Corticosteroid Effect on Granulopoiesis in Mice after Cyclophosphamide

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Abstract

Corticosteroids cause an enhanced return of granulopoiesis as measured by in vitro growth of granulocytic progenitor cells (CFU-C) in mice treated with cyclophosphamide. After methylprednisolone and cyclophosphamide, a greater than threefold increase in marrow CFU-C was measured on day 4 compared to mice given cyclophosphamide alone (29,700±200 vs. 8,400±700/humerus). The accelerated return of marrow CFU-C was observed with cyclophosphamide in doses of 200 and 450 mg/kg and methylprednisolone, 2-20 mg/kg, with no significant differences using >5 mg/kg, and was detected when dexamethasone was used in place of methylprednisolone. This effect was accompanied by similarly enhanced splenic granulopoiesis as measured by CFU-C concentration. Levels of colony stimulating activity did not differ in mice given methylprednisolone and cyclophosphamide or cyclophosphamide alone. Corticosteroids appear to enhance the return of CFU-C by altering the proliferative state of granulocytic progenitor cells. CFU-C survival to in vitro 3HTdR suicide increased from 72±4% on day 1 after cyclophosphamide to 90±6% in animals given both cyclophosphamide and methylprednisolone. Increased survival after 3HTdR suicide was also observed when methylprednisolone alone was given. After treatment with cyclophosphamide and methylprednisolone, blood neutrophils increased more rapidly and improved survival to infection with Candida albicans was observed. These studies demonstrate that corticosteroids have a beneficial effect on marrow regeneration after myelotoxic chemotherapy with cyclophosphamide and suggest that they act by altering cell cycle characteristics of granulocyte progenitor cells.

Authors

Robert A. Joyce, Paul A. Chervenick

Stimulation by Alcohols of Cyclic AMP Metabolism in Human Leukocytes: POSSIBLE ROLE OF CYCLIC AMP IN THE ANTI-INFLAMMATORY EFFECTS OF ETHANOL

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Abstract

In this study ethanol and certain other short-chain aryl (benzyl and phenethyl) and aliphatic (methyl, propyl, butyl, and amyl) alcohols produced up to 10-fold increases in cyclic AMP (cAMP) concentrations in purified human peripheral blood lymphocytes. Ethanol concentrations as low as 80 mg/dl produced significant elevations in lymphocyte cAMP. Significant but less marked augmentation of cAMP in response to alcohols was observed in human platelets, human granulocytes, and rabbit alveolar macrophages. The mechanism of the alcohol-induced cAMP accumulation is probably secondary to membrane perturbation and consequent activation of adenylate cyclase, because ethanol directly stimulated this enzyme in lymphocyte membrane preparations but had no effect on lymphocyte phosphodiesterase activity.

Authors

John P. Atkinson, Timothy J. Sullivan, James P. Kelly, Charles W. Parker

Comparison of Nitroglycerin-, Nitroprusside-, and Phentolamine-Induced Changes in Coronary Collateral Function in Dogs

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Abstract

The recent use of vasodilators to improve ventricular function in acute myocardial infarction led us to investigate the effects of nitroglycerin, nitroprusside, and phentolamine on coronary collateral flow. Dogs were studied 2-4 wk after an ameroid constrictor was placed around the left anterior descending (LAD) coronary artery. Retrograde flow and peripheral coronary pressure were measured from a cannula inserted in the LAD distal to the ameroid. Systemic arterial pressure was held constant by an aortic cuff. When administered intracoronary (i.c.), nitroglycerin, 0.3-100 μg/min, or nitroprusside, 3-100 μg/min, produced quantitatively similar, dose-dependent increases in retrograde flow. Neither drug, i.c., changed peripheral coronary pressure. Nitroglycerin, 3-300 μg/min, intravenous (i.v.), produced dose-dependent increases in retrograde flow; nitroprusside, i.v., increased retrograde flow only in high doses (100-300 μg/min). Nitroglycerin and nitroprusside, i.v., produced similar increases in peripheral coronary pressure. Phentolamine, 1-300 μg/min, i.v., decreased retrograde flow, and did not change peripheral coronary pressure. Nitroprusside was considerably more potent than nitroglycerin in decreasing systemic arterial pressure and in reducing total coronary resistance. Thus, (a) although i.c. nitroglycerin and nitroprusside produce similar effects on collateral function, i.v. nitroglycerin is more effective than i.v. nitroprusside in augmenting collateral flow; (b) phentolamine has deleterious effects on collateral function; and (c) the relative vasodilator potencies of nitroglycerin and nitroprusside vary in different vascular beds; thus, for a given reduction in systemic arterial pressure, nitroprusside is less effective in increasing retrograde flow.

Authors

Norine L. Capurro, Kenneth M. Kent, Stephen E. Epstein

Studies on the Mechanism of Ristocetin-Induced Platelet Agglutination: EFFECTS OF STRUCTURAL MODIFICATION OF RISTOCETIN AND VANCOMYCIN

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Abstract

The mechanism by which ristocetin induces platelet agglutination in the presence of the von Willebrand factor was studied by chemically altering ristocetin and a similar antibiotic, vancomycin, by reaction with a water-soluble carbodiimide in the presence of glycine methyl ester at pH 4.75. Altering ristocetin's phenolic groups (which are thought to be important in its peptide-binding properties) resulted in a loss of both platelet-agglutinating and antibiotic activities. Restoring the phenolic groups with hydroxylamine restored both activities.

Authors

Barry S. Coller, Harvey R. Gralnick

Metabolism of Autologous and Homologous IgG in Rheumatoid Arthritis

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Abstract

The metabolism of radioiodinated IgG was studied in 20 patients with rheumatoid arthritis and 11 normal controls using autologous IgG and homologous IgG pooled from normal donors. Fractional catabolic rates in the controls were 4.44% of the autologous- and 4.29% of the homologous-labeled protein per day. The corresponding rates in the rheumatoid patients were 9.67% of the autologous- and 8.64% of the homologous-labeled protein per day. Extravascular catabolism occurred only in the rheumatoid group and accounted essentially for the entire increased catabolism of IgG observed in these patients. 10 patients were especially hypercatabolic, with fractional catabolic rates for autologous IgG greater than 10%. Moreover, they catabolized their autologous IgG significantly faster than the homologous IgG (12.6 vs. 9.9%). The increment of catabolism of autologous over homologous IgG also occurred in the extravascular compartment. These highly hypercatabolic patients had a significantly increased number of manifestations of extra-articular disease.

Authors

Michael A. Catalano, Edwin H. Krick, David H. De Heer, Robert M. Nakamura, Argyrios N. Theofilopoulos, John H. Vaughan

The Mechanism of Adaptation of Left Atrial Stretch Receptors in Dogs with Chronic Congestive Heart Failure

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Abstract

Chronic congestive heart failure (CHF) was induced in dogs by the construction of an aorto-caval fistula below the level of the renal arteries. Aorto-caval fistula dogs showed signs of CHF which included ascites, hind limb edema, and pulmonary congestion. Ventricular catheterization indicated a significantly higher left ventricular end diastolic pressure and lower maximum velocity of left ventricular pressure development/left ventricular end diastolic pressure in CHF dogs when compared to sham-operated controls. Heart weight/body weight ratios were significantly higher in CHF dogs. Electrophysiological recordings from medullated left atrial type B receptors from the cervical vagus indicated a depressed sensitivity of these receptors in CHF dogs when compared to sham-operated control dogs. For any given change in left atrial pressure, the discharge of left atrial receptors was significantly reduced in CHF dogs compared with sham-operated controls. The mechanism for this depressed sensitivity was investigated. Sonomicrometry of the left atrial appendage indicated a decreased compliance of the left atrial appendage in the dogs with chronic CHF. In addition, microscope examination of the complex unencapsulated receptor endings taken from the left atrial endocardium indicated a marked alteration in receptor morphology. A loss of the end arborization was the most typical finding. It is concluded that chronic CHF brought about by an aorto-caval fistula results in a depressed left atrial stretch receptor response and that both decreased left atrial compliance and structural alterations in the receptor endings may account for this depressed sensitivity.

Authors

Irving H. Zucker, Alvin M. Earle, Joseph P. Gilmore

Phosphate Control and 25-Hydroxycholecalciferol Administration in Preventing Experimental Renal Osteodystrophy in the Dog

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Abstract

Previous studies from this laboratory demonstrated that secondary hyperparathyroidism in dogs with chronic renal disease may occur, at least in part, as a consequence of the need for progressive adaptation in renal phosphorus (P) excretion that occurs as glomerular filtration rate falls. However, the studies were of relatively short duration. Moreover, no information emerged regarding a potential role of calcium malabsorption in the pathogenesis of secondary hyperparathyroidism. The short duration of the protocol did not lend itself to the study of the effect of P control or the administration of vitamin D in the pathogenesis of renal osteodystrophy. In the present studies, 14 dogs with experimental chronic renal disease were studied serially for a period of 2 yr. Each animal was studied first with two normal kidneys on an intake of P of 1,200 mg/day. Then, renal insufficiency was produced by 5/6 nephrectomy. The dogs then were divided into three groups. In group I, 1,200 mg/day P intake was administered for the full 2 yr. In group II, P intake was reduced from the initial 1,200 mg/day, in proportion to the measured fall in glomerular filtration rate, in an effort to obviate the renal adaptation in P excretion. In group III, “proportional reduction” of P intake also was employed; but in addition, 20 μg of 25(OH)D3 were administered orally three times a week.

Authors

W. E. Rutherford, P. Bordier, P. Marie, K. Hruska, H. Harter, A. Greenwalt, J. Blondin, J. Haddad, N. Bricker, E. Slatopolsky

Hormonal Control of Adrenocortical Cell Proliferation: DESENSITIZATION TO ACTH AND INTERACTION BETWEEN ACTH AND FIBROBLAST GROWTH FACTOR IN BOVINE ADRENOCORTICAL CELL CULTURES

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Abstract

A primary bovine adrenocortical cell culture system responsive to physiological concentrations of ACTH has been established. When added to cultures, ACTH inhibited DNA synthesis and cell division over the same concentration range required for stimulation of fluorogenic steroid production (0.01-10 nM). With chronic exposure to ACTH, cells became desensitized to the growth inhibitory effects of ACTH. Though cell growth was initially completely inhibited by ACTH, cells ultimately began to grow in its continued presence. The lag time to initiation of cell growth, the rate of growth, and the final density achieved depended on the ACTH concentration. Desensitization to ACTH1-39 was not induced by monobutyryl cyclic AMP nor by ACTH11-24. Specificity of desensitization was apparent because cells which had become desensitized to ACTH1-39 remained fully responsive to monobutyryl cyclic AMP, prostaglandin E1, and cholera toxin. Though the effects of ACTH on cell growth were readily reversible upon hormone removal, the desensitized response to readdition of ACTH persisted for at least 8 h.

Authors

Peter J. Hornsby, Gordon N. Gill

Effects of Propranolol on Regional Myocardial Function, Electrograms, and Blood Flow in Conscious Dogs with Myocardial Ischemia

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Abstract

The effects of coronary occlusion and of subsequent propranolol administration were examined in 18 conscious dogs. Overall left ventricular (LV) function was assessed by measurements of LV pressure and dP/dt, and regional myocardial function was assessed by measurements of segment length (SL), velocity of SL shortening and regional myocardial “work”, i.e., pressure-length loops in normal, moderately, and severely ischemic zones. Regional intra-myocardial electrograms were measured from the same sites along with regional myocardial blood flow as determined by the radioactive microsphere technique. Coronary occlusion resulted in graded loss of function from the normal to severely ischemic zones with graded flow reduction and graded elevation of the ST segment. Propranolol depressed overall LV function, function in the normal zone (work fell by 17±4%), and in the majority of moderately ischemic segments (work fell by 7±3%). In severely ischemic segments the extent of paradoxical motion and post-systolic shortening was reduced by propranolol. After propranolol regional myocardial blood flow fell in the normal zone (11±2%) and rose in the moderately (15±4%) and severely (63±10%) ischemic zones. Thus, in the conscious dog with regional myocardial ischemia, propranolol induces a redistribution of myocardial blood flow, with flow falling in normal zones and rising in moderately and severely ischemic zones. The improvement in perfusion of ischemic tissue was associated with slight but significant depression of shortening, velocity, and work in the moderately ischemic zones and of paradoxical bulging and post-systolic shortening in the severely ischemic zone.

Authors

Stephen F. Vatner, Hank Baig, W. Thomas Manders, Hermann Ochs, Massimo Pagani

The behavior of alpha2-plasmin inhibitor in fibrinolytic states.

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Abstract

Human plasma alpha2-plasmin inhibitor in fibrinolytic states was studied using immunochemical methods and radioiodinated plasminogen. The concentration and activity of plasma alpha2-plasmin inhibitor decreased when urokinase was added to plasma in vitro or infused intravenously in man. The decrease was associated with the appearance of plasmin-alpha2-plasmin inhibitor complex which subsequently disappeared from the circulation in a short time. A decrease of other major inhibitors, such as alpha2-macroglobulin and alpha1-antitrypsin, was not observed when the amount of urokinase added or infused was relatively small, and conversion of plasminogen to plasmin was not extensive. The formation of plasmin-alpha2-macroglobulin complex was observed only when plasma plasminogen was activated with a larger amount of urokinase, and after most of the alpha2-plasmin inhibitor was consumed by forming complexes with plasmin. The formation of plasmin-alpha1-antitrypsin complex was not observed even in the highly activated plasma unless exogenous plasmin was added to the plasma. alpha2-Plasmin inhibitor was the only inhibitor of which the concentration in plasma was significantly decreased in patients with disseminated intravascular coagulation and fibrinolysis among the major plasmin inhibitors in plasma. The most reactive inhibitor for regulating plasma fibrinolysis very likely is alpha2-plasmin inhibitor.

Authors

N Aoki, M Moroi, M Matsuda, K Tachiya

Evidence for hydroxyl radical generation by human Monocytes.

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Abstract

A number of highly reactive oxygen species have been implicated in the oxygen-dependent mechanisms involved in bactericidal activity of phagocytic leukocytes. Hydrogen peroxide and superoxide, two agents known to occur during phagocytosis, are thought to interact to generate hydroxyl radical, singlet oxygen, and other potentially reactive molecules. Using an assay system of ethylene generation from methional, cell preparations of human monocytes were demonstrated to generate hydroxyl radical or a similar agent during phagocytosis of zymosan particles. The generation of ethylene was impaired by agents which reduce superoxide or hydrogen peroxide concentrations as well as by agents reported to be hydroxyl radical scavengers. The ethylene generation did not appear to be dependent on myeloperoxidase in that azide enhanced ethylene generation. Monocytes from a patient with chronic granulomatous disease failed to generate ethylene during phagocytosis. This assay technique may be useful in exploring the metabolic events integral to the bactericidal and inflammatory activity of phagocytic leukocytes.

Authors

S J Weiss, G W King, A F LoBuglio

Evidence for hydroxyl radical production by human neutrophils.

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Abstract

The possibility that neutrophils produce the hydroxyl radical (OH-) was studied by examining the ability of these cells to support the release of ethylene from methional, a reaction in which it has been shown that OH-, but not O2- or H2O2, may serve as the oxidizing agent. When neutrophils were exposed to opsonized zymosan in the presence of 0.35 mM methional, ethylene was released in quantities amounting to 44.6+/-3.6 pmol/10(6) cells/40 min. Ethylene production required the presence of neutrophils, opsonized zymosan, and methional, indicating that it was formed from methional by stimulated but not resting neutrophils. Ethylene was not produced by zymosan-treated cells from patients with chronic granulomatous disease, confirming the requirement for respiratory burst activity in this process. Ethylene production was suppressed by benzoic acid, an OH- scavenger. Superoxide dismutase (3 microgram/ml) reduced ethylene production to 21% of control levels, but catalase had no significant effect in this system. These findings indicate that stimulated neutrophils produce a highly reactive oxidizing radical, possibly OH-, which releases ethylene from methional, and that the O2-generated during the respiratory burst is involved in the production of this reactive species.

Authors

A I Tauber, B M Babior

Comparative Study of Protoporphyrins in Erythropoietic Protoporphyria and Griseofulvin-Induced Murine Protoporphyria: BINDING AFFINITIES, DISTRIBUTION, AND FLUORESCENCE SPECTRA IN VARIOUS BLOOD FRACTIONS

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Abstract

Excess erythrocyte protoporphyrins of human congenital erythropoietic protoporphyria and of griseofulvin-induced murine hepatic protoporphyria were found to be associated with hemoglobin and stroma fractions in similar relationships. More than 99.5% of total erythrocyte protoporphyrin was bound to hemoglobin in each case. However, profound differences were found when protoporphyrin concentration was measured in erythrocytes that had been segregated into populations of progressive age on discontinuous density gradients. In erythropoietic protoporphyria, porphyrin content diminished rapidly with age; in murine protoporphyria, the aging erythrocyte populations became progressively more porphyrin rich. In vitro diffusion of protoporphyrin from plasma across the intact erythrocyte membrane was demonstrated. The equimolar binding affinity of protoporphyrin to hemoglobin was shown to be 40 times that of protoporphyrin to serum albumin. This strong affinity provides the driving force for the observed transmembrane diffusion, and explains the high erythrocyte/plasma porphyrin ratio in murine hepatic protoporphyria. The opposite rapid efflux of intra-erythrocytic protoporphyrin into plasma previously shown in uncomplicated erythropoietic protoporphyria occurs despite this strong hemoglobin affinity, implying continuous efficient clearance of protoporphyrin from plasma by the liver. Furthermore, these and other data suggest that a hepatic synthetic source for any significant fraction of the blood protoporphyrin in erythropoietic protoporphyria is highly improbable.

Authors

Maureen B. Poh-Fitzpatrick, Angelo A. Lamola, Gregory L. Zalar, Mark Weinstein, Frank Doleiden, Maria Freeman

Stabilization of Factor VIII in Plasma by the von Willebrand Factor: STUDIES ON POSTTRANSFUSION AND DISSOCIATED FACTOR VIII AND IN PATIENTS WITH VON WILLEBRAND'S DISEASE

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Abstract

In normal plasma, the ratio of the procoagulant activity of factor VIII (VIIIAHF) to that of the von Willebrand factor activity (ristocetin cofactor, VIIIVWF) or factor VIII antigen (VIIIAGN) is ∼1, but ratios > 1 (e.g., VIIIAHF > VIIIVWF or VIIIAGN) may be observed in some patients with von Willebrand's disease and in the “late” posttransfusion plasmas of patients with this disorder. The lability of VIIIAHF was studied by incubating plasma, diluted 1:10 in imidazole buffer pH 7.1, for 6 h at 37°C. With normal plasmas, 77±12% (SD) of the original VIIIAHF activity remained after incubation. VIIIAHF was labile (e.g., 35-55% residual activity) in the “late” posttransfusion plasmas (VIIIAHF ≫ VIIIVWF) of a patient with von Willebrand's disease, but not in the “early” posttransfusion plasmas (VIIIAHF ∼ VIIIVWF). VIIIAHF was also labile in the (base-line) plasmas of three patients with von Willebrand's disease in whom the ratios of VIIIAHF to VIIIVWF were 4.4 to 8.1, but not in the plasmas of four other patients in whom the ratio was ∼ 1. The electrophoretic mobility of factor VIII antigen was increased in two of the three patients with labile VIIIAHF. In both of these patients, and in the late posttransfusion plasmas, labile VIIIAHF activity could be stabilized by the addition of purified von Willebrand factor (lacking VIIIAHF activity) or by hemophilic plasma, but not by plasmas of patients with severe von Willebrand's disease. Thus, VIIIVWF may serve to stabilize VIIIAHF and this might explain the posttransfusion findings in von Willebrand's disease.

Authors

Harvey J. Weiss, Ira I. Sussman, Leon W. Hoyer

Autoantibodies to B Lymphocytes in a Patient with Hypoimmunoglobulinemia: CHARACTERIZATION AND PATHOGENIC ROLE

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Abstract

In a young woman with ulcerative colitis, hypoimmunoglobulinemia, and humoral immunodeficiency, lymphocyte counts vary between 600 and 1,000 per mm3 with 0.5-1.5% bone marrow-derived (B) cells and 98-99% thymus-derived (T) cells. Anti-lymphocyte antibodies were detected by immunofluorescence and by microlymphocytotoxicity with increased reactivity at +4°C. They belonged to the IgM class and were polyclonal. Studies performed with various normal lymphocyte subpopulations, several lymphoblastoid cell lines and lymphocytes from immunodeficiency patients showed that these antibodies reacted with B cells. The corresponding antigen(s) is distinct from membrane-bound immunoglobulins, is not an alloantigen, and is probably unrelated to the la-like molecules. Pokeweed mitogen stimulated B cells appear to lose this antigen. Cells from various lymphoproliferative disorders were tested. T-derived and “non T-non-B” leukemic cells did not react with the antibody. Malignant cells from B-derived lymphomas and prolymphocytic leukemias were reactive. The incidence of positivity of the leukemic cells among patients with common B chronic lymphocytic leukemia was surprisingly low (one-third of the patients).

Authors

Thomas Tursz, Jean-Louis Preud'Homme, Sylvaine Labaume, Claude Matuchansky, Maxime Seligmann

The Origin of Chylomicron Phosphatidylcholine in the Rat

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Abstract

This study investigates the pathways of origin of chylomicron phosphatidylcholine (PC) using a lymph- and bile-fistulated rat infused with a stabilized triolein emulsion. [14C-glycerol]PC was used to evaluate chylomicron PC generated by lyso PC acyltransferase. The percentage of chylomicron PC derived from the PC infused was directly proportional to the PC concentration in the infusate. When the infusate PC concentration was 10 mM, essentially all the chylomicron PC was derived therefrom at 4-6 h of infusion. Incorporation of the radiolabel was not found to be as great in the lymph subnatant PC as in chylomicron PC, suggesting that chylomicron and lymph subnatant PC might be supplied from different PC precursor pools.

Authors

Charles M. Mansbach II

The Role of the Liver in Glucagon Metabolism

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Abstract

Total plasma immunoreactive pancreatic glucagon (IRG) was measured in samples taken simultaneously from the proximal portal vein and superior vena cava of 26 healthy rats. The portal-peripheral ratio of IRG was 2.80±0.25, the portal-peripheral difference (Δ) 124±15 pg/ml, and percentage extraction 58±3. Gel filtration of paired portal and peripheral vein samples showed that reduction in the 3,500-dalton IRG component (glucagon) in peripheral samples accounted for almost all the differences, there being minimal and inconsistent changes in the high molecular weight (>40,000) fraction. The portal-peripheral ratio of the 3,500-dalton glucagon was 5.24±1.10, the portal-peripheral difference 130±33 pg/ml, and the percentage extraction 81±5.

Authors

Jonathan B. Jaspan, Alice H-J. Huen, Colin G. Morley, A. Rahim Moossa, Arthur H. Rubenstein

Relationship between bile flow and Na+, K+-adenosinetriphosphatase in liver plasma membranes enriched in bile canaliculi.

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Abstract

The relationship between bile flow and Na+,K+-ATPase activity in liver plasma membranes enriched in bile canaliculi was studied in rats treated with ethinyl estradiol, phenobarbital, or 20-methyl cholanthrene. In comparison with controls (1.49+/-0.12 microliter/min per g liver), bile flow was significantly diminished by ethinyl estradiol, increased by phenobarbital, and unchanged by 20-methyl cholanthrene or the solvent, propanediol (0.92+/-0.31, 2.50+/-0.21, 1.62+/-0.18, and 1.64+/-0.30 microliter/min per g liver, respectively). The corresponding values for canalicular Na+,K+-ATPase activity were 80.7+/-19.2, 50.0+/-18.4, 231.7+/-42.6, 82.7+/-30.7, and 143.6+/-55.3 micronmol Pi/h per g liver. Canalicular Na+,K+-ATPase activity was significantly correlated (r=0.785, n=31) with bile flow. These findings support the hypothesis that a fraction of bile flow is related to Na+,K+-ATPase activity and canalicular Na+ transport.

Authors

J Reichen, G Paumgartner

Studies on the role of cephalic-vagal stimulation in the acid secretory response to eating in normal human subjects.

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Abstract

These experiments were performed to determine the importance of cephalic-vagal stimulation in the acid secretory response to eating in normal human subjects. Cephalic stimulation was induced by a modified sham feeding (MSF) technique, during which subjects chewed and expectorated appetizing food. The response to MSF was compared with that to gastric distention with 600 ml NaCl, glucose, or food. In addition, we measured the extent to which cephalic stimulation augments acid secretion that has been stimulated simultaneously by these other mechanisms. Our conclusions are as follows: (a) cephalic stimulation accounts for approximately one-third of the acid secreted when all mechanisms act simultaneously (food-distention plus MSF); (b) within the limits imposed by the maximal secretory capacity, the response to MSF is approximately the same, regardless of whether acid secretion is otherwise unstimulated or is stimulated simultaneously by gastric distention with NaCl, glucose, or food; and (c) gastric distention prolongs the response to cephalic stimulation.

Authors

C T Richardson, J H Walsh, K A Cooper, M Feldman, J S Fordtran

Perifusion of Isolated Rat Adipose Cells: MODULATION OF LIPOLYSIS BY ADENOSINE

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Abstract

Incubation of isolated rat epididymal fat cells is associated with the accumulation of adenosine in the incubation medium. To more clearly define the effect of adenosine on lipolysis, isolated rat epididymal adipocytes were studied with the perifusion system.

Authors

B. Paul Turpin, William C. Duckworth, Solomon S. Solomon

A New Antigen System Expressed in Human Endothelial Cells

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Abstract

Kidney transplant recipients were previously found to have antibodies that reacted with cells isolated from the endothelium of umbilical cord veins and which were not cytotoxic for lymphocytes from the same donors. Results of the present experiments indicate that endothelial (E) antigens are different from previously known HLA antigens and also from Ia-like antigens of bone marrow-derived (B) lymphocytes. Attempts to absorb E antibodies with lymphocytes from E-positive donors failed in most cases. Antigen redistribution experiments showed that E antigens were located in separate molecules from the products of HLA-A, B, and C. Thus, E cells treated with E antibody became resistant to lysis by the antibody used, but remained susceptible to the effects of typing sera for alleles of HLA-A, B, and C. Antibodies to E cells were also cytotoxic for blood monocytes. Moreover, monocytes were able to absorb E-antibody reactions, indicating that similar antigens were expressed in both cells. E antibodies did not react with B lymphocytes isolated from peripheral blood. In that regard E antibodies were different from antibodies to human Ia-like antigens which reacted with E cells, monocytes, and isolated B lymphocytes. Thus it appears that E antigens constitute a system of human alloantigens which has not been previously identified. The possibility that these antigens play a role in kidney allograft rejection should now be investigated since matching can be performed using monocytes isolated from the blood of recipients and donors.

Authors

J. Roberto Moraes, Peter Stastny

Massive Extraglandular Aromatization of Plasma Androstenedione Resulting in Feminization of a Prepubertal Boy

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Abstract

This report describes the mechanism of origin and the quantity of estrogen produced in a prepubertal boy who developed severe feminization at 8 yr of age as the result of a heretofore undescribed metabolic abnormality. The clinical findings were gynecomastia and accelerated linear growth and bone maturation. At the time feminization developed, there were no signs of growth or development of the otherwise normal prepubertal male external genitalia or any increase of muscle mass that normally accompanies male puberty.

Authors

David L. Hemsell, Clare D. Edman, James F. Marks, Pentti K. Siiteri, Paul C. MacDonald

The Production of Antibody against Human Leukocytic Pyrogen

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Abstract

Human peripheral blood leukocytes were stimulated with killed staphylococci in vitro to release leukocytic pyrogen (LP). Supernates from these stimulated leukocytes were concentrated, emulsified in Freund's complete adjuvant, and injected intradermally into rabbits. After seven monthly booster injections, rabbit antiserum destroyed the pyrogenic activity of human LP, and the titer of this neutralizing ability increased in the subsequent 7 mo. The pyrogen-neutralizing capacity of the rabbit antiserum was recovered in the globulin fraction, the IgG and IgM peaks of Sephadex G-200, and the acid-eluted fraction of a goat anti-rabbit IgG immunoadsorbant. The neutralizing antibody was specific for human LP inasmuch as it had no effect on rabbit, guinea pig, or monkey LP. When coupled to Sepharose, this antibody bound human LP; after acid elution from this immunoadsorbant, LP was recovered without loss of biologic or chemical characteristics. The antiserum was also absorbed with stimulated leukocyte supernates which did not contain LP, and this had no effect on the titer of anti-LP. Crude human LP, eluted from immunoadsorbant columns prepared from absorbed antiserum, contained significantly reduced contaminating protein when evaluated by polyacrylamide gel electrophoresis. These studies have established that specific antibody to human leukocytic pyrogen can be produced. This antibody is useful in the further study and purification of leukocytic pyrogen and its role in the pathogenesis of human fever.

Authors

Charles A. Dinarello, Lois Renfer, Sheldon M. Wolff

Respiratory Muscle Blood Flow Distribution during Expiratory Resistance

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Abstract

When work load on the respiratory system is increased the relative increase in blood flow to each of the muscles of breathing provides an index of how the augmented effort of breathing is partitioned among the different muscles. We have used a radio-active microsphere technique to measure blood flow to each of the muscles of respiration in supine dogs during unobstructed respiration and breathing against graded expiratory threshold loads. 79% of the augmented flow went to expiratory muscles; of this increased flow to expiratory muscles 74% went to abdominal wall muscles and 26% to internal intercostals. In our earlier studies of hyperventilation induced by CO2 rebreathing where expiratory work loads were low, 44% of the increase in flow went to expiratory muscles; of this, only 39% went to abdominal wall muscles and 61% to internal intercostals. During inspiratory resistance which produced small increases in expiratory work, 27% of the increase in blood flow went to expiratory muscles; of this, only 37% went to abdominal wall muscles and 63% to internal intercostals. These results suggest that the internal intercostals are predominantly used for expiration when expiratory work loads are low, whereas the abdominal wall muscles are predominantly used when loads are high.

Authors

Charles H. Robertson Jr., William L. Eschenbacher, Robert L. Johnson Jr.

Activation of Rabbit Platelets by Platelet-Activating Factor Derived from IgE-Sensitized Basophils: CHARACTERISTICS OF THE AGGREGATION AND ITS DISSOCIATION FROM SECRETION

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Abstract

Platelet-activating factor (PAF) is liberated from antigen-stimulated, IgE-sensitized rabbit basophils and induces aggregation of platelets and secretion of their content of vasoactive amines. Experiments were performed to determine the relationship between these two platelet responses to this stimulus.

Authors

Peter M. Henson

Orotic aciduria in two unrelated patients with inherited deficiencies of purine nucleoside phosphorylase.

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Abstract

The urines of two unrelated children with inherited deficiencies of purine nucleoside phosphorylase have been found to contain significant quantities of orotic acid in addition to the previously reported purine nucleosides. The data are consistent with some cell types of these immunodeficient patients being deplete of pyrophosphoribosylphosphate, a precursor of both purine, and pyrimidine nucleosides. It is suggested that the pyrophosphoribosyl-phosphate-depleted cells may be some component of the thymus-dependent immune system.

Authors

A Cohen, G E Staal, A J Ammann, D W Martin Jr

The mobilization of arachidonic acid in platelets exposed to thrombin or ionophore A23187. Effects of adenosine triphosphate deprivation.

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Abstract

In studies conducted with human gel-filtered platelets, we have found: (a) that the release of serotonin and transfer of [3H]arachidonic acid from phosphatidylcholine and phosphatidylinositol to plasmalogen phosphatidylethanolamine which are associated with the activation of platelets by thrombin are both strongly dependent upon the presence of metabolic ATP; (b) that serotonin release and arachidonic acid mobilization in labeled phosphatides are promoted by the calcium ionophore A-23187 in media free of calcium ions; (c) that inhibitors of ATP synthesis, while leading to impairment of the release reaction induced by ionophore, do not inhibit ionophore-stimulated mobilization of arachidonic acid. We conclude that the activation of phospholipase A2 responsible for freeing arachidonic acid from platelet phosphatides is solely dependent upon the increased cytoplasmic levels of calcium ions promoted by either ionophore or, in an energy-dependent fashion by thrombin. Phospholipase activation is not a function of latent hydrolytic activity made available by the release reaction.

Authors

S Rittenhouse-Simmons, D Deykin