Resting Skeletal Muscle Membrane Potential as an Index of Uremic Toxicity: A PROPOSED NEW METHOD TO ASSESS ADEQUACY OF HEMODIALYSIS

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Abstract

Electrochemical disturbances of skeletal muscle cells in untreated uremia are characterized by an increase in the intracellular sodium and chloride content, a decrease in intracellular potassium, and a low resting membrane potential. In this study, we have reexamined the foregoing and, in addition, have examined the effects of hemodialysis. Three groups of patients were studied. In the first group of 22 uncomplicated uremic patients, whose creatinine clearance (Ccr) ranged from 2 to 12 cm3/min per 1.73 m2, resting transmembrane potential difference (Em) of skeletal muscle cells was measured. In each of the nine patients whose Ccr ranged between 6.3 and 12 cm3/min, the Em was normal (i.e., −90.8±0.9 mV, mean±SEM). However, as Ccr dropped below 6.3 cm/min, the Em became progressively reduced and assumed a linear relationship with the Ccr.

Authors

James R. Cotton, Terry Woodard, Norman W. Carter, James P. Knochel

Production of Erythrocytes that Contain Fetal Hemoglobin in Anemia: TRANSIENT IN VIVO CHANGES

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Abstract

Serial microscopic immunodiffusion assays of F cells, i.e., erythrocytes that contain fetal hemoglobin (HbF), in four individuals recovering from anemia demonstrate initial increases in the percentage of circulating reticulocytes that contain HbF (F reticulocytes) and subsequent increases in the percentage of mature erythrocytes that contain HbF (F erythrocytes). In one individual responding to therapy for iron-deficiency anemia, the average percentage of F reticulocytes increased from 4.8±1.1 to 16.0±2.8% (mean±SD), while the mean level of F erythrocytes increased from 3.5±0.7 to 7.2±0.6%. Two normal children with transient erythroblastopenia exhibited F reticulocyte percentages of 71.3±6.7 and 41.5±1.5%, respectively, when erythropoiesis resumed. With recovery these values fell to finally measured values of 33.7±4.7 and 12.6±1.1%, respectively. In an adolescent with sickle cell anemia, F-reticulocyte percentages fluctuated between 0.6±1.1 and 34.0±2.8% and paralleled the rise and fall of total reticulocytes associated with therapy for a nasopharyngeal carcinoma.

Authors

George J. Dover, Samuel H. Boyer, William H. Zinkham

Changes in Lymphocyte Activity after Thermal Injury: THE ROLE OF SUPPRESSOR CELLS

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Abstract

The high incidence of fatal septicemia associated with severe thermal injury is believed to result from a loss of immunocompetence. To detect burn-mediated immune defects, lymphocyte function in peripheral blood leukocytes from 18 individuals sustaining 20-80% full thickness thermal burns was investigated. We examined the kinetics of the mitogen responses, the development of suppressive activity, and the correlation of mononuclear cell functional abnormalities with the incidence of sepsis. Patients were divided into three groups corresponding to their clinical course. The phytohemagglutinin responses of Ficoll-Hypaque purified leukocytes from eight of these patients (group III) were normal at day 1-2 after injury, but were significantly depressed (mean 16% of normal) at days 5-10 after injury. All of these group III patients experienced multiple, severe, septic episodes, and septic mortality was 75%. The other 10 burned individuals showed either augmented (group II) or unaltered (group I) mitogen responsiveness.

Authors

Carol L. Miller, Christopher C. Baker

Motility and Adhesiveness in Human Neutrophils: EFFECTS OF CHEMOTACTIC FACTORS

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Abstract

Human peripheral blood neutrophils (PMN) obtained from healthy adults were examined in vitro with techniques adapted to assess the effects of chemotactic factors (CF) on cellular configuration and adhesiveness. The results were compared with those that use certain conventional techniques for assessing chemotaxis and chemokinesis. Exposure of PMN to N-formyl-l-methionyl-l-phenylalanine (f-Met-Phe), zymosan-activated serum, bacterial chemotactic factor, or a low molecular weight chemotactic factor from activated serum (C5a) in the absence of a gradient resulted in a change in cellular shape from a spherical to a polarized configuration in a high percentage of cells. This occurred rapidly in suspension, under conditions designed to exclude a role for cell adhesiveness, and was reversible upon removal of the CF. Restimulation of cells with the CF resulted in reappearance of the polarized configuration to the same extent as on initial stimulation with one exception: f-Met-Phe pretreated cells failed to respond to f-Met-Phe, though they responded fully to the other CF. Each CF caused a significant increase in PMN attachment to protein-coated glass. This enhanced adhesiveness was not reversible upon removal of the CF when the cells were treated under conditions shown to produce chemotactic deactivation. Cells treated under these conditions also exhibited significantly reduced motility on glass and in micropore filters in the absence of a gradient of CF. Bacterial chemotactic factor, even at high concentrations, failed to produce deactivation and did not cause a sustained enhancement of adhesiveness.

Authors

C. Wayne Smith, James C. Hollers, Richard A. Patrick, Clare Hassett

Adrenergic Modulation of Pancreatic A, B, and D Cells: α-ADRENERGIC SUPPRESSION AND β-ADRENERGIC STIMULATION OF SOMATOSTATIN SECRETION, α-ADRENERGIC STIMULATION OF GLUCAGON SECRETION IN THE PERFUSED DOG PANCREAS

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Abstract

The effects of adrenergic substances on pancreatic insular secretions were studied in a completely isolated canine pancreas with exclusion of the duodenum from the perfusion circuit. To ensure adequate blockade, blockers were infused before agonists. A dose range of β-receptor blockade was tested, and putative α-adrenergic effects were confirmed by combined α- and β-adrenergic receptor blockade.

Authors

Ellis Samols, Gordon C. Weir

Some Effects of the Administration of Endotoxin in Mice: SPECIFIC CLEAVAGE OF SERUM ALBUMIN BY AN ACID PROTEASE AND THE GENERATION OF AMYLOID SERUM COMPONENT

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Abstract

Endotoxin has been shown to induce amyloidosis in mice and to result in the appearance in serum of large amounts of amyloidrelated protein (SAA). After injection of 300 μg lipopolysaccharide Escherichia coli, SAA behaves as an acute phase reactant with levels reaching a peak of >600 μg/ml at 18-22 h and returning to base line (<50 μg/ml) by 48 h in each of four strains tested; only the endotoxin-resistant C3H/HeJ strain showed a smaller response. Lesser, though significant, elevations were also found after subcutaneous injection of 25 mg of casein, bovine serum albumin, ovalbumin, or monomeric immunoglobulin G, whereas pyrogen-free human serum albumin/U. S. Pharmacopeia failed to raise SAA levels. SAA generation may thus be a result of endotoxin contamination of these protein preparations.

Authors

Peter D. Gorevic, Yoram Levo, Prem C. Chatpar, Blas Frangione, E. C. Franklin

Dopamine during α- or β-Adrenergic Blockade in Man: HORMONAL, METABOLIC, AND CARDIOVASCULAR EFFECTS

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Abstract

We studied the contribution of α- and β-adrenergic receptor activation to the cardiovascular, metabolic, and hormonal effects of dopamine. At a concentration of 1.5 μg/kg·min, the infusion of dopamine in 12 normal volunteers was associated with a transient but significant rise in pulse rate, which was prevented by propranolol. Venous plasma glucose did not change throughout the experiments, and a mild increase in plasma free fatty acid levels observed during the administration of dopamine alone was antagonized by propranolol. In contrast, neither the β-adrenergic blocker, propranolol, nor the α-adrenergic blocker, phentolamine, was effective in inhibiting the dopamine-induced rise in plasma glucagon (from 82±9 to 128±14 pg/ml; P < 0.005) and serum insulin (from 7.5±1 to 13±1.5 μU/ml; P < 0.005) or its suppression of plasma prolactin (from 8.5±1 to 5.2±0.8 ng/ml; P < 0.001). Although serum growth hormone levels did not change during the infusion of dopamine alone, an obvious rise occurred in three subjects during the combined infusion of propranolol and dopamine.

Authors

Mara Lorenzi, John H. Karam, Eva Tsalikian, Nancy V. Bohannon, John E. Gerich, Peter H. Forsham

Synergistic Interactions of Physiologic Increments of Glucagon, Epinephrine, and Cortisol in the Dog: A MODEL FOR STRESS-INDUCED HYPERGLYCEMIA

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Abstract

To evaluate the role of anti-insulin hormone actions and interactions in the pathogenesis of stress-induced hyperglycemia, the counterregulatory hormones, glucagon, epinephrine, and cortisol were infused alone as well as in double and triple combinations into normal conscious dogs in doses that were designed to simulate changes observed in severe stress. Infusion of glucagon, epinephrine, or cortisol alone produced only mild or insignificant elevations in plasma glucose concentration. In contrast, the rise in plasma glucose produced by combined infusion of any two counterregulatory hormones was 50-215% greater (P < 0.005-0.001) than the sum of the respective individual infusions. Furthermore, when all three hormones were infused simultaneously, the increment in plasma glucose concentration (144±2 mg/dl) was two- to fourfold greater than the sum of the responses to the individual hormone infusions or the sum of any combination of double plus single hormone infusion (P < 0.001).

Authors

Neal Eigler, Luigi Saccà, Robert S. Sherwin

Cholic Acid Biosynthesis: THE ENZYMATIC DEFECT IN CEREBROTENDINOUS XANTHOMATOSIS

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Abstract

Cholic acid biosynthesis is defective in individuals with cerebrotendinous xanthomatosis (CTX) and is associated with the excretion of 5β-cholestane-3α,7α, 12α,25-tetrol, an intermediate in the 25-hydroxylation pathway of cholic acid in CTX. To define the enzymatic defect in CTX, two suspected precursors of cholic acid, namely 5β-[7β-3H]cholestane-3α,7α, 12α-triol and 5β-[24-14C]cholestane-3α,7α, 12α,24S,25-pentol were examined by both in vivo and in vitro experiments. A third precursor, 5β-[7β-3H]-cholestane-3α,7α, 12α,25-tetrol, was compared with them in vitro.

Authors

Gerald Salen, S. Shefer, F. W. Cheng, B. Dayal, A. K. Batta, G. S. Tint

Mechanisms of Lymphocyte Activation: THE ROLE OF SUPPRESSOR CELLS IN THE PROLIFERATIVE RESPONSES OF CHRONIC LYMPHATIC LEUKEMIA LYMPHOCYTES

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Abstract

Binding of 125I-leukoagglutinin (LPHA) to lymphocyte membrane receptors at equilibrium generated similar curvilinear Scatchard plots in 20 patients with bursa-derived (B)-cell-type chronic lymphatic leukemia (CLL) and 15 controls. If biphasic plots are assumed, the two linear components show markedly diminished receptor capacity (15 and 137 ng/106 lymphocytes) in CLL as compared to controls (60 and 668 ng). In contrast, affinity was similar in patients (1.0 × 108 M−1 and 2.1 × 106 M−1) and controls (1.8 × 108 M−1 and 1.5 × 106 M−1). Highly purified B cells from patients and controls generated binding data comparable to that obtained from the mixed lymphocyte (ML) suspensions from which they originated. Maximal DNA synthesis of highly purified, normal, thymus-derived (T) and B cells in response to LPHA stimulation was comparable to that of ML (mitotic index [MI] 19.9, 20.1, and 23.4, respectively), though B-cell responses were slightly delayed. In CLL the markedly decreased and delayed DNA synthesis by ML (MI 2.3), and by highly purified T (MI 1.6) and B (MI 1.9) cells seemed out of proportion to their decreased receptor capacity for LPHA. The impaired mitogenic responses of leukemic cells from five patients were not enhanced when cocultured with normal lymphocytes. In contrast, cells from eight patients inhibited cocultured normal lymphocyte responses to LPHA by 94.3%. Sera from these patients and supernates from their cultured cells did not mediate this suppressor effect. These observations indicate that the decreased DNA synthesis observed in CLL is not an attribute of B cells and does not represent the expected response of a few residual normal T lymphocytes, but rather reflects impaired responses by all CLL cells. The defect does not relate to the density or function of membrane receptors for LPHA, to the presence of inhibitors in these patients' sera, or to depletion of helper T cells. Our data strongly suggest that one mechanism for the immunoincompetence observed in CLL reflects excessive suppressor-cell activity.

Authors

Guy B. Faguet