Turnover of plasma cholesterol in man

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Abstract

Cholesterol-4-14C was injected intravenously into a series of normal men, untreated hyperlipidemic patients, and hyperlipidemic patients being treated with cholestyramine. The specific radioactivity of plasma total cholesterol was measured during the ensuing 10 wk. 16 studies were carried out in 10 subjects. Analysis of the turnover curves of plasma cholesterol revealed that in every study the turnover of plasma cholesterol conformed to a two-pool model. Each turnover curve was analyzed in terms of this model, as expressed by the equation: specific activity = CAe-αt + CBe-βt. The parameters which were calculated included the constants CA, CB, α, and β; the size of the first pool (MA); the rate constants for the total rate of removal of cholesterol from each pool (kAA and kBB); and the production rate in pool A (PRA). In two normal men and five untreated patients the average size of pool A was 25g.

Authors

DeWitt S. Goodman, Robert P. Noble

The renal tubular handling of aldosterone and its acid-labile conjugate

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Abstract

Stop-flow studies using infusions of aldosterone-3H or its 3H acid-labile conjugate were done on five rhesus monkeys. The aldosterone-3H urine-to-plasma (U/P) ratio decreased in the same distal urine samples as sodium. The 3H acid-labile conjugate U/P-to-inulin U/P ratio increased in the more proximal samples either with conjugate formed endogenously during aldosterone-3H infusions or with labeled conjugate infused alone. Aldosterone reabsorption occurred at a distal site in the renal tubule, and secretion of its acid-labile conjugate occurred at a proximal site.

Authors

Murphy T. Scurry, Leroy Shear, Kevin G. Barry

Leukokinetic studies: XIII. A non-steady-state kinetic evaluation of the mechanism of cortisone-induced granulocytosis

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Abstract

The mechanism by which adrenocortical steroids induce granulocytosis in man has been investigated using granulocytes labeled with radioactive diisopropylfluorophosphate.

Authors

C. R. Bishop, J. W. Athens, D. R. Boggs, H. R. Warner, G. E. Cartwright, M. M. Wintrobe

Bile salt malabsorption in regional ileitis, ileal resection, and mannitol-induced diarrhea

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Abstract

Fecal bile salt excretion was studied in healthy volunteers, patients with regional ileitis, and patients with ileal resection. 10 μc of carboxyl-14C-cholic acid was given orally. Stools and urine were collected daily for 5-10 days, the bile salts extracted, and the radioactivity assayed. Urinary excretion was negligible. All patients with ileal resection excreted bile salts in the feces significantly faster than controls, and five of the six excreted 50% of the radioactivity within 24 hr. Their mean intestinal transit time was 5.6 hr compared to 26 hr for the controls. Two of the three patients with regional ileitis excreted bile salts almost as rapidly as patients with ileal resection. Vitamin B12 absorption was also defective in those patients, but the intestinal transit time was not decreased.

Authors

Walter E. Meihoff, Fred Kern Jr.

A pathological inhibitor of fibrin cross-linking

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Abstract

Lewis et al. recently reported on a patient who died of hemorrhages attributable to an acquired inhibitor of fibrin-stabilizing factor. They indicated that the inhibitor was associated with the immune globulins. Using the postmortem serum in the isolated fibrin cross-linking system, we have now further localized the site of inhibition in the scheme of blood coagulation. The interference occurs at the transpeptidation step catalyzed by the thrombin-activated fibrin-stabilizing factor. The patient's serum also uniquely delayed the clotting time of Homarus plasma, a test for specific inhibitors of transpeptidation. Since the inhibitor was effective in two such widely different systems, it probably is not an antibody, but falls into the category of cross-linking inhibitors which we have previously described (4, 5, 10, 12-17). While the exact nature of the inhibitor remains unknown, we raise the question whether some unusual metabolic transformation of isonicotinic acid hydrazide (with which the patient was treated and which itself we found to be a potent inhibitor fibrin cross-linking), in combination with a macromolecule, might not have given rise to an inhibitory compound.

Authors

L. Lorand, A. Jocobsen, Joyce Bruner-Lorand

Effects of alpha adrenergic blockade and tissue catecholamine depletion on pulmonary vascular response to hypoxia

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Abstract

The highly reactive pulmonary vascular bed of the neonatal calf was utilized to determine whether the hypoxic pulmonary pressor response is modified by α-adrenergic blockade with phenoxybenzamine (Group A) or by tissue catecholamine depletion with reserpine (Group B). In addition, in Group A, the effects of hypoxia on the pulmonary circulation were compared and contrasted with those of l-norepinephrine (α-receptor stimulator) and isoproterenol (β-receptor stimulator).

Authors

Eric D. Silove, Robert F. Grover

The role of bile salts in controlling the rate of intestinal cholesterogenesis

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Abstract

According to current concepts, the liver and gastrointestinal tract are considered to be the major, if not the sole, sources of circulating serum cholesterol. While several mechanisms have been described which control the rate of hepatic cholesterogenesis, only biliary diversion is known to alter the rate of sterol synthesis in the intestine. The present study was designed to identify the inhibitory constituent of bile and to define its anatomic and biochemical sites of action.

Authors

John M. Dietschy

The nature of human serum insulin-like activity (ILA): characterization of ILA in serum and serum fractions obtained by acid-ethanol extraction and adsorption chromatography

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Abstract

Studies were undertaken in an attempt to clarify the apparent heterogeneous nature of human serum insulin-like activity. Methods of preparative zone electrophoresis on Pevikon, acid-ethanol extraction of trichloroacetic acid serum protein precipitates, adsorption chromatography on DEAE-cellulose and Dowex 50, gel filtration chromatography, and insulin antiserum immunoreactivity were used. The results establish the presence of a substance in serum with in vitro biological properties similar to insuln but with different physicochemical properties. The major portion of serum ILA measured by bioassay techniques can be attributed to the effects of this substance. Whereas the in vitro biological effects of this substance on muscle and adipose cells were similar to those of crystalline insulin, the substance is distinguished from insulin by: (1) the failure of insulin antiserum to inhibit its in vitro biological effect; (2) a slower electrophoretic mobility (in the gamma-beta globulin zone); and (3) a larger molecular weight, between 40,000 and 50,000 in these studies. It is similar to insulin since both are soluble in acid-ethanol. The results further indicate that previously described insulin-like activity in gamma-beta globulin preparations, the major portion of total serum insulin activity described in acid-ethanol extracts of serum, “bound” insulin, “atypical” insulin, and antibody nonsuppressible insulin-like activity bioassayed in diluted serum are all one and the same substance.

Authors

Philip L. Poffenbarger, John W. Ensinck, Dieter K. Hepp, Robert H. Williams

Study of the Hurler syndrome using cell culture: definition of the biochemical phenotype and the effect of ascorbic acid on the mutant cell

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Abstract

Fibroblasts from patients with Hurler syndrome retain a distinctive biochemical phenotype when grown in culture which is characterized by increased synthesis of both nonsulfated and sulfated glycosaminoglycans. Ascorbic acid reinforces the phenotypic expression of the biochemical abnormality, producing not only increased synthesis of sulfated glycosaminoglycans, but selective retention of sulfated glycosaminoglycans within the cell. Although the synthesis of nonsulfated glycosaminoglycans is also increased, these compounds, particularly hyaluronic acid are not retained by the cell but are secreted into the medium.

Authors

Irwin A. Schafer, Julia C. Sullivan, Jiri Svejcar, Jorge Kofoed, William Van B. Robertson

The influence of saline loading on renal glucose reabsorption in the rat

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Abstract

Glucose titration studies were performed in normal rats under control conditions and during expansion of the extracellular fluid volume. In association with expansion, the maximal rate of glucose transport (Tmglucose) decreased while glomerular filtration rate (GFR) typically increased; thus there was a consistent increase in the GFR/Tmglucose ratio. In previous studies, marked reduction of the nephron population was associated with an alteration in the kinetics of glucose transport and GFR/Tmglucose ratios were observed to increase. In both volume-expanded rats and in animals and human beings with uremia, the splay in the titration curve is increased. Finally in both volume-expanded animals and uremic animals fractional reabsorption of sodium is depressed. One interpretation of the present data is that the natriuretic “third factor” may influence a key rate-limiting step in glucose transport; and it is possible that this step is shared by or coupled to a rate-limiting step in sodium transport.

Authors

Alan M. Robson, Prem L. Srivastava, Neal S. Bricker

Surface tension, metabolic activity, and lipid composition of alveolar cells in washings from normal dog lungs and after pulmonary artery ligation: Importance of a highly surface-active acellular layer

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Abstract

Lung-washings from mammalian species are a rich source of surfactant and of cells, predominantly alveolar macrophages, that could be important in the metabolism of the surfactant. We obtained washings from normal dogs, and from dogs that had had one pulmonary artery (PA) ligated 1 or 2 days earlier. Centrifugation of wash (400 × g for 20 min) separated a sediment, made up of cells at the bottom and a white layer, largely acellular, from the supernatant. The volume of sediment averaged 2.1 ± 1.4 ml,. 75% of which was white layer. The cells resembled the large alveolar (type II) cells found in the lung; however they differed by at least one major histochemical reaction. The white layer had greater surface activity than the cells or the supernate, and was richest in phospholipids and lecithin. The cells lost their surface activity when rinsed and resuspended. These observations suggest that surfactant is normally present, mainly in an acellular fraction and possibly at the surface of the alveolar cells. The alveolar macrophages may either store surfactant, rather than synthesize it, or simply acquire a coat of surfactant during sedimentation. After PA ligation, the earliest abnormality was a decrease in the white layer; the cells were fewer, smaller, and weaker in metabolic activity.

Authors

Sami I. Said, William R. Harlan Jr., George W. Burke, Charles M. Elliott

Glycogen in human peripheral blood leukocytes: I. Characteristics of the synthesis and turnover of glycogen in vitro

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Abstract

In the present paper a model system is described utilizing suspensions of peripheral blood leukocytes in which glycogen synthesis and degradation can be studied.

Authors

Robert B. Scott

Glycogen in human peripheral blood leukocytes: II. The macromolecular state of leukocyte glycogen

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Abstract

Glycogen of normal human blood leukocytes was studied in cell suspensions containing chiefly neutrophiles.

Authors

Robert B. Scott, W. J. S. Still

Genetic variants of hemophilia B: detection by means of a specific PTC inhibitor

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Abstract

Hemophilia B can be divided into at least two mutant forms different from the mild, moderate, and severe categories previously described. In about 90% of hemophilia B patients, PTC-inhibitor-neutralizing activity is reduced in proportion to PTC clotting activity. In about 10% of the patients, PTC-inhibitor-neutralizing activity is fully effective, whereas PTC clotting activity is reduced. Extensive pedigree studies indicate that the presence or absence of inhibitor-neutralizing activity is genetically determined. It is suggested that those hemophilia B mutants with decreased inhibitor-neutralizing material produce decreased amounts of PTC-protein. It is further suggested that those with normal levels of inhibitor-neutralizing material produce normal amounts of PTC-protein, which is structurally altered so as to lose procoagulant activity but which retains inhibitor-neutralizing activity. The latter group may be analogous to CRM+ mutants described in bacteria and Neurospora.

Authors

Harold R. Roberts, James E. Grizzle, William D. McLester, George D. Penick

Alveolar cells: incorporation of carbohydrate into protein and evidence for intracellular protein transport

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Abstract

Alveolar cells incubated with radioactive glucosamine, galactose, and mannose incorporate radioactivity into protein, that is, into material insoluble in cold and hot trichloroacetic acid and not extracted by lipid solvents. This incorporation is incompletely inhibited by puromycin hydrochloride. The kinetics of the subcellular distribution of radioactivity are consistent with a precursor-product relationship between microsomal protein and the protein of particles sedimenting at 15,000 g. It is thus suggested that alveolar cells incorporate these substrates intact into protein at the microsomal level with subsequent transfer of this newly formed material to particles sedimenting at 15,000 g.

Authors

Donald Massaro

Control of myocardial oxygen consumption: relative influence of contractile state and tension development

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Abstract

Myocardial oxygen consumption was measured in 11 anesthetized, open-chest dogs in order to compare in the same heart the relative influence on oxygen usage of tension development and the contractile or inotropic state, as reflected in Vmax. the maximum velocity of shortening of the unloaded contractile elements. The isovolumetrically contracting left ventricle was studied with left ventricular volume, heart rate, and systemic perfusion rate controlled. Wall tension, contractile element velocity, and Vmax were calculated. Peak developed tension was increased at a constant Vmax by increasing ventricular volume, and the effect on oxygen consumption was determined. Oxygen utilization was then redetermined at an increased Vmax but at a constant peak developed tension by infusing norepinephrine (0.76 to 7.6 μg/min) and decreasing ventricular volume to match the tension existing before norepinephrine infusion. Oxygen consumption consistently increased with increases in both developed tension and Vmax with the following multiple regression equation relating these variables: myocardial oxygen consumption (μl/beat per 100 g in LV) = K + 0.25 peak developed tension (g/cm2) + 1.43 Vmax (cm/sec). These data indicate that the oxygen cost of augmentation of contractility is substantial, can be independent of any change in fiber shortening, and is similar in order of magnitude to the effect of alterations in tension development

Authors

Thomas P. Graham Jr., James W. Covell, Edmund H. Sonnenblick, John Ross Jr., Eugene Braunwald

Quantitative immunological determination of 12 plasma proteins excreted in human urine collected before and after exercise

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Abstract

Urine was collected from 6 healthy male adults at rest and from 20 male adults after a marathon race (25 miles). The concentrated urines were quantitatively analyzed, by single radial immunodiffusion, for their content in 12 different plasma proteins: tryptophan-rich prealbumin, albumin, α1-acid glycoprotein, α1-antitrypsin, ceruloplasmin, haptoglobin, Gc-globulin, transferrin, hemopexin, β2-glycoprotein I, γA-globulin, and γG-globulin.

Authors

Jacques Poortmans, Roger W. Jeanloz

Fat-mobilizing action of amphetamine

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Abstract

The effects of amphetamine and methamphetamine on plasma free fatty acid (FFA), blood glucose, serum total fat, and triglyceride concentrations were investigated in 21 subjects; the effect of epinephrine were studied in an identical manner in 14 subjects.

Authors

E. J. Pinter, C. J. Pattee

Role of anaerobic metabolism in the preservation of functional capacity and structure of anoxic myocardium

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Abstract

Employing an isolated perfused rat heart preparation, we investigated the contribution of anaerobic metabolic energy to the performance, recoverability, and ultrastructure of the heart perfused at 32°C in 5% albumin in Krebs-Ringer Bicarbonate solution. During exposure to anoxia for 30 min, inclusion in the perfusate of the anaerobic substrate, glucose, resulted in marked improvement in electrical and mechanical performance of the heart and in enhanced recovery during the subsequent period of reoxygenation. Lactate production was fivefold greater in the glucose-supported anoxic heart than in the anoxic heart without glucose. Electron microscope sections of the hearts exposed to anoxia in the absence of glucose revealed alterations in mitochondrial morphology and dilatation of the longitudinal tubules. These morphologic changes during anoxia were averted by inclusion of glucose in the perfusion fluid. The data are consistent with the hypothesis that anaerobic energy generation plays a significant role in preserving myocardial function and structure and in promoting recoverability of the anoxic mammalian heart.

Authors

Arnold M. Weissler, Fred A. Kruger, Nobuhisa Baba, Dante G. Scarpelli, Richard F. Leighton, Judith K. Gallimore

Absorption of l-methionine from the human small intestine

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Abstract

Absorption of L-methionine was measured in all parts of the human small intestine using transintestinal intubation and perfusion. In four normal subjects, adsorption was higher in the proximal than in the distal intestine. In two patients with nontropical sprue in relapse, there was a proximal zone of low absorption with higher absorption distally. In all parts of the small intestine, absorption showed rate-limiting kinetics as methionine concentration was increased. In normal subjects, the proximal Km (Michaelis constant) was more than 3 times higher than the distal, which suggests a difference in transport mechanisms between the two segments.

Authors

Harold P. Schedl, Charles E. Pierce, Alan Rider, James A. Clifton