Studies on the Protein Defect in Tangier Disease: ISOLATION AND CHARACTERIZATION OF AN ABNORMAL HIGH DENSITY LIPOPROTEIN

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High density lipoproteins (d 1.063-1.210 g/ml) were isolated from the plasma of normal individuals (HDL) and seven homozygous patients with Tangier disease (HDLt). In Tangier patients, the concentration of protein in the high density region (HDLt) was only 0.5-4.5% of normal. Immunochemical studies, including mixing experiments conducted in vivo and in vitro, indicated that HDLt was different from HDL. HDLt was the only high density lipoprotein detectable in the plasma of Tangier homozygotes. In heterozygotes both HDL and HDLt were present. HDLt was not detected in the plasma of over 300 normal persons and 10 patients with secondary high density lipoprotein deficiency and appeared to be a unique marker for Tangier disease.

Authors

Samuel E. Lux, Robert I. Levy, Antonio M. Gotto, Donald S. Fredrickson

Oxygen Equilibrium Characteristics of Abnormal Hemoglobins: Hirose (α₂β₂^37Ser), L Ferrara (α₂^47Glyβ₂), Broussais (α₂^90Asnβ₂), and Dhofar (α₂β₂^58Arg)

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The oxygen equilibrium characteristics of four structural variants of hemoglobin A were correlated with their amino acid substitutions.

Authors

Shigeru Fujita

Decreased Red Cell Uroporphyrinogen I Synthetase Activity in Intermittent Acute Porphyria

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Intermittent acute porphyria has recently been distinguished biochemically from other genetic hepatic porphyrias by the observation of diminished hepatic uroporphyrinogen I synthetase activity and increased δ-aminolevulinic acid synthetase activity. Since deficient uroporphyrinogen I synthetase may be reflected in nonhepatic tissues, we have assayed this enzyme in red cell hemolysates from nonporphyric subjects and from patients with genetic hepatic porphyria. Only patients with intermittent acute porphyria had decreased erythrocyte uroporphyrinogen I synthetase activity which was approximately 50% of normal. The apparent Km of partially purified uroporphyrinogen I synthetase was 6 × 10−6m in both nonporphyrics and patients with intermittent acute porphyria. These data provide further evidence for a primary mutation affecting uroporphyrinogen I synthetase in intermittent acute porphyria. Further-more, results of assay of red cell uroporphyrinogen I synthetase activity in a large family with intermittent acute porphyria suggest that this test may be a reliable indicator of the heterozygous state.

Authors

L. James Strand, Urs A. Meyer, Bertram F. Felsher, Allan G. Redeker, Harvey S. Marver

The Human Rosette-Forming Cell as a Marker of a Population of Thymus-Derived Cells

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Sheep red blood cells can surround, in vitro, some human peripheral blood lymphocytes in a formation called a rosette. The number of rosetteforming cells (RFC) in 50 normal persons had a wide range (4-40%).

Authors

Joseph Wybran, Martin C. Carr, H. Hugh Fudenberg

Renal Sodium-Potassium-Activated Adenosine Triphosphatase and Sodium Reabsorption

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The role of renal Na+,K+-ATPase in sodium reabsorption was further examined in dogs in which digoxin, a specific inhibitor of the enzyme system, was infused into one renal artery in doses ranging from 0.4 to 0.9 μg/kg/min (low dose) and from 1.0 to 4.0 μg/kg/min (high dose). A significant natriuresis occurred with both dose ranges which was accompanied by inhibition of Na+,K+-ATPase of cortex and medulla in the infused kidney. Despite over 90% enzyme inhibition in many experiments, at least 80% of the filtered sodium continued to be reabsorbed. The per cent change in enzyme activity correlated with the rate of digoxin administration and the total dose administered but not with changes in sodium excretion. Changes in medullary Na+,K+-ATPase activity, however, bore a direct relationship to alterations in fractional solute free water reabsorption (TcH2O). Inhibition of cortical enzyme activity alone was not associated with natriuresis, suggesting that medullary enzyme activity must be depressed for increased sodium excretion to occur during digoxin infusion. In high-dose experiments, significant inhibition of cortical and medullary enzyme in the contralateral control kidney was also observed, but natriuresis did not occur. In these experiments the rate at which digoxin reached the control kidney rose progressively but never equaled the rates in the directly infused kidney with either dose. Nevertheless, it is clear that under certain circumstances enzyme inhibition of either cortex or medulla need not be accompanied by natriuresis. We conclude that the major role of renal Na+,K+-ATPase is in sodium reabsorption in the medulla (ascending limb of Henle's loop) and that it has a relatively small role in proximal sodium reabsorption. The kidney can rely on other sodium reabsorptive mechanisms depending on the rate of enzyme inhibition, so that natriuresis may not occur at all if depression in activity occurs “slowly.” The nature of these mechanisms is not clear.

Authors

M. Martinez-Maldonado, J. C. Allen, C. Inagaki, N. Tsaparas, A. Schwartz

Effects of Androgen Treatment on the Male Rat Aorta

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Androgen was given to male rats to determine if it exerted effects on the aortic wall distinct from those of estrogen deficit. Although a general anabolic effect was avoided, significant vascular effects were observed. The amounts of mural fibrous proteins, elastin and collagen, were significantly increased in treated animals; noncollagenous, alkali-soluble protein, thought to reflect the cellular component, was unchanged with treatment. These effects were not detectable on microscopic examination and measurement of the vessel wall despite attempts to duplicate closely in vivo wall dimensions before study. These findings of distinct and marked effects of androgen on vascular metabolism extend the growing evidence for an important role of sex hormones in vessel wall structure and function.

Authors

Harvey Wolinsky

Myocardial Blood Flow in Man: Effects of Coronary Collateral Circulation and Coronary Artery Bypass Surgery

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The effects of coronary artery bypass graft (CAB) and coronary collaterals (CC) on myocardial blood flow (MBF) were studied in 24 patients undergoing 29 CAB's. MBF after CAB was compared to preexisting MBF by intraoperatively injecting 133xenon via distal CAB with proximal CAB first occluded then open. Pressure gradients across bypassed obstructions were measured. The results were correlated with preoperative coronary arteriograms to determine the effects of CC on MBF and postobstructive perfusion pressures. Mean MBF was increased by CAB from 32±6 (se) ml/min per 100 g (CAB occluded) to 118±13 ml/min per 100 g (CAB open). The 133Xe clearance curves with CAB open were resolved into slow (19±2 ml/min per 100 g) and rapid (133±12 ml/min per 100 g) phases, suggesting that MBF remained heterogeneous after CAB. Vessels with less than 80% stenosis by angiography had pressure gradients less than 20 mm Hg across obstructions, high postobstructive perfusion pressures (75±7 mm Hg), and normal MBF (87±6 ml/min per 100 g) even with CAB occluded. Vessels with greater than 80% stenosis or total occlusion by angiography had significant pressure gradients with marked reduction of postobstructive MBF. No significant difference in postobstructive MBF was found when vessels with CC (21±4 ml/min per 100 g) were compared to those without CC (17±4 ml/min per 100 g) (P > 0.4).

Authors

Sidney C. Smith Jr., Richard Gorlin, Michael V. Herman, Warren J. Taylor, John J. Collins Jr.

Functional Aspects of a Second Mechanism of Candidacidal Activity by Human Neutrophils

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We tested the ability of human neutrophils to kill five Candida species and the yeast Torulopsis glabrata. C. parapsilosis and C. pseudotropicalis were found to be killed readily by normal and myeloperoxidase-deficient neutrophils and were selected to probe the myeloperoxidase-independent fungicidal mechanisms of the neutrophil.

Authors

Robert I. Lehrer

The Anrep Effect Reconsidered

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Evidence is presented supporting the hypothesis that the positive inotropic effect after an abrupt increase in systolic pressure (Anrep effect) is the recovery from subendocardial ischemia induced by the increase and subsequently corrected by vascular autoregulation of the coronary bed. Major evidence consists of data obtained from an isolated heart preparation showing that the Anrep effect can be abolished with coronary vasodilation, and that with an abrupt increase in systolic pressure there is a significant reduction in the distribution of coronary flow to subendocardial layers of the ventricle. Furthermore, the intracardiac electrocardiogram shows S-T segment and T wave changes after an abrupt increase in ventricular pressure similar to that noted after coronary constriction. Major implications are that normally there may be ischemia of the subendocardial layers tending to reduce myocardial contractility which may account, in part, for the positive inotropic effect of various coronary vasodilators; that with an abrupt increase in ventricular pressure the subendocardium is rendered temporarily ischemic, placing the heart in jeopardy from arrhythmias until this is corrected; and that end-diastolic pressure and the intracardiac electrocardiogram may provide a means of evaluating the adequacy of circulation to subendocardial layers in diseased ventricles when systolic pressure is abruptly increased.

Authors

R. G. Monroe, W. J. Gamble, C. G. Lafarge, A. E. Kumar, J. Stark, G. L. Sanders, C. Phornphutkul, M. Davis

Cholesterol Metabolism and Placental Transfer in the Pregnant Rhesus Monkey

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The placental transfer of cholesterol (5-cholesten-3β-ol) was investigated by giving pregnant rhesus monkeys cholesterol-1α-3H or cholesterol-4-14C and then determining the cholesterol specific activity (SA) in maternal serum and in fetal serum and tissues. An isotopic steady state was established in five pregnant animals by the daily feeding of a tracer dose of cholesterol-4-14C. Comparison of maternal and fetal serum cholesterol SA revealed that an average of 42.6% of the serum cholesterol in the term fetus originated by transfer from the maternal blood. The remainder presumably arose by fetal synthesis de novo. Fetal tissues had cholesterol SA equal to or slightly less than that of fetal serum, except for brain which had a SA only 5% that of fetal serum.

Authors

Roy M. Pitkin, William E. Connor, Don S. Lin

Studies on the Response of Patients with Classic Hemophilia to Transfusion with Concentrates of Antihemophilic Factor: A DIFFERENCE IN THE HALF-LIFE OF ANTIHEMOPHILIC FACTOR AS MEASURED BY PROCOAGULANT AND IMMUNOLOGIC TECHNIQUES

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Antihemophilic factor (AHF, factor VIII) levels were measured by a standard coagulation method and by an immunologic technique before and after infusion of AHF concentrates into patients with classic hemophilia. After infusion of AHF concentrates, the half-life of the AHF procoagulant (i.e., clot-promoting) activity varied from 12 to 14 hr, whereas that of the antigen ranged from 24 to 40 hr. The half-life of the antigen was similar in patients with and without circulating anticoagulants to AHF. The data are compatible with the suggestion that the antigen may be carried on a precursor molecule which the patient with hemophilia produces but cannot convert to the functional clot-promoting agent. Other explanations of the observations are, however, recognized.

Authors

Bruce Bennett, Oscar D. Ratnoff

Immunologic Studies in von Willebrand's Disease: EVIDENCE THAT THE ANTIHEMOPHILIC FACTOR (AHF) PRODUCED AFTER TRANSFUSIONS LACKS AN ANTIGEN ASSOCIATED WITH NORMAL AHF AND THE INACTIVE MATERIAL PRODUCED BY PATIENTS WITH CLASSIC HEMOPHILIA

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Antihemophilic globulin (AHF, factor VIII) levels were measured by a standard coagulation assay and by an immunological technique before and serially after infusion of fresh frozen plasma or cryoprecipitate into patients with von Willebrand's disease. Initial levels of AHF, measured both as procoagulant and as antigen, were low. Immediately after transfusions, the rise in levels of AHF-like antigen was compatible with the quantity of antigen present in the infused plasma or cryoprecipitate. Thereafter, levels of antigen declined rapidly and reached preinfusion values in approximately 24 hr. In contrast, procoagulant activity remained elevated, and sometimes continued to rise, for longer periods of time. One possible explanation of this finding is that the AHF molecule produced by patients with von Willebrand's disease, in response to transfusion of as yet unidentified factors, lacks the antigenic site associated with the normal AHF molecule or the inactive molecule produced by patients with hemophilia A.

Authors

Bruce Bennett, Oscar D. Ratnoff, Jack Levin

Studies on Human Platelet Gangliosides

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Gangliosides, glycosphingolipids which contain sialic acid, were studied in human platelets. They represented 0.5% of the platelet lipids and accounted for 6% of the total neuraminic acid content of platelets. Three major ganglioside fractions were identified and characterized. Ganglioside I was hematoside (G6) and comprised 92% of the platelet gangliosides. It contained glucose, galactose, and sialic acid in molar ratios of 1:1:1 and no hexosamine. The major fatty acid was behenate (22:0). Ganglioside I was also identified in isolated platelet granules and membranes. Ganglioside II (5%) contained glucose, galactose, sialic acid, and hexosamines (molar ratios 1:2:1:1). The hexosamines were glucosamine (72%) and galactosamine (28%). It was therefore designated as ganglioside lacto-N-neotetraose. Ganglioside III (2%) contained disialosyllactosyl ceramide (G3A) as well as two other gangliosides which could not be precisely characterized. Gangliosides I, II, and III were susceptible to the action of Clostridium perfringens neuraminidase as evidenced by full recovery of sialic acid in its free form after incubation. Neutral platelet glycolipids were qualitatively examined by thin-layer chromatography. The major component was lactosyl ceramide.

Authors

Aaron J. Marcus, Harris L. Ullman, Lenore B. Safier

Mechanism of the Antidiuretic Effect Associated with Interruption of Parasympathetic Pathways

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The present experiments were undertaken to investigate the mechanism whereby the parasympathetic nervous system may be involved in the renal regulation of solute-free water excretion. The effects of interruption of parasympathetic pathways by bilateral cervical vagotomy were examined in eight normal and seven hypophysectomized anesthetized dogs undergoing a water diuresis. In the normal animals cervical vagotomy decreased free-water clearance (CH2O) from 2.59±0.4 se to −0.26±0.1 ml/min (P < 0.001), and urinary osmolality (Uosm) increased from 86±7 to 396±60 mOsm/kg (P < 0.001). This antidiuretic effect was not associated with changes in cardiac output, renal perfusion pressure, glomerular filtration rate, renal vascular resistance, or filtration fraction and was not affected by renal denervation. A small but significant increase in urinary sodium and potassium excretion was observed after vagotomy in these normal animals. Pharmacological blockade of parasympathetic efferent pathways with atropine, curare, or both was not associated with an alteration in either renal hemodynamics or renal diluting capacity. In contrast to the results in normal animals, cervical vagotomy was not associated with an antidiuretic effect in hypophysectomized animals. CH2O was 2.29±0.26 ml/min before and 2.41±0.3 ml/min after vagotomy, and Uosm was 88±9.5 mOsm/kg before vagotomy and 78±8.6 mOsm/kg after vagotomy in the hypophysectomized animals. Changes in systemic or renal hemodynamics or electrolyte excretion were also not observed after vagotomy in these hypophysectomized animals. On the basis of these results, we conclude that the antidiuretic effect associated with cervical vagotomy is initiated by interruption of parasympathetic afferent pathways and is mediated by increased endogenous release of vasopressin. This antidiuresis was also demonstrated to occur in the absence of renal nerves and alterations in systemic and renal hemodynamics.

Authors

Robert W. Schrier, Tomas Berl, Judith A. Harbottle

The Relation of Size to the Relative Rates of Degradation of Intestinal Brush Border Proteins

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Proteins associated with intestinal brush borders and their various fractions were solubilized with sodium dodecyl sulfate and β-mercaptoethanol, and separated by electrophoresis on acrylamide gels containing sodium dodecyl sulfate. Brush borders contain at least 15 proteins or subunits, ranging in molecular weight from 19,000 to 270,000. The largest proteins (170-270,000 mol wt), including the disaccharidases, are removed from the brush borders by papain. Proteins belonging to the remaining membrane, including alkaline phosphatase, have an intermediate size (53-140,000 mol wt). The proteins corresponding to the filamentous “core” of the microvilli are the smallest (19-45,000).

Authors

David H. Alpers

A Humoral Component of the Natriuretic Mechanism in Sustained Blood Volume Expansion

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A natriuretic and diuretic response to whole blood infusion in the rat, exaggerated and sustained by intravenous reinfusion of excreted urine, was shown to be associated with increased glomerular filtration and reduced tubular reabsorption. Cross-circulation of animals so responding (donor rats) with isovolemic recipients led to a modest natriuretic and diuretic response in the latter, not accounted for by altered physical composition of the blood nor by observed changes in filtration rate or arterial blood pressure. The recipient natriuresis was unchanged when nephrectomized donors were used and it occurred in experiments in which donor urine was simultaneously replaced by intravenously infused Ringer-Locke solution; the natriuretic property of the cross-circulating blood could therefore not have been due to reinfusion of urinary constituents, nor to accumulation of metabolites, nor to a factor of renal origin. A recipient natriuresis was also observed when the expanded and urine reinfused donor had been acutely adrenalectomized, ruling out an altered secretion of adrenal cortical or medullary hormones as a principal cause of this natriuresis; the data, however, do not exclude participation of reduced aldosterone secretion in the normal effector mechanism. In control experiments in which whole blood was exchanged for donor blood, a small delayed natriuresis did occur in the recipient; this could be completely prevented by administration of aldosterone. In similar exchange experiments with adrenalectomized donors, a small natriuresis developed in the recipient before blood administration but declined afterwards. These minor natriuretic effects probably resulted from altered mineralocorticoid content of the cross-circulating blood due to factors other than blood volume change. The larger natriuretic response seen in all recipients when the donor was volume expanded must have been due largely to a humoral natriuretic factor of other than renal or adrenal origin.

Authors

Harald Sonnenberg, Anthony T. Veress, James W. Pearce

Studies of the Control of Plasma Aldosterone Concentration in Normal Man: III. RESPONSE TO SODIUM CHLORIDE INFUSION

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The peripheral plasma levels of aldosterone, renin activity, potassium, sodium, corticosterone, and cortisol were measured in six normal subjects four times daily—10 a.m., 2 p.m., 5 p.m., 11 p.m.—on 3 consecutive days. A constant daytime activity program was maintained throughout the study. After 5 days on a 10 mEq sodium/100 mEq potassium isocaloric intake, the mean upright 10 a.m. plasma renin activity was 1773±186 ng/100 ml per 3 hr and the mean plasma aldosterone, 81±14 ng/100 ml. These two parameters fell continuously throughout the day parallel to the fall in plasma cortisol and corticosterone. In response to 2 liters of normal saline infused from 10 a.m. to 2 p.m. on 2 consecutive days, plasma aldosterone levels fell significantly to 13±5 ng/100 ml at 2 p.m. after the 1st day's infusion and to 6±1 ng/100 ml at 2 p.m. after the 2nd. Plasma renin activity demonstrated a parallel fall to 368±63 ng/100 ml per 3 hr and 189±27 ng/100 ml per 3 hr at 2 p.m. on the 1st and 2nd days, respectively. There was no significant alteration in plasma levels of cortisol, corticosterone, potassium, or sodium on the 2 days of sodium loading in comparison with the control day. In an additional study, five normal supine subjects received 500 ml saline/hr for 6 hr. As in the 2 day study, plasma aldosterone and renin activity had parallel decrements at 1, 2, 4, and 6 hr after the start of the saline infusion. From these studies, it is concluded that plasma renin activity is the dominant factor controlling plasma aldosterone when sodium-depleted normal subjects are acutely repleted.

Authors

Gordon H. Williams, Michael L. Tuck, Leslie I. Rose, Robert G. Dluhy, Richard H. Underwood

Carbonic Anhydrase Function and the Epithelial Organization of H⁺ Secretion in Turtle Urinary Bladder

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The function of carbonic anhydrase in H+ secretion by the turtle bladder was studied in vitro. Dose response curves were obtained for the carbonic anhydrase inhibitors, acetazolamide and ethoxzolamide, with and without addition of CO2 to the system. In addition, carbonic anhydrase was assayed in homogenates of mucosal cells. The activity in the homogenates was 155±16 U/g dry wt, of which only 11 U represented contamination from erythrocytes; after addition of 5 × 10−6m acetazolamide, no enzyme activity was detectable.

Authors

John H. Schwartz, Seymour Rosen, Philip R. Steinmetz

The Pathogenesis of Esophageal Dysfunction in Scleroderma and Raynaud's Disease

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To determine the pathogenesis of esophageal dysfunction in scleroderma and Raynaud's disease, the lower esophageal sphincter (LES) was tested with: (a) methacholine acting directly at the cholinergic receptor on the muscle; (b) edrophonium, a cholinesterase inhibitor, enhancing the effect of released acetylcholine; and (c) gastrin I, acting through the release of acetylcholine. 10 patients with Raynaud's disease and 22 patients with scleroderma were compared with 20 normals and 20 patients with isolated LES incompetence. The mean basal LES pressure in normals was significantly greater than that recorded in both patients with scleroderma and Raynaud's disease. Six patients having scleroderma with normal peristalsis had an LES pressure significantly greater than that noted in 16 patients having scleroderma with abnormal peristalsis. In all groups, the per cent increase in LES pressure was similar when tested by direct muscle stimulation by methacholine. The response to agents that acted indirectly through intact cholinergic nerves differed in these groups. The LES response to gastrin I distinguished patients with normal peristalsis from those with abnormal peristalsis. The patients with normal peristalsis, either with scleroderma or with Raynaud's disease showed only a partial reduction in their response to gastrin I. The response to gastrin I was markedly reduced only in patients with abnormal peristalsis. These data indicate that in patients with scleroderma and Raynaud's disease, the LES response to direct muscle stimulation by methacholine was intact while the response to gastrin I and edrophonium was diminished.

Authors

Sidney Cohen, Robert Fisher, William Lipshutz, Robert Turner, Allen Myers, Ralph Schumacher

Cellular Immunity to Nuclear Antigens in Systemic Lupus Erythematosus

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Cellular immune repsonses were determined by skin testing and mitogen- and antigen-induced blastic transformation of peripheral blood lymphocyte cultures in 24 patients with systemic lupus erythematosus (SLE) and 24 normal subjects. The incidence of positive skin tests with Candida albicans, PPD (tuberculin-purified protein derivative) intermediate strength, Trichophyton and histoplasmin was not significantly different in the two groups nor was lymphocyte stimulation by the mitogen phytohemagglutinin-M (PHA-M), implying that cellular immunity is normal in SLE. However, the SLE patients had a significantly increased incidence of positive skin tests and stimulated lymphocyte cultures to a number of nuclear antigens compared with normal subjects. No correlation could be made between the test results and the activity of the SLE at the time of study except for a significant association between lymphocyte culture stimulation by rabbit thymus native DNA and active SLE nephritis. Patients with a membranous antinuclear factor (ANF) pattern had positive skin tests with rabbit thymus native DNA and usually had active disease.

Authors

John A. Goldman, Allen Litwin, Louis E. Adams, Robert C. Krueger, Evelyn V. Hess

Effects of Heparin and ε-Aminocaproic Acid in Dogs on Plasmin- ¹²⁵I Generation in Response to Urokinase Injections and Venous Injury

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The isotopic method described previously for quantification of plasmin- 125I by disc gel electrophoresis was modified by inclusion of euglobulin precipitation to expand its applicability to plasmas containing low radioactivity of plasmin- 125I and plasminogen- 125I. It was found that the euglobulin precipitation method precipitates 72.4±2.1 (sd)% of both plasmin- 125I and plasminogen- 125I. Using this method and plasminogen- 125I as a tracer, studies were first made of the effects of heparin and ε-aminocaproic acid in dogs on plasmin- 125I generation in responese to a single injection of urokinase and to venous injury; second, of the effects of venous occlusion and thrombosis on plasmin- 125I generation; and third, in vitro studies of plasminogen- 125I affinity to fibrin and its activation in blood clots. The venous injury was produced by the damage of venous endothelium by an injection of 90% phenol and the thrombosis by a thrombin injection into an occluded vein. Heparin and ε-aminocaproic acid under the present experimental conditions inhibited about 78 and 100%, respectively of plasmin- 125I generation by the urokinase injection. Similar inhibitory effects of heparin and ε-aminocaproic acid were observed on plasmin- 125I generation in response to venous injury. The venous occlusion caused a small degree of plasmin- 125I generation, but thrombin thrombosis did not seem to stimulate the generation of plasmin- 125I. The in vitro studies showed that plasminogen- 125I does not have a specific affinity to fibrin and is incorporated into blood clots in approximately equal concentrations as those in serum during clotting processes, and that blood clots per se do not stimulate plasmin- 125I generation. These results suggest that injured veins release considerable amounts of vascular plasminogen activators into circulation and that these play an important role in thrombus dissolution in vivo.

Authors

Y. Takeda, T. R. Parkhill, M. Nakabayashi

The Transport of Exogenous Cholesterol in the Rabbit: I. ROLE OF CHOLESTEROL ESTER OF LYMPH CHYLOMICRA AND LYMPH VERY LOW DENSITY LIPOPROTEINS IN ABSORPTION

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Thoracic lymph duct cannulations were performed shortly after a meal in rabbits trained to ingest a moderate fat, low cholesterol diet. A tracer dose of cholesterol-3H was administered to label exogenous (dietary) cholesterol during absorption. Sequential lymph samples were collected up to 24 hr postprandially, after which ultracentrifugal fractionation of lymph lipoproteins was carried out. The d < 1.006 lipoproteins were separated into two classes, chylomicra and very low density lipoproteins (VLDL).

Authors

L. L. Rudel, M. D. Morris, J. M. Felts

Critical Role of the Carbohydrate Side Chains of Collagen in Platelet Aggregation

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The reaction between human platelet membrane glucosyl transferase and collagen has recently been proposed as the mechanism for pletelet-collagen adhesion. Collagen contains glucosyl-galactose and galactose side chains linked through the galactose to hydroxylysine. Oxidation of the 6-hydroxymethyl position of the galactosyl residue to aldehydes with galactose oxidase completely abolishes platelet aggregation. This enzymatic modification of collagen can be fully reversed by reduction of the aldehydes formed by NaBH4 with complete restoration of platelet aggregating ability. Limited digestion with bacterial collagenase abolishes the ability of collagen to aggregate platelets. Removal of the N-terminal telopeptides from collagen with trypsin does not affect platelet aggregation. Tertiary structure of soluble collagen is essential for platelet aggregation. Normal collagen is less effective than lathyritic collagen, which contains only a small number of cross-links. The decreased number of aldehyde groups in the lathyritic collagen are not responsible for the increase in aggregating ability, since reduction with NaBH4 does not alter platelet aggregation. These results suggest that integrity and accessibility of the galactose receptor site may be crucial for the formation of a ternary collagenenzyme-platelet membrane complex which must precede platelet aggregation.

Authors

Carolyn McI. Chesney, Elvin Harper, Robert W. Colman

Studies of Isolated Fetal Mouse Hearts in Organ Culture: EVIDENCE FOR A DIRECT EFFECT OF TRIIODOTHYRONINE IN ENHANCING CARDIAC RESPONSIVENESS TO NOREPINEPHRINE

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Definitive confirmation or denial of the hypothesis that thyrotoxic hearts are supersensitive to catecholamines has been difficult to obtain, largely because secondary alterations in neural and humoral factors that occur after thyroid administration in vivo may obscure the primary changes induced by the hormone on the myocardium itself. To study the direct action of thyroid hormone apart from secondary factors, thyrotoxicosis should be induced in isolated hearts in vitro, but the slow onset of thyroid action plus the rapid deterioration of conventional in vitro preparations have precluded such experiments.

Authors

Kern Wildenthal, Jacquline R. Wakeland

Coronary Artery Reperfusion: I. EARLY EFFECTS ON LOCAL MYOCARDIAL FUNCTION AND THE EXTENT OF MYOCARDIAL NECROSIS

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The effects of coronary artery reperfusion 3 hr after coronary occlusion on contractile function and the development of myocardial damage at 24 hr was studied experimentally. In 14 control and 6 reperfused dogs, relationships between epicardial ST segment elevation 15 min after coronary occlusion and myocardial creatine phosphokinase activity (CPK) and histologic appearance 24 hr later were examined. The electrocardiograms were recorded from 10 to 15 sites on the left ventricular epicardium and transmural samples for CPK and histology were obtained from the same sites where epicardial electrocardiograms had been recorded. An inverse relation existed between ST segment elevation (mv) 15 min after occlusion and log CPK activity (IU/ mg of protein) 24 hr later, log CPK = − 0.06ST + 1.26. In dogs subjected to coronary artery reperfusion, there was significantly less CPK depression (log CPK = − 0.01ST + 1.31, [P < 0.01]) than that expected from the control group. In the control group 97% of specimens showing ST segment elevations over 2 mv at 15 min showed abnormal histology 24 hr later. In contrast, in the reperfused group 43% of sites exhibiting elevated ST segment at 15 min showed abnormal histology 24 hr later. In six additional dogs it was shown that the paradoxical movement of the left ventricular wall could be reversed within 1 hr of perfusion. Therefore, by enzymatic and histologic criteria, as well as by functional assessment, coronary artery reperfusion 3 hr after occlusion resulted in salvage of myocardial tissue.

Authors

P. R. Maroko, P. Libby, W. R. Ginks, C. M. Bloor, W. E. Shell, B. E. Sobel, J. Ross Jr.

Coronary Artery Reperfusion: II. REDUCTION OF MYOCARDIAL INFARCT SIZE AT 1 WEEK AFTER THE CORONARY OCCLUSION

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The question of whether or not the size of an area of myocardial infarction, measured at 1 wk after coronary occlusion, can be influenced by coronary artery reperfusion was examined in dogs. In seven control experiments the anterior descending coronary artery was ligated, while in seven other studies the occlusion was released after 3 hr. In all animals calibrated photographs were used to assess the zone of hypoperfusion and the acutely injured area of epicardial ST segment elevation, as well as the extent of damage at postmortem 1 wk later. In control dogs, the gross infarct size at postmortem averaged 63.8±7.3% of that predicted from the acutely injured zone. However, in reperfused hearts the average gross infarct size at 1 wk was only 10.2±4.4% of that predicted. Transmural specimens were obtained at autopsy for histology and measurement of myocardial creatine phosphokinase (CPK) activity from sites initially used for epicardial electrocardiography. In control animals, there was a direct relationship between the degree of ST segment elevation and the degree of cell necrosis in transmural histologic sections. ST segment elevation also predicted myocardial CPK (international units per milligram protein): log CPK = − 0.0613 ST + 1.17 (r = 0.66, n = 56 sites). In the reperfused animals, log CPK = − 0.166 ST + 1.36 (r = 0.69, n = 46 sites) showing almost complete preservation of CPK activity at 1 wk, sparing being most prominent in the epicardial zone. Similarly, there was a good correlation between myocardial CPK activity and the histological assessment of cell destruction, the degree of cell damage = − 0.152 CPK + 3.86 (r = 0.86; n = 102 sites). Thus, control dogs showed severe myocardial CPK depletion and histologic evidence of extensive cell destruction, whereas animals subjected to coronary artery reperfusion had little CPK depletion and much less evidence of myocardial cell necrosis 1 wk later.

Authors

W. R. Ginks, H. D. Sybers, P. R. Maroko, J. W. Covell, B. E. Sobel, J. Ross Jr.

Studies of Blood Flow in Aorta-to-Coronary Venous Bypass Grafts in Man

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Pressure-flow measurements were obtained from the vein graft of 57 patients undergoing a single aorta-to-coronary bypass procedure.

Authors

Joseph C. Greenfield Jr., Judith C. Rembert, W. Glenn Young Jr., H. Newland Oldham Jr., James A. Alexander, David C. Sabiston Jr.

The Interaction of Hageman Factor and Immune Complexes

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Abstract

The possible interaction of Hageman factor from human or rabbit plasma with a variety of immunologic reactants was studied. Evidence of an interaction was not obtained and neither binding of radiolabeled Hageman factor to immune aggregates nor depletion of the Hageman factor from the supernate was observed. Cleavage of the labeled Hageman factor molecule into its 30,000 molecular weight-active fragments was not detectable after incubation with immune complexes.

Authors

Charles G. Cochrane, Kirk D. Wuepper, Barbara S. Aiken, Susan D. Revak, Hans L. Spiegelberg

The Use of Lithium in the Treatment of Thyrotoxicosis

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Abstract

Since lithium has been shown to inhibit release of iodine from the thyroid, we have investigated its therapeutic potential in thyrotoxicosis. Eight detailed 131I kinetic studies were performed on seven thyrotoxic women and data was analyzed using a computer program. Lithium at serum levels of about 1 mEq liter decreased the loss of 131I from the thyroid, led to a fall in serum 131I levels and diminished urinary 131I excretion. Computer simulation of the lithium effect required, in every case, that lithium inhibit hormonal and nonhormonal thyroid iodine release. In five cases a second lithium effect was required for a satisfactory fit of the model soluton with observed data: namely, an inhibition of hormone disappearance from serum.

Authors

R. Temple, M. Berman, J. Robbins, J. Wolff

Resistance to Symptomatic Insulin Reactions after Fasting

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Abstract

This study was carried out to determine if, in fasting, an adaptation to utilization of ketones could prevent cerebral dysfunction during periods of acute, insulin-induced glucopenia.

Authors

Ernst J. Drenick, Lia C. Alvarez, Gabor C. Tamasi, Arnold S. Brickman

An Effect of Dexamethasone on Adenosine 3′,5′ -Monophosphate Content and Adenosine 3′,5′ -Monophosphate Phosphodiesterase Activity of Cultured Hepatoma Cells

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Abstract

The effect of dexamethasone on adenosine 3′,5′-monophosphate (cAMP) phosphodiesterase activity in cultured HTC hepatoma cells was investigated. Homogenates of these cells contain phosphodiesterase activity with two apparent Michaelis constants for cAMP (2-5 μm and 50 μm). At all substrate concentrations tested, phosphodiesterase activity was decreased 25-40% in cells incubated for 36 hr or more with 1 μm dexamethasone. Acid phosphatase activity in the same cells was not decreased. α-Methyl testosterone, 1 μm, was without effect on phosphodiesterase activity.

Authors

Vincent Manganiello, Martha Vaughan

Correction for Mechanical Dead Space in the Calculation of Physiological Dead Space

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Abstract

When physiological dead space (Vdp) is calculated for a patient who has alveolar dead space, e.g., after pulmonary vascular occlusion, less than the full volume of attached mechanical dead space (Vdm) appears in the measured dead space (Vdn). Under these conditions the traditional subtraction of Vdm from Vdn leads to underestimation of Vdp and can give a falsely small ratio of Vdp to tidal volume (Vt) when, in fact, an abnormally large Vdp/Vt exists. To make the proper correction for Vdm, two equations have been derived and validated with seven subjects having Vdp/Vt from 0.29 to 0.87, using Vdm's from 120 to 322 ml. With only a small modification, these equations are suitable for routine clinical use and give Vdp/Vt within 0.02 of that by the validated equations (32 of 33 comparisons). The fraction of Vdm subtracted from Vdn is the square of the ratio of effective alveolar to total alveolar ventilation and is never > 1. This fraction is (PaCO2/PaCO2)2, where PaCO2 and PaCO2 are the mean partial pressures of expired alveolar and of arterial CO2; in the other equation this fraction is [PeCO2/PaCO2 (Vt — Vdan — Vdm)]2 where PeCO2 is mixed expired Pco2 and Vdan is anatomical dead space. The second equation requires an estimated Vdan and is applicable when PaCO2 is not measured or does not plateau (as in exercise).

Authors

Gloria J. Singleton, C. Robert Olsen, Richard L. Smith

The Amino Acid Sequence of a Major Nonimmunoglobulin Component of Some Amyloid Fibrils

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Abstract

The complete amino acid sequence of a protein, acid soluble fraction, (ASF) which constitutes up to 50% of amyloid fibrils from a patient with familial Mediterranean fever has been obtained. Partial amino acid sequences of three other proteins from patients with secondary amyloidosis were identical in the regions studied except for an alanine-valine interchange in one. The ASF contains no cysteine, does not resemble any known immunoglobulin, and has not been detected as yet in myeloma-associated amyloid.

Authors

Mark Levin, Edward C. Franklin, Blas Frangione, Mordechai Pras

Transfer of Aminonucleoside Nephrosis by Renal Transplantation

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Abstract

The pathogenesis of aminonucleoside of puromycin (PA) nephrotic syndrome in rats was studied using renal transplantation to separate systemic from renal factors. The nephrotic syndrome was transferred by transplantation of kidneys from rats with established proteinuria. Bilaterally nephrectomized normal rats receiving kidneys removed as early as 15 min after intravenous PA injection (100 mg/kg) of donors also developed proteinuria (602±125 mg/24 hr) and a nephrotic syndrome after the usual induction period of 4-7 days observed in this disease. Arterial perfusion of isolated kidneys with PA (50 mg/kg) followed by perfusion with isotonic saline 3 min later and then transplantation to normal bilaterally nephrectomized rats led to a nephrotic syndrome. Urine protein excretion was 494±42 mg on the 7th day after transplantation. In contrast, urine protein excretion after transplantation of normal kidneys to normal bilaterally nephrectomized rats was 40±20 mg on the 7th day. Exposure of a normal kidney to a nephrotic host environment by transplantation of a normal kidney to a unilaterally nephrectomized PA-injected rat did not transfer the disease to the normal kidney. After removal of the nephrotic kidney 11-13 days after transplantation, proteinuria of the donor kidney was normal (21±13 mg on day 15). These studies indicate that pathogenesis of aminonucleoside nephrosis involves programming of the kidney directly by PA within minutes after exposure although increased urinary protein excretion does not occur until several days later.

Authors

John R. Hoyer, Jean Ratte, Anne H. Potter, Alfred F. Michael