Hemodynamic effects of isoproterenol in canine endotoxin shock

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Abstract

Myocardial function and peripheral hemodynamic alterations were measured through the late stages of canine endotoxin shock. 60 min postendotoxin paired animals were given infusions of either 5 ml/kg per hr of 5% dextrose or dextrose plus isoproterenol (0.25 μg/kg per min). Comparable blood lactic and pyruvic acid levels were determined, the excess lactic acid calculated, and pH values were obtained. During the initial stages the classic pattern of hemodynamic alterations was observed; an excess of lactic acid appeared and the pH decreased. Outstanding was evidence of markedly reduced myocardial function in the late stages of shock with progressive rise in left ventricular end diastolic pressure (LVEDP), low cardiac index, rise of central venous pressure, increased central blood volume, tachycardia, and declining arterial pressure. Analyses of left ventricular function curves also indicated myocardial failure.

Authors

Boleslaw Starzecki, Wesley W. Spink

Erythrocytes in human transplantation: effects of pretreatment with ABO group-specific antigens

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Abstract

Erythrocyte group antigens A and B can act as potent and group-specific transplantation antigens in man. ABO group-incompatible recipients pretreated with such antigens have rejected skin allografts obtained from donors incompatible for the same antigens in an accelerated (4-5 days) or white graft manner. Skin grafts applied to the same recipients from ABO-compatible donors were accorded first-set survival times. Intact erythrocyte suspensions and antigens isolated from hog (A substance) and horse (B substance) stomachs, were equally capable of inducing this type of allograft sensitivity. The latter observation broadens the spectrum of heterologous antigens capable of inducing allograft sensitivity in the mammalian host and provides a readily available, heat-stable, and water-soluble source of antigens for further studies of allograft rejection mechanisms in man.

Authors

F. T. Rapaport, J. Dausset, L. Legrand, A. Barge, H. S. Lawrence, J. M. Converse

Increased synthesis of phospholipid during phagocytosis

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Abstract

Incorporation in vitro of 32P-labeled lysolecithin (LPC) or lysophosphatidylethanolamine (LPE) into respectively lecithin (PC) and phosphatidylethanolamine (PE) of rabbit granulocytes and alveolar macrophages was compared in the absence and in the presence of ingestible particles. Maximal synthesis of PC by intact cells occurred at added LPC concentrations of less than 0.05 mmole/liter, i.e., at levels found in plasma. Accumulation of PC-32P proceeded linearly for at least 30 min and varied directly with cell concentration. While per cell granulocytes and macrophages converted comparable amounts of medium LPC to cellular PC, per milligram of protein, the granulocytes were approximately four times more active than the much larger macrophages. After 30 min newly synthesized PC-32P represented as much as 5% of total granulocyte PC. For macrophages this fraction did not exceed 1%. Addition of polystyrene or zymosan particles to the cell suspension resulted in up to 3-fold stimulation of incorporation of LPC-32P or LPE-32P into their respective diacyl derivatives. This stimulation did not occur when the cells were homogenized. Breakdown of LPC to water-soluble products during phagocytosis of polystyrene particles was the same as at rest. By use of doubly labeled LPC, the mechanism of PC synthesis by the two cell types has been identified as direct acylation of medium LPC, both at rest and during engulfment. Evidence presented in the case of granulocytes suggests that the increased translocation of medium LPC-32P during phagocytosis and its conversion to PC represents net synthesis.

Authors

Peter Elsbach

Metabolism of the stimulated rat spleen: I. Ferrochelatase activity as an index of tissue erythropoiesis

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Abstract

Assay of the enzyme ferrochelatase in marrow, liver, spleen, and red cells has been employed to assess the extent of erythropoietic stimulation in animals bearing the Walker 256 carcinosarcoma and in rats treated by administration of phenylhydrazine, cobalt chloride, human urinary erythropoietin, or chronic blood loss. In all instances, the spleen sustains the most marked increase of ferrochelatase activity, per gram of tissue. Spleen erythropoietic activity stimulation was confirmed by quantitative measurements in respiring slices of 59Fe and 14C incorporation into hemoglobin and ferritin. Increased spleen ferrochelatase activity in cobalt chloride-treated rats is prevented by actinomycin D, indicating that stimulated synthesis of the enzyme is associated with the metabolism of RNA.

Authors

Abraham Mazur

The metabolic fate of vitamin D₃-³H in chronic renal failure

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Abstract

The absorption and metabolism of vitamin D3-3H was studied in eight patients with chronic renal failure. Although the intestinal absorption of vitamin D3-3H was normal, the metabolic fate of the vitamin was abnormal as characterized by a twofold increase in fractional turnover rate, an abnormal accumulation of biologically inactive lipid-soluble metabolites, and the urinary excretion of both vitamin D3-3H and biologically inactive metabolites. Neither alterations in water-soluble vitamin D3 metabolites nor qualitative abnormalities in protein-binding of vitamin D3 were observed in the uremic subjects. Although hemodialysis proved ineffectual in reversing the observed abnormalities in vitamin D3 metabolism and excretion, renal homotransplantation was completely successful in this regard. These experiments support the conclusion that the resistance to therapeutic doses of vitamin D often seen in patients with chronic renal failure and renal osteodystrophy results from an acquired defect in the metabolism and excretion of vitamin D.

Authors

Louis V. Avioli, Stanley Birge, Sook Won Lee, Eduardo Slatopolsky

Control of jejunal sucrase and maltase activity by dietary sucrose of fructose in man: A model for the study of enzyme regulation in man

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Abstract

The specific effect of dietary sugars on jejunal disaccharidase activity in seven normal nonfasted male volunteers was studied. The sugars tested were sucrose, maltose, lactose, glucose, fructose, and galactose. Comparisons were made of the effects of each sugar in an isocaloric liquid diet.

Authors

Norton S. Rosensweig, Robert H. Herman

Red cell life span after splenectomy in hereditary spherocytosis

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Abstract

Despite the persistence of spherocytosis after splenectomy in hereditary spherocytosis, it has usually been assumed that red cell life span returns completely to normal after this treatment. Diisopropyl fluorophosphate. DF32P, a noneluting red cell label, was given intravenously to 11 patients in five unrelated families 2-27 yr after splenectomy for typical hereditary spherocytosis. Hemoglobin ranged from 14.0 to 19.8 g/100 ml in this group and reticulocytes from 1.1 to 2.9%, showing the excellent clinical response to splenectomy. Loss of red cell radioactivity corrected for radiophosphorus decay was linear with time during the 60-70 days of the study. Red cell survival as indicated by this rate of loss was 96 ± 13 days (range 76-118 days), significantly less than the 123 ± 14 days observed with the same method in 12 persons with normal red cells (P < 0.0005). I conclude that splenectomy does not eliminate the decreased red cell survival in hereditary spherocytosis. The residual 22% decrease in red cell survival is clinically unimportant, but it must be considered in evaluation of biochemical differences observed in hereditary spherocytic red cells.

Authors

Robert G. Chapman

Encephalopathy of thiamine deficiency: studies of intracerebral mechanisms

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Abstract

Thiamine-deficient encephalopathy is characterized by morphologic lesions in the brainstem and less extensively in the cerebellum, but the early neurologic signs reverse rapidly and fully with thiamine, indicating a metabolic disorder. The suggested causal mechanisms of the encephalopathy involve two thiamine-dependent enzymes: (a) impairment of pyruvate decarboxylase activity with decreased cerebral energy (ATP) synthesis, and (b) reduction of transketolase activity with possible impairment of the hexose monophosphate shunt and subsequent decrease in NADPH formation. The latter may be important in maintaining glutathione in a reduced form (GSH), which apparently functions by keeping enzymes in a reduced (active) conformation.

Authors

David W. McCandless, Steven Schenker

Adenine phosphoribosyltransferase deficiency: a previously undescribed genetic defect in man

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Abstract

A deficiency of adenine phosphoribosyltransferase (A-PRTase) is described in four members in three generations of one family. A-PRTase is coded by an autosome and the mutants described in this report are heterozygotes for this enzyme defect. The level of enzyme activity in these heterozygotes was inappropriately low, ranging from 21 to 37% of normal rather than the expected 50% of normal. Examination of various physical and chemical properties of the A-PRTase obtained from the mutant heterozygotes failed to reveal differences from the normal enzyme. These patients have no discernable abnormality in uric acid production despite the finding that patients with a deficiency of a closely related enzyme, hypoxanthine-guanine phosphoribosyltransferase, invariably produce excessive quantities of uric acid. A relationship of the A-PRTase deficiency to the disturbance in lipoprotein metabolism observed in the propositus has not been firmly established. Possible manifestations of the homozygous form of this enzyme deficiency will require identification of such individuals in the future.

Authors

William N. Kelley, Robert I. Levy, Frederick M. Rosenbloom, J. Frank Henderson, J. Edwin Seegmiller

Immunogenetics of human haptoglobins: I. The antigenic structure of normal Hp phenotypes

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Abstract

The various antigenic determinants of serum haptoglobins (Hp) may be studied semiquantitatively in a radioimmunoassay system. Using three antisera of overlapping specificities, we constructed an antigenic model of the various Hp phenotypes comprising four distinct determinants. This adds a new determinant, situated near the hemoglobin binding site, to the three determinants reported in the literature.

Authors

Jamshid Javid, Wendy Yingling

Immunogenetics of human haptoglobins: II. Hp Bellevue, a cross-reacting mutant

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Using a radioimmunoassay method in conjunction with double diffusion studies, we characterized the antigenic determinants of the three Hp Bellevue phenotypes. An antigenic model based on these data indicates that each phenotype comprises a heterogeneous group of proteins with properties depending on their content of normal (hpβ) and of mutant (hpβ-Bellevue) chains of haptoglobin. The loss of the hemoglobin binding capacity and of a specific Hb-sensitive antigenic determinant is a consequence of the structural alteration in hpβ-Bellevue and is expressed to various extents by the populations of proteins containing this chain. It is suggested that those molecules with a preponderance of mutant β-chains are without significant hemoglobin binding capacity and are degraded more slowly in vivo than the ones capable of hemoglobin binding.

Authors

Jamshid Javid, Wendy Yingling

Characterization of response of circulating glucagon to intraduodenal and intravenous administration of amino acids

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Abstract

Studies were carried out to determine if hyperaminoacidemia stimulates the secretion of pancreatic glucagon, and, if so, to evaluate the effect of endogenous and exogenous pancreozymin and of hyperglycemia upon this response. The intravenous administration to 16 dogs of 1 g/kg of a 10 amino acid mixture over a 60 min period raised amino nitrogen to a mean level of 13.5 mg/100 ml; mean pancreaticoduodenal vein insulin rose from 84 to 459 μU/ml and glucagon from 1.1 to 2.7 mμg/ml. Further augmentation of both insulin and glucagon secretion was achieved during hyperaminoacidemia by infusing pancreozymin.

Authors

Akira Ohneda, Eugenio Parada, Anna M. Eisentraut, Roger H. Unger

Catabolism of human γG-immunoglobulins of different heavy chain subclasses: I. Catabolism of γG-myeloma proteins in man

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Abstract

The rates of catabolism of human γG-immunoglobulins of subclasses γG1, γG2, γG3, and γG4 were studied by determining the rates of elimination from the circulation of pairs of 131I-and 125I-labeled γG-myeloma proteins in 57 patients suffering from cancer other than multiple myeloma. On the average, γG1-, γG2-, and γG4-myeloma proteins were catabolized at a rate similar to that of normal γG-immunoglobulin, whereas γG3-myeloma proteins were catabolized more rapidly than normal γG-immunoglobulin. The average half-lives for the myeloma proteins were 12.3 days for normal γG, 11.6 days for γG1, 12.4 days for γG2, 8.2 days for γG3, and 11.3 days for γG4. However, significant differences in catabolic rates were observed when individual myeloma proteins of a single subclass were compared. These individual variations were present within all four heavy chain subclasses. The extent of differences ranged from 10 to 47%. The catabolic rate of normal γG was in an intermediate range when compared with myeloma proteins of relatively long and short half-lives. The rate of catabolism of an individual myeloma protein did not correlate with its light chain type, Gm factor, carbohydrate content, or electrophoretic mobility. These findings indicate that the structure(s) related to the catabolism of γG-immunoglobulins are complex and differ from one immunoglobulin molecule to another.

Authors

Hans L. Spiegelberg, Ben G. Fishkin, Howard M. Grey

Effects of guanidine derivatives on mitochondrial function: I. Phenethylbiguanide inhibition of respiration in mitochondria from guinea pig and rat tissues

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Abstract

Derivatives of guanidine, such as phenethylbiguanide, are potent inhibitors of mitochondrial respiration in vitro, but the relevance of this inhibition to their in vivo blood sugar-lowering action is not clear. We have studied the metabolism of pyruvate and long chain fatty acids by mitochondria from several tissues of guinea pigs and rats and observed the effects of phenethylbiguanide on these processes. The rate of pyruvate decarboxylation and of β-oxidation of long chain fatty acyl-CoA derivatives by guinea pig heart mitochondria in vitro has been found to exceed the flux of substrate through the citric acid cycle, both in the presence and absence of phosphate acceptor.

Authors

Frank Davidoff

Effects of guanidine derivatives on mitochondrial function: II. Reversal of guanidine-derivative inhibition by free fatty acids

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Abstract

Long chain free fatty acids interfere with the inhibitory action of phenethylbiguanide and related compounds on mitochondrial respiration in vitro. This interference depends on binding of fatty acids to mitochondria and diminishes with decreasing chain length. Reversal of guanidine-derivative inhibition by fatty acids differs from that caused by dinitrophenol in that the effect of fatty acid is achieved without alteration in coupling or respiratory control. The binding of phenethylbiguanide to mitochondria is inhibited by both fatty acid and dinitrophenol. Serum albumin potentiates the inhibitory potency of guanidine derivatives, probably by removing endogenous mitochondrial free fatty acids.

Authors

Frank Davidoff

Catecholamine turnover in normotensive and hypertensive man: effects of antiadrenergic drugs

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Abstract

Intravenous administration of tritium-labeled 3,4-dihydroxyphenylalanine (dopa) to human subjects resulted in the labeling of endogenous catecholamines and vanillylmandelic acid (VMA). Determination of the changes in specific activity of these compounds with time in fractional collections of urine and in cardiac biopsies from patients undergoing corrective cardiac surgery permitted estimation of apparent turnover rates. The average half-time of the exponential decline in specific activity of labeled urinary norepinephrine was about 8 hr and that of VMA was 11-16 hr in five normal subjects. No significant differences from normal were observed in eight patients with essential hypertension. The average half-life of norepinephrine was only 5 hr in cardiac patients undergoing surgery, and the levels and rate of decline of cardiac norepinephrine specific activity correlated well with the exponential phase of the urinary disappearance curve. There were significant effects of treatment with alpha-methyltyrosine, reserpine, and pargyline hydrochloride on the labeling and apparent turnover rates of norepinephrine and VMA; the effects noted were consistent with known actions of these three drugs. It is suggested that the technique used is a suitable means of assessing “over-all” catecholamine metabolism in man, particulary if combined with quantitative assay of urinary catecholamine metabolites.

Authors

Vincent DeQuattro, Albert Sjoerdsma

Antibacterial activity of human urine

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Abstract

The fate of bacteria in human urine was studied after inoculation of small numbers of Escherichia coli and other bacterial strains commonly implicated in urinary tract infection. Urine from normal individuals was often inhibitory and sometimes bactericidal for growth of these organisms. Antibacterial activity of urine was not related to lack of nutrient material as addition of broth did not decrease inhibitory activity. Antibacterial activity was correlated with osmolality, urea concentration and ammonium concentration, but not with organic acid, sodium, or potassium concentration. Between a pH range of 5.0-6.5 antibacterial activity of urine was greater at lower pH. Ultrafiltration and column chromatography to remove protein did not decrease antibacterial activity.

Authors

Donald Kaye

Infectious mononucleosis: immunoglobulin synthesis by cell lines

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Abstract

Immunoglobulin synthesis by 16 long-term suspension cultures of mononuclear cells derived from peripheral blood of nine patients with heterophile-positive infectious mononucleosis (IM) has been demonstrated by radioimmunoelectrophoretic techniques. All cell lines synthesized molecules with IgG (γ) heavy chain specificity. 14 cell lines produced molecules with IgM (μ) heavy chain specificity and 11 cell lines produced molecules with IgA (α) heavy chain specificity. No detectable synthesis of molecules with IgD (δ) heavy chain specificity was observed by these cell lines derived from peripheral blood of patients with IM. 13 cell lines produced molecules with type K (κ) light chain specificity and 6 cell lines produced molecules with type L (λ) light chain specificity. Of interest, 9 of 16 lines produced IgG (γ), IgA (α), and IgM (μ) heavy chain molecules and 5 of these cell lines produced molecules with type K (κ) and type L (λ) light chain specificity as well.

Authors

Philip R. Glade, Lawrence N. Chessin

The determination of total body exchangeable O₂ stores

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Abstract

A method is described for the measurement of total body exchangeable oxygen stores (TBO2). It is based on the dilution of the stable oxygen isotope, 18O2, by the body exchangeable oxygen stores under circumstances in which 18O2 steady-state equilibrium was evaluated simultaneously for both arterial and venous blood compartments. After evaluation of several simplifying assumptions, TBO2 values in dog, normal man, and anemic patients were measured. The magnitude of the exchangeable nonlung oxygen stores was 11.0 ± 3.1 ml/kg (SD) in 5 dogs, 11.9 ± 2.1 ml/kg in 10 normal subjects, and 7.0 ± 1.6 ml/kg in 8 patients with severe anemia (hematocrits of 25% or less).

Authors

Carroll E. Cross, Bernard S. Packer, Michael Altman, J. Bernard L. Gee, H. Victor Murdaugh Jr., Eugene D. Robin

Pressure-flow studies in man during atrial fibrillation

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Abstract

In 13 patients who had atrial fibrillation the ascending aortic pressure-flow relationships were measured by the pressure gradient technique. Both the pressure and flow curves were similar in contour to ones previously obtained by this method. From these recordings, relationships between the phases of systole, the ventricular filling time, and various derived parameters of pressure and flow such as the pulse pressure, stroke volume, peak flow, stroke work, and peak power were evaluated. For stroke volumes greater than 15 cm3 there was little change in the duration of systole in an individual patient. In each patient both the preejection period and the duration of ejection showed a good correlation with stroke volume, peak flow, stroke work, and peak power. When data from all patients were examined, the relationship between stroke volume and duration of ejection was found to be curvilinear and had an overall correlation of r=0.91. There was marked variation from patient to patient in duration of both the preejection period and systole. Similar correlations between the phases of systole were noted with peak flow, peak power, and stroke work. A positive but mediocre correlation was found between the previous RR interval (an index of ventricular filling time) and the subsequent stroke volume. The correlation, in six patients, between two previous RR intervals and stroke volume was considerably better. The relationship between the pulse pressure and stroke volume was reasonably close except in one patient; however, the group correlation was poor due to differences between individuals.

Authors

Joseph C. Greenfield Jr., Alexander Harley, Howard K. Thompson, Andrew G. Wallace