas, L. G. Israels

Demonstration of Iodide Transport Defect but Normal Iodide Organification in Nonfunctioning Nodules of Human Thyroid Glands

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Abstract

Benign and malignant nodules in human thyroid glands, which did not concentrate iodide in vivo, were also unable to accumulate iodide in vitro. The mean thyroid-to-medium ratio (T/M) in seven benign nodules was 0.8±0.2 compared with 7±2 in adjacent normal thyroid tissue. In four malignant thyroid nodules, the mean T/M was 0.5±0.1 compared with 11±4 in adjacent normal thyroid. Despite the inability of such nodules to concentrate iodide, iodide organification was present but was only one-half to one-third as active as in surrounding normal thyroid. Thyroid-stimulating hormone (TSH) increased iodide organification equally in both benign nodules and normal thyroid although it had no effect in three of the four malignant lesions. The reduction in organification is probably related to the absence of iodide transport, since incubation of normal thyroid slices with perchlorate caused similar diminution in iodide incorporation but no change in the response to TSH. Monoiodotyrosine (MIT) and di-iodotyrosine (DIT) accounted for most of the organic iodide in both the nodules and normal tissue. The MIT/DIT ratio was similar in normal and nodule tissue. The normal tissue contained much more inorganic iodide than the nodules, consistent with the absence of the iodide trap in the latter tissue. The thyroxine content of normal thyroid was 149±17 μg/g wet wt and 18±4 μg/g wet wt in the nodules. The transport defect in the nodules was not associated with any reduction in total, Na+-K+- or Mg++-activated ATPase activities or the concentration of ATP. Basal adenylate cyclase was higher in nodules than normal tissue. Although there was no difference between benign and malignant nodules, the response of adenylate cyclase to TSH was greater in the benign lesions.

Authors

James B. Field, P. Reed Larsen, Kamejiro Yamashita, Keith Mashiter, Andrew Dekker

Comparative Pharmacology of Δ⁹-Tetrahydrocannabinol and its Metabolite, 11-OH-Δ⁹-Tetrahydrocannabinol

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Abstract

A comparison of the psychologic and physiologic effects of intravenously administered Δ9-tetrahydrocannabinol (Δ9-THC) and 11-hydroxy-Δ9-tetrahydrocannabinol (11-OH-Δ9-THC) was carried out in nine casual marihuana smokers. A marked tachycardia and psychologic “high” occurred within 3-5 min after the i.v. administration of 11-OH-Δ9-THC (1 mg) to all subjects. In contrast, the peak psychologic “high” was delayed 10-20 min after the i.v. administration of Δ9-THC (1 mg). There was some individual variation in response among subjects. Psychologic effects correlated well with plasma levels of unchanged [3H]11-OH-Δ9-THC. About 75% of the administered radioactive dose was excreted in urine (25%) and feces (50%) after [3H]11-OH-Δ9-THC administration. The disposition, excretion, and metabolism of [3H]11-OH-Δ9-THC appear to be similar to that previously reported after [14C]Δ9-THC administration. These findings, in conjunction with the marked psychologic high seen after 11-OH-Δ9-THC, suggest that in man, Δ9-THC, the active constituent in marihuana, is converted to 11-OH-Δ9-THC, which is in part responsible for the psychologic effects.

Authors

Louis Lemberger, Robert Martz, Bruce Rodda, Robert Forney, Howard Rowe

Micropuncture Study of Diuretic Effects on Sodium and Calcium Reabsorption in the Dog Nephron

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Abstract

A close relationship has been observed between the clearance rates of sodium and calcium under a variety of diuretic conditions. The thiazide diuretics act differently in dissociating the renal tubular reabsorption of sodium and calcium. This phenomenon has been further investigated using recollection micropuncture and clearance techniques in a group of 14 dogs subjected to three consecutive experimental phases: expansion to 3% of body weight (BWt) with Ringer's solution, chlorothiazide infusion at 20 mg/kg/h, and furosemide in a prime of 10 mg/kg/ and a 10 mg/kg/h infusion. Diuretic losses were balanced with infusion of equal volumes of Ringer's solution throughout the experiment. Chlorothiazide increased the fractional excretion (FE) of sodium almost threefold while FECa was not significantly altered. Furosemide increased FENa and FECa to an approximately equal, and more marked, degree. This dissociation of sodium and calcium reabsorption after chlorothiazide was also evident in the superficial distal tubule, where (tubule fluid/plasma sodium) (TF/PNa) increased from 0.32 to 0.49 (P < 0.01) and TF/(ultrafiltrate)UFCa was unchanged (0.35-0.31). Furosemide markedly reduced the transtubular concentration gradient for both sodium (0.86) and calcium (0.94). TF/PInul in decreased progressively from 3.79 to 2.78 to 2.33 in three phases. In the late proximal tubule, chlorothiazide induced a fall of TF/PInul in from 1.57 to 1.44 (P < 0.01), but the ratio TF/UFCa: TF/PNa was unchanged. Furosemide had no significant proximal effect. It is concluded that acute administration of chlorothiazide reduces sodium reabsorption in the distal hephron, presumably the cortical diluting segment, without affecting calcium reabsorption.

Authors

B. R. Edwards, P. G. Baer, R. A. L. Sutton, J. H. Dirks

Synthesis and Degradation of Hyaluronic Acid in the Cultured Fibroblasts of Marfan's Disease

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Abstract

Increased amounts of hyaluronic acid accumulate in fibroblasts cultured from patients with Marfan's disease, an autosomal dominant disorder. In the recessive Hurler's disease, the storage of glycosaminoglycan (GAG) is due to impaired degradation. This study examines the kinetics of GAG accumulation in Marfan's disease in order to determine whether the mechanism of accumulation differs from that in Hurler's disease.

Authors

Stanford I. Lamberg, Albert Dorfman

Acute Parathyroid Hormone Response to Epinephrine In Vivo

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Abstract

The acute effects of epinephrine, norepinephrine, and isoproterenol on the plasma immunoreactive parathyroid hormone (iPTH) response were studied in 13 550-600 kg cows. Catecholamines were infused for 7.0 min. During epinephrine infusions at 0.08 μmol/min iPTH increased from 0.48±0.12 (mean±SE, ng/ml) to 1.09±0.18 ng/ml (P < 0.02). Small increases in plasma free fatty acids and glucose could be detected with 0.08 μmol/min epinephrine; the iPTH response to epinephrine was as sensitive as the free fatty acid and glucose responses and possibly of physiological importance. Plasma calcium (total and ionized) and magnesium did not change.

Authors

Jan A. Fischer, Jürg W. Blum, Ulrich Binswanger

Fluid Secretion in Isolated Proximal Straight Renal Tubules EFFECT OF HUMAN UREMIC SERUM

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Abstract

We have examined the effect of normal and uremic human sera on the transtubular flow of fluid in isolated perfused segments of rabbit proximal convoluted and straight renal tubules. Proximal convoluted and straight tubules absorbed fluid from the lumen when the external bath was normal rabbit serum. Normal human sera in the bath depressed net fluid absorption in both tubular segments, but more importantly, uremic human serum caused proximal straight tubules to secrete fluid into the lumen. Fluid secretion was also demonstrated indirectly by observing in nonperfused proximal straight, but not proximal convoluted tubules, that the normally collapsed lumens opened widely in uremic serum. Nonperfused proximal straight tubules developed expanded lumens even after a 25-fold dilution of human uremic serum with normal rabbit serum, whereas lumen expansion occurred only in undiluted normal human serum, on the average. Serum from acutely uremic rabbits possessed secretory activity but normal rabbit serum did not. The secretory effect of uremic sera in proximal straight tubules was inhibited by cooling and ouabain and probenecid. The secretory activity of uremic sera was removed by dialysis, but not by freezing or boiling. Para-aminohippurate and benzoate caused fluid secretion in proximal straight tubules but urea, creatinine, guanidinosuccinate, and urate did not. On the basis of these results, we suggest that the secretory factor in serum may be a substance or group of substances possibly related to the hippurate class of organic molecules that are accumulated to relatively high concentrations in renal failure. The secretory material in the serum of uremic patients may significantly influence the transport of salt and water in relatively intact residual nephrons.

Authors

Jared J. Grantham, Richard L. Irwin, Patti B. Qualizza, Donald R. Tucker, Frederick C. Whittier

Inhibition of Liver Fibrosis by L-Azetidine-2-Carboxylic Acid in Rats Treated with Carbon Tetrachloride

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Abstract

L-Azetidine-2-carboxylic acid (AZC), an analogue of proline, has been shown to partially ameliorate hepatic cirrhosis induced in rats by CCl4. AZC caused a diminution in formation of collagen in the liver accompanied by a relative decrease in the pool of free proline. The synthesis of noncollagenous proteins in the livers of treated rats did not appear to be affected.

Authors

Marcos Rojkind

Inhibition of Primary ADP-Induced Platelet Aggregation in Normal Subjects after Administration of Nitrofurantoin (Furadantin)

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Abstract

The evidence indicating that platelets may play a role in the occurrence of certain thromboembolic phenomena has stimulated a search for inhibitors of platelet function. This report presents data to indicate that nitrofurantoin is a potent inhibitor of primary ADP-induced platelet aggregation. The addition of 10 μM nitrofurantoin to citrated platelet-rich plasma obtained from 12 normal subjects produced a 29±6% (2 SD) inhibition of the velocity of platelet aggregation induced by 2 μM ADP. The inhibitory effect of nitrofurantoin demonstrated competitive kinetics in respect to ADP. The intravenous (180 mg) or oral (200 mg) administration of nitrofurantoin produced a serum nitrofurantoin concentration ranging from 2.7 to 23 μM in 28 normal subjects. Platelet-rich plasma obtained from these subjects demonstrated inhibition of the velocity of ADP-induced platelet aggregation that correlated with the log of the serum nitrofurantoin concentration (P < 0.001). Collagen-induced platelet aggregation was also inhibited in a dose-related manner, and the bleeding time was significantly prolonged in the two subjects with the highest serum nitrofurantoin concentration. These studies indicate that nitrofurantoin in vivo inhibits platelet function to a degree that is proportional to the serum nitrofurantoin concentration.

Authors

Ennio C. Rossi, Nathan W. Levin

The Kinetics of Intramolecular Distribution of ¹⁵N in Uric Acid after Administration of [¹⁵N]Glycine A REAPPRAISAL OF THE SIGNIFICANCE OF PREFERENTIAL LABELING OF N-(3 + 9) OF URIC ACID IN PRIMARY GOUT

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Abstract

The concept of an abnormality of glutamine metabolism in primary gout was first proposed on the basis of isotope data: when [15N]glycine was administered to gouty subjects, there was disproportionately great enrichment of N-(3 + 9) of uric acid, which derive from the amide-N of glutamine. An unduly high concentration of 15N in glutamine was postulated, and attributed to a hypothetical defect in catabolism of glutamine. Excess glutamine was proposed as the driving force of uric acid overproduction.

Authors

Oded Sperling, James B. Wyngaarden, C. Frank Starmer

Brush Border Disaccharidases in Dog Kidney and Their Spatial Relationship to Glucose Transport Receptors

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Abstract

The localization of disaccharidases in kidney has been studied by means of the multiple indicator dilution technique. A pulse injection of a solution containing Evans blue dye (plasma marker), creatinine (extracellular marker), and a 14C-labeled disaccharide (lactose, sucrose, maltose, and αα-trehalose), is made into the renal artery of an anesthetized dog, and the outflow curves are monitored simultaneously from renal venous and urine effluents. Lactose and sucrose have an extracellular distribution. Trehalose and maltose remain extracellular from the postglomerular circulation. About 75% of filtered tracer maltose or trehalose is extracted by the luminal surface of the nephron. Thin-layer chromatography of urine samples shows that all of the excreted 14C radiolabel is in the form of the injected disaccharide. Following the administration of phlorizin, all of the filtered radioactivity is recoverable in the urine, but chromatography of the urine samples now reveals that there is a significant excretion of [14C]glucose, approximating the amount previously extracted under control conditions (in the absence of phlorizin). It has been verified that no hydrolysis of maltose or trehalose to their constituent glucose subunits occurred during the transit of tracer between the point of injection (renal artery), and the point of filtration (glomerular basement membrane). Similarly, after addition of [14C]disaccharides to fresh urine there is no chromatographically recoverable [14C]glucose.

Authors

Melvin Silverman

Collagen-Mediated Platelet Aggregation EFFECTS OF COLLAGEN MODIFICATION INVOLVING THE PROTEIN AND CARBOHYDRATE MOIETIES

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Abstract

In an effort to elucidate the nature of the collagen-platelet interaction, the effects of collagen modification on platelet aggregation have been studied. We have shown that purified rat skin (salt) soluble collagen is effective at about 20 nM in mediating platelet aggregation in human platelet-rich plasma. This concentration is somewhat greater than that required of several skin insoluble collagens (ca. 10 nM). Both the α1(I) and α2 chains from rat skin soluble collagen produced platelet aggregation, but only at concentrations of about 13 μM and 55 μM, respectively. In contrast, heat-denatured collagen and chains (e.g., 65 μM α1(I) and 160 μM α2) failed to induce platelet aggregation and to inhibit platelet aggregation by native collagen.

Authors

David Puett, Betty Kay Wasserman, John D. Ford, Leon W. Cunningham

Studies on the Distribution of Surface Immunoglobulins on Human B-Lymphocytes

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Abstract

Normal human peripheral blood lymphocytes were studied with fluorescent anti-immunoglobulin antibodies and shown to have a patchy distribution of immunoglobulin on their surfaces that does not form a cap after complexing with antibody. Use of freeze-etch electron microscopy confirmed the distribution of immunoglobulin in isolated patches on the membrane. Evidence is presented that this distribution may explain the absence of capping of these human cells as compared with mouse B-lymphocytes.

Authors

Kenneth A. Ault, Morris J. Karnovsky, Emil R. Unanue

The Mutual Independence of the Endolymphatic Potential and the Concentrations of Sodium and Potassium in Endolymph

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Abstract

The relationship between the endolymphatic potential (EP) and the sodium and potassium concentration gradients between endolymph and interstitial fluid was studied both by measuring the EP at varying concentrations of sodium and potassium in endolymph and by measuring the effect of a depressed EP on the concentrations of these cations. Ethacrynic acid was used in dogs to change the concentration of sodium and potassium (meq/liter) in endolymph from 5.8 and 148 to 134 and 24.3, respectively. No change in the EP accompanied these alterations. In a second series of experiments the EP was reduced from + 72 mV to + 31 mV for a mean duration of 20 min. No change in the concentration of sodium and potassium in endolymph was found during the period of reduced EP. These data suggest that there is little relationship between the EP and the sodium and potassium concentrations in endolymph.

Authors

Saul W. Brusilow, Ellen Gordes

Triiodothyronine and Thyroxine in the Serum and Thyroid Glands of Iodine-Deficient Rats

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Abstract

Triiodothyronine (T3) and thyroxine (T4) were measured by immunoassay in the serum and thyroid hydrolysates of control (group A), mildly iodine-deficient (group B), and severely iodine-deficient rats (group C). These results were correlated with changes in thyroidal weight, 131I uptake and 127I content as well as with the distribution of 131I in Pronase digests of the thyroid. There was a progressive increase in thyroid weight and 131I uptake at 24 h with decrease in iodine intake. The 127I content of the thyroids of the group B animals was 44% and that of the group C animals 2% of that in group A. The mean labeled monoiodotyrosine/diiodotyrosine (MIT/DIT) and T3/T4 ratios in group A were 0.42±0.07 (SD) and 0.12±0.01, 0.59±0.06 and 0.11±0.03 in group B, and 2.0±0.3 and 1.8±0.9 in the group thyroid digests.

Authors

G. M. Abrams, P. R. Larsen

The Effects of Triglyceride Absorption upon Glucagon, Insulin, and Gut Glucagon-Like Immunoreactivity

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Abstract

The effects of a fat meal upon plasma insulin, glucagon, and glucagon-like immunoreactivity (GLI) have been studied in conscious dogs and in human volunteers. In dogs the intraduodenal instillation of 10 g/kg of peanut oil was accompanied by increases in the mean plasma levels of all three polypeptides that averaged 5 μU/ml, 107 pg/ml, and 2.1 ng/ml, respectively. 3 g/kg of peanut oil, when emulsified with egg yolk, elicited a much greater response of the three hormones, and a physiologic dose of 1 g/kg in emulsified form also caused a significant rise in glucagon and GLI. The islet cell hormone response was not ascribable to chylomicronemia since intravenous infusion of canine chyle failed to stimulate glucagon secretion; moreover, in dogs with a thoracic duct fistula in which chyle was excluded from the circulation, the intraduodenal administration of a fat meal elicited the normal islet cell hormone response, as well as a rise in GLI. 10 g/kg of medium-chain triglycerides failed to elicit these same responses. In six human volunteers the oral administration of 3 g/kg peanut oil was accompanied by increments of 2 μU/ml, 26 pg/ml, and 1.5 ng/ml in the mean levels of insulin, glucagon, and GLI. The changes in insulin and glucagon in man were neither statistically significant nor biologically impressive.

Authors

Ingolf Böttger, Richard Dobbs, Gerald R. Faloona, Roger H. Unger

Effects of Cyanate and 2,3-Diphosphoglycerate on Sickling RELATIONSHIP TO OXYGENATION

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Abstract

Cyanate and 2,3-diphosphoglycerate (2,3-DPG) both influence the oxygen affinity of hemoglobin. The studies presented here concern the effects of these compounds on the sickling phenomenon. The inhibitory effect of cyanate on sickling is largely due to the fact that it increases the percentage of oxyhemoglobin S at a given oxygen tension. In addition, cyanate inhibits sickling by a mechanism that is independent of oxygenation. In this paper, we have demonstrated that the viscosity of carbamylated sickle blood was lower than that of non-carbamylated controls at the same oxygen saturation. Furthermore, carbamylation resulted in an increase in the minimum concentration of deoxy-sickle hemoglobin required for gelation.

Authors

Michael Jensen, H. Franklin Bunn, George Halikas, Yuet Wai Kan, David G. Nathan

Effect of Extracellular Volume Expansion upon Sodium Reabsorption in the Distal Nephron of Dogs

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Abstract

Micropuncture studies have disclosed that extracellular fluid (ECF) volume expansion inhibits sodium reabsorption in the proximal tubule. The diuresis that ensues represents only a portion of the increment in sodium and water escaping proximal reabsorption, since a large and variable fraction of the increment is reabsorbed distally. In certain experimental models proximal reabsorption may be depressed by ECF volume expansion, yet only a negligible amount of sodium appears in the final urine. This suggests that saline diuresis is the consequence of depressed distal sodium reabsorption. Previous clearance and micropuncture studies have not conclusively proven this. Eight dogs were studied repeatedly: in some studies glomerular filtration rate and distal delivery were increased markedly without sodium administration; in others comparably high distal sodium loads were achieved by progressive 1/2 isotonic saline infusion. CH2O at high distal sodium loads was depressed by expansion of the ECF volume with hypotonic saline. The difference in free water formation between dogs which did and did not receive hypotonic saline was accounted for by the difference in sodium excretion. In one dog hypotonic saline expansion failed to depress free water formation; likewise the level of natriuresis in this dog was severely attenuated. The results of these experiments provide strong evidence that the natriuresis that occurs following ECF volume expansion with saline is a consequence of alteration in function of the distal nephron.

Authors

Cleaves M. Bennett

Renal Bicarbonate Wasting during Phosphate Depletion A POSSIBLE CAUSE OF ALTERED ACID-BASE HOMEOSTASIS IN HYPERPARATHYROIDISM

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Abstract

With hyperparathyroidism, serum bicarbonate (HCO3-) is low, urinary excretion of HCO3- is increased and the apparent Tm for HCO3- is reduced. These findings have been ascribed to a direct renal action of parathyroid hormone (PTH). Since hypophosphatemia and phosphate depletion may occur in hyperparathyroidism, it is possible that phosphate depletion could account for the abnormal renal HCO3- handling. To test this possibility, renal reabsorption of HCO3- was evaluated in dogs before and after phosphate depletion. Serum HCO3- was significantly lower in phosphate depleted dogs than in normal animals, and serum HCO3- was directly related to serum phosphorus. Both the threshold at which HCO3- appeared in the urine and the Tm for HCO3- were reduced during phosphate depletion. Intracellular pH of muscle was significantly higher in phosphate depleted dogs than in normals and the pH returned to normal after phosphate repletion. These data show that phosphate depleted dogs, which probably have physiological hypoparathyroidism, display abnormalities in both serum HCO3- and its renal handling which are similar to those seen in hyperparathyroidism, supporting the concept that the PTH-induced alterations in HCO3- homeostasis may be due to phosphate depletion. The latter could alter cell metabolism, resulting in reduced intracellular H+ concentration, which may then impair H+ secretion by the renal tubules and decrease their ability to reabsorb HCO3-. Consequently, Tm HCO3- and serum HCO3- fall.

Authors

Lawrence W. Gold, Shaul G. Massry, Allen I. Arieff, Jack W. Coburn

Mediation of Cytotoxic Effects of Streptococcal M Protein by Nontype-Specific Antibody in Human Sera

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Abstract

The cytotoxic moiety(ies) in highly purified streptococcal M protein has been shown to be distinct from the type-specific M determinant. This nontype-specific M-associated determinant(s) (NTSM) causes humoral and cellular immunotoxic responses in man. NTSM is common to M protein prepared from all streptococcal serotypes studied so far. In this study, immunoabsorbents prepared by entrapping purified M proteins in polyacrylamide gel were employed to identify, separate, and purify antibodies directed against NTSM as well as against the type-specific M (TSM) determinants.

Authors

Edwin H. Beachey, Gene H. Stollerman

A Collagen Defect in Homocystinuria

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Abstract

The biochemical mechanism accounting for the connective tissue abnormalities in homocystinuria was explored by examining the effects of various amino acids known to accumulate in the plasma of patients with this disease on cross-link formation in collagen. Neutral salt solutions of purified, rat skin collagen, rich in cross-link precursor aldehydes, were polymerized to native type fibrils by incubating at 37°C in the presence of homocysteine, homocystine, or methionine. After the polymerization was completed, each sample was examined for the formation of covalent intermolecular cross-links, assessed indirectly by solubility tests and directly by measuring the cross-link compounds after reduction with tritiated sodium borohydride and hydrolysis.

Authors

Andrew H. Kang, Robert L. Trelstad

Early Estimation of Myocardial Damage in Conscious Dogs and Patients with Evolving Acute Myocardial Infarction

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Abstract

To estimate the ultimate extent of myocardial damage during evolving myocardial infarction in conscious dogs and patients, we analyzed early serum creatine phosphokinase (CPK) changes with nonlinear curve-fitting techniques. In experiments with dogs, serial serum CPK changes were fit to a log-normal function by the least squares method; the extent of the completed infarct was calculated by analysis of observed serum CPK changes and verified by measurement of myocardial CPK depletion 24 h after coronary occlusion. Early prediction of myocardial damage was based on projected serum CPK values from best fit curves based on data obtained during the first 5 h after initial elevation of enzyme activity. The correlation between predicted and observed values was close (r > 0.96, n = 11). In 11 additional conscious animals subjected to coronary occlusion, isoproterenol was administered continuously as soon as damage had been estimated from projected serum CPK values. The extent of the completed infarct was assessed by analysis of all serial serum CPK values and verified by analysis of myocardial CPK depletion 24 h after coronary occlusion. In each experiment the calculated completed infarct size exceeded infarct size projected before administration of isoproterenol (average increase = 44±10 [SE]%). When similar calculations were applied in experiments with eight dogs treated with propranolol, myocardial salvage was detected in 50% of the animals.

Authors

William E. Shell, John F. Lavelle, James W. Covell, Burton E. Sobel

The Fibrinolytic Pathway of Human Plasma II. THE GENERATION OF CHEMOTACTIC ACTIVITY BY ACTIVATION OF PLASMINOGEN PROACTIVATOR

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Abstract

The conversion of plasminogen proactivator to plasminogen activator by Hageman factor fragments results in the generation of chemotactic activity for human neutrophils. This chemotactic activity can be distinguished from that generated by Hageman factor activation of prekallikrein and is demonstrable in plasma that is genetically deficient in prekallikrein (Fletcher factor deficiency). Both the plasminogen-activating activity and chemotactic activity produced by the interaction of Hageman factor fragments and plasminogen proactivator to yield plasminogen activator were inhibited by diisopropyl fluorophosphate (DFP) indicating an essential role for the enzymatic site in both these activities. The finding that the plasminogen proactivator tolerated a dose of DFP, which completely inactivated the plasminogen activator, reveals that the active site is protected in the precursor protein.

Authors

Allen P. Kaplan, Edward J. Goetzl, K. Frank Austen

Metabolic Effects of Exogenous Glucocorticoids in Fasted Man

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Abstract

The influence of administering excessive amounts of glucocorticoids on circulating substrates and hormones and on urinary excretion of nitrogenous compounds and ketone bodies was examined in man after prolonged starvation.

Authors

O. E. Owen, G. F. Cahill Jr.

Rapid Intravenous Sodium Acetoacetate Infusion in Man METABOLIC AND KINETIC RESPONSES

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Abstract

The metabolic and kinetic responses to rapidly intravenously administered sodium acetoacetate (1.0 mmol/kg body wt) was studied after an overnight fast in 12 male and female adults weighing between 88 and 215% of average body weight. Blood was obtained before, during, and after the infusion for determination of circulating concentrations of immunoreactive insulin, glucose, acetoacetate, β-hydroxybutyrate and free fatty acids. In three obese subjects the studies were repeated after 3 and 24 days of total starvation.

Authors

O. E. Owen, G. A. Reichard Jr., H. Markus, G. Boden, M. A. Mozzoli, C. R. Shuman

Episodic Luteinizing Hormone Secretion in Man PULSE ANALYSIS, CLINICAL INTERPRETATION, PHYSIOLOGIC MECHANISMS

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Abstract

The demonstration that luteinizing hormone (LH) release from the pituitary is episodic rather than constant raises fundamental questions regarding the physiologic control of pulsatile LH secretion and its possible alteration in patients with gonadal disorders. To evaluate this mode of LH secretion, quantitative means of analyzing LH pulse amplitude, frequency, shape, and area were established and utilized to study normal subjects and patients with disorders of gonadotropin secretion. Similar patterns of LH secretion were observed in normal men, in women during the follicular phase of the menstrual cycle, and in patients with hyper- and hypogonadotropism, hirsuitism, and amenorrhea (mean pulse amplitude 39-179% from nadir to peak, frequency 2.7-3.9 secretory spikes/6 h). These observations suggested that the pattern of LH secretion is similar in both normal individuals and in those with a variety of pathologic conditions. By contrast, the pattern of pulsatile secretion appeared to differ in the following conditions. LH pulses of higher amplitude (333±170%) and lower frequency (1.6±0.24 SEM/6 h) characterized the secretory patterns of women during the luteal phase of the menstrual cycle, suggesting that gonadal steroids may modulate LH pulses. LH pulses of low amplitude (26±2.1%) and frequency (1.3±0.36/6 h) were observed in women with anorexia nervosa.

Authors

R. J. Santen, C. W. Bardin

Effects of Corticosteroids on Immunity in Man I. DECREASED SERUM IgG CONCENTRATION CAUSED BY 3 OR 5 DAYS OF HIGH DOSES OF METHYLPREDNISOLONE

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Abstract

To study the effects of methylprednisolone on immune mechanisms in the absence of other immunosuppressive agents or immunologically mediated diseases, we gave 17 normal adult male volunteers 96 mg of methylprednisolone daily for 3-5 days and compared results with 12 untreated controls who were studied simultaneously, 86% of treated volunteers had significant decreases in the concentrations of serum IgG. 2-4 wk after methylprednisolone, the treated volunteers had a mean decrease in IgG of 22% compared with a decrease of only 1% in untreated controls. Likewise, significant decreases in IgA concentration occurred in 43% of treated volunteers, whereas significant decreases in IgM occurred in only 14%. The lowest immunoglobulin levels occurred during the 2nd wk after a 3 day course of methylprednisolone and during the 3rd wk after a 5 day course of drug. Slightly decreased plasma concentration of [125I]IgG was seen in six of seven volunteers who received a 5 day course but in only one of four who received a 3 day course of drug. However, an increase in the rate of plasma clearance of IgG occurred only during the treatment period itself. During the period when the serum concentration of IgG was falling, the specific activity of IgG in the serum was relatively higher in treated men than in controls indicating decreased entry of newly synthesized IgG into the circulation. These findings suggest that a short course of methylprednisolone treatment causes a pronounced and sustained decrease in serum IgG due to increased catabolism during drug administration and to decreased synthesis during and for a variable time after drug administration.

Authors

William T. Butler, Roger D. Rossen

Sodium-Independent Active Potassium Reabsorption in Proximal Tubule of the Dog

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Abstract

Prior studies of proximal tubule reabsorption have failed to distinguish conclusively between a separate active K+ transport system and K+ movement linked to Na+ reabsorption. To attempt to dissociate movement of K+ from Na+ and Ca++, recollection micropuncture experiments were performed in proximal tubules of intact and thyroparathyroidectomized (TPTX) dogs under two different conditions known to inhibit Na+ reabsorption: saline expansion to 5% body wt, and 5 mg/kg acetazolamide. A control hydropenic group was also studied. Tubular concentrations of K+, Na+, and Ca++ were measured by electron probe analysis. During initial collections, mean±SEM tubular fluid/plasma (TF/P)K+ was 1.07 ±0.05, 1.05±0.05, and 1.00±0.03 in intact hydropenic (n = 7), saline (n = 6), and acetazolamide (n = 8) groups; fractional reabsorption (FR) of K+ in proximal tubules was 0.35, 0.39, and 0.31 respectively. After saline, (TF/P)Inul in fell from 1.81 to 1.34 (P < 0.01); (TF/P)K+, (TF/P)Na+, and tubular fluid/ultrafiltrate, (TF/UF)Ca++ did not change, so that FR of all three ions fell proportionately. After acetazolamide, however, despite a 24% inhibition of FR of Na+ and Ca++, (TF/P)K+ fell to 0.85±0.04 (P < 0.005) so that FR of K+ was unchanged at 0.34.

Authors

Laurence H. Beck, Dorothy Senesky, Martin Goldberg

The Effects of Colestipol Resin and of Colestipol Plus Clofibrate on the Turnover of Plasma Cholesterol in Man

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Abstract

Studies were conducted to determine the effects of colestipol hydrochloride, a new bile acid-sequestrant resin, on some of the parameters of cholesterol turnover and metabolism in man. Three normal volunteers and eight hyperlipidemic patients participated in three sets of cholesterol turnover studies carried out at intervals of approximately 1 yr. The effects of colestipol were assessed by comparing the results obtained before therapy with those obtained on repeat study after several months of resin therapy. Colestipol treatment significantly reduced the serum cholesterol concentration (mean reduction 21%), and produced a large increase in the production rate of cholesterol (mean 86%) and in the turnover rate of cholesterol in pool 1 (mean 46%). The values of the intercompartmental rate constants and of the size of the rapidly exchangeable pool were unchanged with therapy.

Authors

DeWitt S. Goodman, Robert P. Noble, Ralph B. Dell

Calcium-Mobilizing Effect of Large Doses of 25-Hydroxycholecalciferol in Anephric Rats

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Abstract

The effect of high doses of 25-hydroxycholecalciferol on plasma calcium concentration was studied in rats receiving a low-calcium normal vitamin D diet. In bilaterally nephrectomized animals, as in sham-operated controls, 62.5 nmol of 25-hyroxycholecalciferol did not produce a rise of plasma calcium concentration. In contrast, the administration of 125 or 625 nmol, doses 1,000-5,000 times the minimal active dose in D-deficient rats, was followed in both groups of animals by a significant increase of plasma calcium concentration. Removal of either parathyroids alone or parathyroid and thyroid glands did not suppress this effect. These data suggest that when large doses are used in vivo, the renal conversion of 25-hydroxycholecalciferol to more polar metabolites is not an obligatory step for its calcium-mobilizing action. The present study does not elucidate, however, the exact mechanism(s) of this effect.

Authors

Henriette Pavlovitch, Michele Garabedian, Sonia Balsan

Acute Changes in Oxyhemoglobin Affinity EFFECTS ON OXYGEN TRANSPORT AND UTILIZATION

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Abstract

It has been postulated that 2,3-diphosphoglycerate (DPG)-mediated changes in oxyhemoglobin affinity play an important role in oxygen delivery; however, the effect of an acute increase in affinity without changing red cell mass has not been systematically evaluated. This study was designed to measure changes in oxygen transport and oxygen consumption produced by an acute increase in oxyhemoglobin affinity caused by an autologous exchange transfusion using DPG-depleted stored blood.

Authors

Thomas E. Riggs, A. William Shafer, Clarence A. Guenter