Red cell aging in vivo

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Abstract

Previous studies of red cell structure and metabolism during the aging process have relied upon in vitro techniques of cell separation into various age populations. Probably the most common approach is to isolate the older red cells with the assumption that they are more dense. This may lead to a number of inconsistencies in observations, and may certainly raise questions about possible cell changes secondary to manipulative procedures. For this reason, an experimental system was devised where a normal red cell population could be studied, while aging, in an in vivo environment. The initial red cell mass of a large number of inbred rats was transferred repeatedly into an ever smaller number of animals, making it possible to follow an aging population of red cells up to 48 days while preventing contamination with newly produced cells by suppression of erythropoiesis with transfusion-induced polycythemia. During this period, samples of progressively older red cells could be obtained for measurements of red cell constant. It was noted that the normal rat red cell undergoes both volume reduction and significant hemoglobin content loss with aging. In addition, the hemoglobin concentration within the cell demonstrated an early rise after a return to nearly normal values. These findings are noteworthy in that they help to explain the characteristics of life-spans of cohort labeled red cell populations in small animals, and provide a possible example of a cell's remodeling process within the spleen.

Authors

A. M. Ganzoni, R. Oakes, R. S. Hillman

Accelerated reabsorption in the proximal tubule produced by volume depletion

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Abstract

The renal response to chronic depletion of extracellular volume was examined using the techniques of micropuncture. Depletion of salt and water was produced by administration of furosemide to rats maintained on a sodium-free diet. There was a marked fall in body weight, plasma volume, and glomerular filtration rate. The intrinsic reabsorptive capacity of the proximal tubule, measured by the split-droplet technique, was greatly enhanced. The acceleration of proximal fluid reabsorption could not be accounted for by changes in filtration rate, tubular geometry, or aldosterone secretion. The half-time of droplet reabsorption in the distal tubule was not altered by sodium depletion.

Authors

Michael W. Weiner, Edward J. Weinman, Michael Kashgarian, John P. Hayslett

Effect of Free Fatty Acids on Myocardial Function and Oxygen Consumption in Intact Dogs

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Abstract

Myocardial function and oxygen consumption (MV̇O2) were studied during increased myocardial uptake of free fatty acids (FFA) induced by intravenous infusion of a fat emulsion (Intralipid) after heparinization in anesthetized and intact dogs. During raised myocardial uptake of FFA, MV̇O2 increased in all experiments. On the average, MV̇O2 rose from 8.6 to 10.7 ml/min·100 g, or 26% (P < 0.001). This was mainly due to elevated myocardial oxygen extraction, as myocardial blood flow was unchanged, or increased slightly. In the recovery period, MV̇O2 returned to normal. Left ventricular pressure, the maximal rate of rise of left ventricular pressure (dP/dt), heart rate, and cardiac output remained unchanged during the raised myocardial uptake of FFA.

Authors

Ole D. Mjøs

The human alveolar macrophage: isolation, cultivation in vitro, and studies of morphologic and functional characteristics

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Abstract

Human alveolar macrophages were lavaged from surgically resected lungs and from lungs of normal subjects. Macrophages that had been purified by glass adherence were maintained in tissue culture for as long as 54 days. After 3-4 wk in vitro they underwent transformation into multinucleated giant cells. These aged cells had more than 30 times the phagocytic capacity that the same group of cells had had after 1 day in vitro.

Authors

Allen B. Cohen, Martin J. Cline

The effect of insulin upon glucose metabolism by adipose cells of different size: Influence of cell lipid and protein content, age, and nutritional state

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Abstract

Glucose metabolism and insulin sensitivity of isolated rat epididymal fat cells and of their delipidated derivatives (“ghosts”) was studied as a function of cellular lipid content (fat cell size), cellular protein content, animal age, and state of nutrition in an effort to examine the relationship of adipose cell size to adipose tissue insulin sensitivity.

Authors

Lester B. Salans, James W. Dougherty

Deposition and clearance of 2 μ particles in the tracheobronchial tree of normal subjects—smokers and nonsmokers

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Abstract

Deposition and clearance of inhaled particles of iron oxide labeled with 198Au were studied in 19 normal subjects (10 nonsmokers and 9 smokers). For this purpose, monodisperse aerosols of particles with a 2 μ diameter were produced in a spinning disc atomizer. Thoracic counts and images with a scintillation camera were begun immediately after inhalation of the aerosol and continued for 6 hr.

Authors

Ruy V. Lourenço, Mary F. Klimek, Claudia J. Borowski

The potential use of xylitol in glucose-6-phosphate dehydrogenase deficiency anemia

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Abstract

NADP-linked xylitol dehydrogenase has been found to be present in human red blood cells. This enzyme activity is normal in most glucose-6-phosphate dehydrogenase (G6PD)-deficient red cells. Xylitol was explored as a potential agent for treatment of hemolysis in patients with G6PD-deficiency. Intracellular GSH (glutathione, reduced) was first converted to its oxidized form by incubation of the erythrocytes with acetylphenylhydrazine or by pretreatment with methyl phenyldiazenecarboxylate. The addition of 0.15 M xylitol was shown to be more effective than 0.15 M glucose in maintaining the levels of GSH in G6PD-deficient red cells during such oxidative challenge. Rabbit erythrocytes contain less activity of G6PD and glutathione reductase compared with the normal human adult values, but have an active xylitol dehydrogenase. The rabbit erythrocyte is sensitive to acetylphenylhydrazine and primaquine phosphate. In both in vivo and in vitro experiments, xylitol was found to partially prevent acetylphenylhydrazine induced acute hemolysis of the rabbit red cell and GSH content was found to be preserved. The intravenous injection of xylitol (0.5 g/kg body weight per 6 hr) for 6 days, seemed to be nontoxic to the animal. The results suggest that xylitol should be further investigated as an agent for the treatment of G6PD-deficient patients during acute hemolytic episodes.

Authors

Y. M. Wang, J. H. Patterson, J. Van Eys

Effect of renal vasodilatation on the distribution of cortical blood flow in the kidney of the dog

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Abstract

Studies were performed to evaluate the validity of using the radioactive microsphere technique to measure regional blood flow in the renal cortex. A technique was developed in which the renal cortex was divided into four equal zones, and the fractional and absolute distribution of blood flow in these zones was determined. It was consistently found that approximately 70% of the renal blood flow was distributed to the two outer cortical zones with the remaining 30% going to the two inner cortical zones. In addition, there was a reproducible pattern of distribution of blood flow in different areas of the same kidney after a single injection of microspheres and in the same area of the kidney after multiple injections of microspheres.

Authors

Jay H. Stein, Thomas F. Ferris, James E. Huprich, Timothy C. Smith, Richard W. Osgood

Effect of lipids on growth hormone secretion in humans

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Abstract

To determine the effect of elevations of plasma lipids on growth hormone secretion in humans, paired insulin hypoglycemia tests and paired arginine infusion tests were performed on eight and six normal female volunteers respectively. On 1 of the 2 test days for each growth hormone stimulus, subjects were given 60 g corn oil (Lipomul) 3 hr before testing followed by intravenous heparin (5000 U) at the time of insulin or arginine administration.

Authors

William G. Blackard, Edgar W. Hull, Alfredo Lopez-S

Diazoxide effects on biphasic insulin release: “adrenergic” suppression and enhancement in the perifused rat pancreas

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Abstract

An in vitro system for perifusion of rat pancreas has been used to investigate the effects of diazoxide on glucose-induced insulin release. Administration of diazoxide with a stimulating concentration of glucose produced a dose-dependent suppression of insulin release. This effect was partly reversed by phentolamine. In the presence of nonstimulatory concentrations of glucose, diazoxide plus phentolamine, but neither alone, stimulated a biphasic release of insulin similar to that observed with 1-isopropyl norepinephrine. A prior period of perifusion with a low concentration of diazoxide enhanced the primary component of subsequent glucose-stimulated insulin release, an effect inhibited by addition of either phentolamine or propranolol to the diazoxide during this “prestimulation” period. These effects are similar to those observed with epinephrine. By contrast with epinephrine however, increasing the concentration of diazoxide during the period before glucose stimulation enhanced both the primary and secondary components of subsequent glucose-induced insulin release. These data suggest that at least some of the direct effects of diazoxide on the pancreas are mediated through α- and β-adrenergic receptor mechanisms.

Authors

Ian M. Burr, Errol B. Marliss, Werner Stauffacher, Albert E. Renold

Alteration in the rheologic properties of plasmodium knowlesi-infected red cells. A possible mechanism for capillary obstruction

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Abstract

Red cells parasitized by Plasmodium knowlesi concentrate within the microcirculation of many organs including cerebral capillaries in rhesus monkeys. The possibility that P. knowlesi could alter the rheologic properties of red cells so that they are trapped within capillaries was investigated in the present study. The viscosity of P. knowlesi-infected red cells suspended in Ringer's solution was increased at all shear rates at hematocrits above 30%. At moderate parasitemia the resistance to flow through 5 μ polycarbonate sieves was increased; at high parasitemia the pores were obstructed. Mature trophozoites caused more obstruction than young trophozoites (rings) at any given level of parasitemia. The reduction of deformability of red cells infected by schizonts of P. knowlesi was further demonstrated by their exclusion from rouleaux in a plasma suspension. Therefore, the red cells infected by P. knowlesi become less deformable, and this reduction in red cell deformability may explain the obstruction of cerebral capillaries.

Authors

Louis H. Miller, Shunichi Usami, Shu Chien

Mechanical properties of the esophageal wall

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Abstract

Pressure-diameter curves of the esophagus were obtained to define its mechanical properties. The mucosal contribution to the strength of the esophagus was negligible until the outer diameter almost doubled, suggesting that small intraluminal pressures are held by the muscle layer alone. For larger deformations mucosal contribution increased and at failure the mucosa held over one-half of the failure pressure of the esophagus.

Authors

Raj K. Goyal, Piero Biancani, Aris Phillips, Howard M. Spiro

Measurement of cardiac output in man with a nonrecirculating indicator

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Abstract

The present investigation was undertaken to evaluate the utility of constant-rate injection of a nonrecirculating indicator (H2) for the measurement of cardiac output in man. 42 patients were studied during cardiac catheterization and 8 during acute complications of arteriosclerotic heart disease, including acute myocardial infarction. Pulmonary (or systemic) arterial H2 concentration was measured chromatographically from 2.0 ml blood samples drawn during constant-rate injection of dissolved H2 into the systemic venous circulation (or left heart). The chromatograph was a thermal conductivity unit housed in a constant-temperature water bath to achieve an improved signal-to-noise ratio. Intrapulmonary H2 elimination from mixed venous blood was measured directly in 14 patients and averaged 98 ±1.5% (SD). Reproducibility of output measurements was evaluated using triplicate determinations obtained over 45-60 sec in 25 consecutive patients. Coefficients of variation (SD/Mean × 100) averaged 3.4 ±2.0%, making it possible to evaluate relatively small changes in measured output with conventional statistical tests. Individual measurements could be repeated at 10-15 sec intervals. Comparisons of H2 and direct Fick measurements were made in 14 patients; H2 outputs averaged 106 ±4% (SEM) of Fick outputs (P > 0.1). Comparisons of H2 and dye dilution measurements were performed in an additional 24 patients. Seven had angiographically-negligible valvular regurgitation and dye outputs averaged 106 ±3% of H2 outputs (P > 0.1). 17 had moderate-to-severe regurigation and dye outputs averaged 91 ±4% of H2 outputs (P < 0.05), suggesting a small but systematic error due to undetected recirculation of dye. The H2 technique appears advantageous for rapidly repeated determinations of output, for quantitation of small changes in output, and for situations in which recirculation of conventional indicators is a potentially significant problem.

Authors

Stephen M. Wittenberg, Francis J. Klocke, David G. Greene, Ivan L. Bunnell, Herman L. Falsetti, Joseph A. Zizzi

Lysozyme turnover in the rat

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Abstract

Lysozyme turnover in the rat was studied with 125I-labeled rat lysozyme. It was found that plasma lysozyme has a rapid disappearance rate with a half-life of 75 min. The rate of synthesis was calculated at 3.4 μg/min per 100 g rat. This rate of synthesis was compared with figures from the literature for the turnover rate of neutrophilic granulocytes, and the data were consistent with the concept that disintegrating neutrophils are the main source of plasma lysozyme.

Authors

Niels Ebbe Hansen, Hans Karle, Vagn Andersen

Role of antidiuretic hormone in the abnormal water diuresis of anterior hypopituitarism in man

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Abstract

To evaluate the role of antidiuretic hormone (ADH) in the defect in water excretion which is characteristic of glucocorticoid deficiency, the effects of hydrocortisone and ethanol upon urinary dilution during a sustained water load were studied in patients with anterior hypopituitarism. A spectrum of defects in urinary dilution was found in the seven patients with anterior hypopituitarism, and the subjects were separable into two groups. Four patients were unable to excrete a urine hypotonic to plasma (group I) while three diluted the urine (group II). In two of the group II patients, despite maintenance of hydration, urinary osmolality later rose to hypertonicity. Physiological doses of hydrocortisone improved urinary dilution in all patients. Submaximal doses of oral hydrocortisone, when given to the group I patients, converted their response to hydration to one characteristic of the group II patients, i.e., an initial hypotonic urine followed by a secondary rise to hypertonicity. Ethanol, a known inhibitor of ADH secretion, had no effect in the group I patients. When two of these patients were pretreated with sub-maximal doses of hydrocortisone, however, so that they were able to transiently dilute the urine, ethanol prevented the secondary rise in urine osmolality. Similarly, the administration of ethanol to the untreated group II patients, when the urine was hypotonic, improved diluting ability as characterized by a lowering of urinary osmolality and an increased excretion of solute-free water in all three patients. Hydrocortisone did not improve urinary dilution in three patients with complete hypophyseal diabetes insipidus and one with both anterior and posterior insufficiency receiving constant infusions of vasopressin. These data suggest, therefore, that inappropriately elevated levels of ADH play a major role in the defect in water excretion of anterior hypopituitarism. Glucocorticoids appear to be necessary for a normal neurohypophyseal response to inhibitory stimuli.

Authors

Zalman S. Agus, Martin Goldberg

The plasma estradiol as an index of fetoplacental function

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Abstract

A radioligand assay has been developed for the measurement of unconjugated 17β-estradiol in as little as 0.01 ml of pregnancy plasma employing rabbit uterine cytosol as specific binder and activated charcoal as nonspecific absorbant. Large numbers of samples could be processed simultaneously at relatively little expense and results were obtainable within 3 hr. The procedure was sensitive to 1 ng/ml. No diurnal or positional variations were found. Values from 250 unselected normal patients showed a constantly rising mean plasma E2 from 18 to 35 wk gestation from 4.5 to 14 ng/ml. From 35 to 40 wk, mean E2 rose only to 15 ng/ml and the range of values increased substantially. When 22 normal pregnant subjects were followed serially, rising levels of plasma E2 were found with no significant fall ever seen. By contrast, patients exhibiting fetal distress generally had falling or reduced E2 levels. However, 3 cases of Rh isoimmunization had elevated or normal E2 concentrations even after clearcut evidence of fetal demise. A decrease of 45% in E2 concentration was associated with intraamniotic instillation of hypertonic saline prior to delivery supporting the view that placental conversion of maternal adrenal precursors is responsible for about half of the E2 production in pregnancy. The postpartum clearance of endogenous E2 was measured and found to fit a two compartment model with mean half-time of 22 min and 7 hr. Follicular phase levels of E2 were attained by 35 hr postpartum. The concentration of unconjugated E2 in pregnancy plasma correlated as well with the state of the placenta as other placental hormone measurements and holds promise of being a rapid, inexpensive, and reliable method of following patients with high-risk pregnancies in a variety of clinical settings.

Authors

Dan Tulchinsky, Stanley G. Korenman

Micropuncture studies of proximal tubule albumin concentrations in normal and nephrotic rats

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Abstract

The concentration of serum albumin in proximal tubule fluid of normal rats and animals with aminonucleoside nephrosis was studied using renal micropuncture techniques. Albumin was quantitated by an ultramicrodisc electrophoresis method capable of measuring 3 χ 10-11 g of albumin, in 10 nl volumes. With this sensitivity, only small samples of tubule fluid were required for analysis. Collection times could be kept short, therefore decreasing the opportunity for sample contamination with extraneous serum albumin. The measured mean concentration of albumin in proximal tubule fluid (1 mg/100 ml in females and 0.7 mg/100 ml in males) was somewhat lower than values reported by others, but even these values are apt to have been artifactually high as a result of animal preparation and trace contamination of samples during micropuncture. Rats injected with aminonucleoside of puromycin 4 days earlier, showed a significant increase in tubule-fluid albumin concentration coincident with a fall in serum albumin concentration and a 43-fold increase in urine albumin concentration. Tubular absorption of albumin was small relative to that of water. Although albumin filtration was significantly increased over that in normal animals, the glomerular basement membrane still served as a highly efficient barrier to albumin transfer.

Authors

Donald E. Oken, Walter Flamenbaum

The effect of fibrin-stabilizing factor on the subunit structure of human fibrin

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Abstract

The formation of human fibrin from fibrinogen has been examined by polyacrylamide gel electrophoresis in sodium dodecyl sulfate, a method which separates a mixture of proteins on the basis of differences in molecular weight. It has been found that the plasma from a patient with a congenital deficiency of fibrin-stabilizing factor forms clots lacking the cross links among the α- and γchains found in normal, cross-linked human fibrin. The addition of purified fibrin-stabilizing factor or normal plasma to the deficient plasma results in extensive cross-linking of the chains. Thus, the fibrinogen in the fibrin-stabilizing factor deficient plasma appears to be normal and forms fibrin which contains dimeric, cross-linked γ-chains and polymeric, high molecular weight forms of α-chains. By the use of these electrophoretic methods, it has also been possible to develop a highly sensitive method for measuring the content of fibrin-stabilizing factor in plasma. This method depends upon the use of urea-treated fibrinogen, which is completely devoid of fibrin-stabilizing factor, but which forms the usual cross-linked subunits after conversion to fibrin by thrombin in the presence of fibrin-stabilizing factor.

Authors

Martin L. Schwartz, Salvatore V. Pizzo, Robert L. Hill, Patrick A. McKee

Studies of human sera with cytotoxic activity

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Abstract

42 human sera showing in vitro cytotoxic activity of restricted or broad HL-A specificities with test human lymphocytes were studied for the molecular and immunoglobulin class of cytotoxic antibody using sucrose gradient separations, DEAE-cellulose chromatography, and Sephadex G-200 gel filtration. Sera originated from patients with previous multiple pregnancies (19), multiply transfused patients (8), subacute bacterial endocarditis (4), systemic lupus (2), and human umbilical cord sera (9). In 32 of 42 instances, predominant cytotoxic activity was found in high molecular weight gradient fractions; however, DEAE chromatographic separations revealed cytotoxic activity in initial buffer fractions containing primarily γG globulin. Gradient separations of cytotoxic activity within initial γG DEAE fractions showed localization of cytotoxicity only in high molecular weight materials. Confirmation of high molecular weight γG cytotoxic activity was obtained by resistance to mercaptoethanol treatment, abolition of activity after absorption only with specific anti-γG antisera, and by the finding that high molecular weight cytotoxic activity in gradients or gel filtration run at neutral pH 7.4 became 7S when separations were rerun at an acidic pH of 4.0. Such 7S activity again became rapidly sedimenting when the same fractions were again rerun in gradients at neutral pH.

Authors

Ralph C. Williams Jr., Jean D. Emmons, Edmond J. Yunis

Glomerular basement membrane—reactive antibody in anti-lymphocyte globulin

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Abstract

Equine immunoglobulin was detected along the glomerular basement membrane of three human homograft recipients who had been treated with equine anti-lymphocyte globulin. Anti-lymphocyte globulins, given these patients, were obtained by immunization of horses with lymphocytes from human spleens and/or lymph nodes and contained glomerular basement membrane-reactive antibodies. Quantitative paired-label isotope experiments (in rats) demonstrated that 30-170 μg/ml of kidney-fixing antibodies were present in these preparations. The anti-lymphocyte globulins formed a line of identity with a sheep anti-human glomerular basement serum when reacted against collagenase-solubilized human glomerular basement membrane in double diffusion in agar. The renal fixation of these antibodies was blocked by absorption with human glomerular basement membrane, but not by buffy-coat leukocytes, indicating that they were directed specifically toward antigens in the basement membrane and were not cross-reacting anti-lymphocyte antibodies.

Authors

Curtis B. Wilson, Frank J. Dixon, Joseph G. Fortner, G. James Cerilli

Human forearm metabolism during progressive starvation

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Abstract

Forearm muscle metabolism was studied in eight obese subjects after an overnight, 3 and 24 day fast. Arterio-deep-venous differences of oxygen, carbon dioxide, glucose, lactate, pyruvate, free fatty acids, acetoacetate, and β-hydroxybutyrate with simultaneous forearm blood flow were measured. Rates of metabolite utilization and production were thus estimated. Oxygen consumption and lactate and pyruvate production remained relatively constant at each fasting period. Glucose, initially the major substrate consumed, showed decreased consumption after 3 and 24 days of fasting. Acetoacetate and β-hydroxybutyrate consumption after an overnight fast was low. At 3 days of fasting with increased arterial concentrations of acetoactate and β-hydroxybutyrate, consumption of these substrates rose dramatically. At 24 days of fasting, despite further elevation of arterial levels of acetoacetate and β-hydroxybutyrate, the utilization of acetoacetate did not increase further and if anything decreased, while five out of eight subjects released β-hydroxybutyrate across the forearm. Acetoacetate was preferentially extracted over β-hydroxybutyrate. At 24 days of starvation, free fatty acids were the principal fuels extracted by forearm muscle; at this time there was a decreased glucose and also ketone-body consumption by skeletal muscle.

Authors

O. E. Owen, George A. Reichard Jr.

Ventricular arrhythmias induced in monkeys by the inhalation of aerosol propellants

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Abstract

After inhaling fluoroalkane gases, which are used as aerosol propellants, some people have died suddently and unexpectedly. Seeking an explanation, we had 14 monkeys inhale these gases. All developed ventricular premature beats, bigeminy, or tachycardia, which began at an average of 39 (SE ±4.2) sec. Fluoroalkanes were present in blood, but arterial hypoxemia or hypercapnia was absent, and arterial pressure was reduced only slightly. In contrast, without fluoroalkanes, 3 min of asphyxia or anoxia caused arrhythmias in only one monkey whose arterial oxygen tension had fallen to 16 mm Hg. The ventricular arrhythmias caused in well oxygenated monkeys by fluoroalkane gases may either be mediated through beta adrenergic receptors, since propranolol abolished these arrhythmias, or result from a nonadrenergic, direct, toxic effect of these gases on the heart. These results suggest that some deaths after propellant inhalation may be caused by ventricular tachycardia or fibrillation.

Authors

George J. Taylor IV, Willard S. Harris, Morton D. Bogdonoff

Dose-Response relationship of luteinizing hormone to luteinizing hormone—releasing hormone in man

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Abstract

In previous clinical studies with highly purified porcine luteinizing hormone-releasing hormone (LH-RH), administration of the somewhat arbitrarily chosen doses of 700-1500 μg resulted in increased serum levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). The present study determined the minimum effective dose as well as the relationship of the response of serum LH and FSH to the dose of LH-RH administered. Three normal men received i.v. injections of 1.1-810 μg of LH-RH. A dose of 10 μg of LH-RH caused a statistically significant elevation in serum LH. 30 μg of LH-RH significantly increased serum FSH levels. A highly significant linear trend was observed in the log dose-response curve. The results indicate that both LH and FSH release occurs in man with doses of LH-RH much lower than previously used and that a linear log dose-response relationship can be obtained.

Authors

Abba J. Kastin, Andrew V. Schally, Carlos Gual, A. Rees Midgley Jr., M. Clinton Miller III, Angela Cabeza

Oxygen equilibrium of hemoglobin J Cape Town

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Abstract

Polycythemia in carriers of hemoglobin J Cape Town or hemoglobin Chesapeake is thought to be produced by increased oxygen affinity of their blood. Both hemoglobins involve substitution of amino acid residue α FG-4. Measurements reported here, of the oxygen equilibrium of purified hemoglobin J Cape Town, permit direct comparison of the two hemoglobins. J Cape Town exhibits lower oxygen affinity, and greater heme-heme interaction, than Chesapeake; both exhibit normal Bohr effects. Substitution of one polar amino acid residue for another of opposite charge (arginine → glutamic acid) thus appears to create less disruption of the interface between α- and β-chains than substitution of a nonpolar residue (arginine → leucine).

Authors

Samuel Charache, Trefor Jenkins