Effects of vasopressin and prostaglandin E₁ on the adenyl cyclase—cyclic 3′,5′-adenosine monophosphate system of the renal medulla of the rat

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Abstract

Vasopressin increased adenyl cyclase activity in homogenates of both inner and outer renal medulla of the rat. It also increased the concentration of cyclic 3′,5′-adenosine monophosphate (AMP) in slices of both inner and outer medulla but not in renal cortex. In the inner medulla, a concentration of prostaglandin E1 (PGE1), which was ineffective by itself significantly reduced the stimulation of adenyl cyclase activity and cyclic AMP concentration induced by vasopressin. These results are consistent with the hypothesis that PGE1 can compete with vasopressin for adenyl cyclase-binding sites. However, the findings in the outer medulla suggest the situation is more complex. Although 10-8 M PGE1 had no effect by itself and inhibited the vasopressin-induced elevation of cyclic AMP, larger amounts of PGE1 increased both adenyl cyclase activity and cyclic AMP levels. The maximum effect on the latter parameter was at least 6 times as great as that of maximum amounts of vasopressin.

Authors

Nama P. Beck, Toshio Kaneko, Uriel Zor, James B. Field, Bernard B. Davis

Oxidant injury of caucasian glucose-6-phosphate dehydrogenase—deficient red blood cells by phagocytosing leukocytes during infection

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Abstract

Patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency of red blood cells (RBC) may develop sudden hemolytic anemia during infection. Since phagocytizing polymorphonuclear leukocytes (PMN) are known to generate hydrogen peroxide, we explored the influence of this oxidant product of PMN on juxtaposed G6PD-deficient and normal RBC. The oxidant stress induced by phagocytosis depleted G6PD-deficient RBC of reduced glutathione (GSH) and this was associated with rapid removal of these cells from the circulation by the liver and spleen. No such effect was observed on normal RBC. Phagocytizing chronic granulomatous disease (CGD) PMN which lack hydrogen peroxide generation, failed to diminish GSH level in G6PD-deficient RBC. Thus, PMN can pose as a source of oxidant damage to G6PD-deficient RBC due to hydrogen peroxide generated during phagocytosis.

Authors

Robert L. Baehner, David G. Nathan, William B. Castle

Effects of 3-nitro-l-tyrosine on thyroid function in the rat: an experimental model for the dehalogenase defect

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Abstract

The effects on thyroid function of an inhibitor of tyrosine dehalogenase, 3-nitro-L-tyrosine (MNT) have been investigated in rats. In preliminary studies, marked inhibition of iodotyrosine deiodination was demonstrated in rats drinking 8 mM MNT. A series of experiments was then performed in which rats received Remington low iodine diet and 8 mM MNT as drinking fluid. This regimen had the following effects, compared to the effects of a low iodine diet alone: (a) a decrease in serum protein-bound iodine, elevation of serum thyrotropin level, goiter, and growth inhibition all prevented or reversed by iodine supplements: (b) on initiation of MNT, a 2- to 3-fold increase in the rate of release of radioiodine from the thyroid and concomitant urinary excretion of large amounts of organic iodine: and (c) after 2 wk of MNT, a greatly increased rate of thyroidal uptake and release of 131I, an increase in the ratio of monoiodotyrosine-131I to diiodotyrosine-131I in thyroid proteolysates and the appearance of labeled iodotyrosines in serum.

Authors

William L. Green

Defective control of ribosomal RNA processing in stimulated leukemic lymphocytes

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Abstract

The kinetics of ribosomal RNA transcription and processing were assessed in chronic lymphocytic leukemia (CLL) lymphocytes during the initial phases of their delayed response to phytohemagglutinin. When compared to cultures of normal lymphocytes, CLL cultures developed normal augmentations in 45S rRNA precursor transcription and cleavage after a 1 hr incubation with PHA. However, failure to conserve 18S RNA subunits persisted in the CLL cultures. Subsequently the PHA-induced progressive rise in 45S RNA transcription became aborted and the over-all rate of RNA synthesis lagged far behind the levels attained by normal cultures incubated with PHA for 48 hr. CLL cultures responding to PHA in a delayed fashion exhibited efficient conservation of 18S RNA at 168 hr. In normal cultures, PHA-induced conservation of 18S RNA appeared to be independent of any effect on 45S ribosomal RNA precursor transcription. Therefore, the sluggish growth response of CLL lymphocytes was associated with a defect in one of the important mechanisms regulating assembly of new ribosomes.

Authors

Arnold D. Rubin

Inhibition by sulfonamides of the candidacidal activity of human neutrophils

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Abstract

Sulfonamides reduced substantially the ability of normal human neutrophils to kill strains of Candida albicans and Candida tropicalis, and impaired to a lesser extent their activity against Staphylococcus aureus 502A and Serratia marcescens. Sulfonamides also inhibited (a) iodination of Candida cells by normal neutrophils; (b) candidacidal activity in cell-free systems containing purified human myeloperoxidase, hydrogen peroxide, and potassium iodide; and (c) accumulation of molecular iodine in analogously constructed cell-free systems. In contrast to these effects on reactions catalyzed by myeloperoxidase, sulfonamides exerted relatively little effect on the levels of microbicidal activity manifested by human neutrophils that lacked myeloperoxidase. Sulfonamides appear to influence the function of human neutrophils predominantly by interfering with myeloperoxidase-mediated pathways. Certain basic and clinical implications of these data are discussed.

Authors

Robert I. Lehrer

The effect of supplemental oral phosphate on the bone mineral changes during prolonged bed rest

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Abstract

Five healthy young men were studied during 24-30 wk of continuous bed rest. During the first 12 wk of bed rest, untreated subjects increased calcium excretion in the urine by 109 mg/day and in the feces by 147 mg/day. The rate of total body calcium loss was 0.5-0.7% per month. Losses of central calcaneus mineral, assessed by gamma ray transmission scanning, occurred at a tenfold higher rate, whereas the mineral content of the radius did not change. Changes in phosphorus balance resembled the calcium pattern, and increased excretion of nitrogen and hydroxyproline also occurred during bed rest. Upon reambulation, the subjects' calcium balance became positive in 1 month and recovery of their calcaneus mineral was complete within 10-20 wk.

Authors

Stephen B. Hulley, John M. Vogel, Charles L. Donaldson, Jon H. Bayers, Ronald J. Friedman, Sheldon N. Rosen

Formation, mineralization, and resorption of bone in hypophosphatemic rats

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Quantitative morphologic methods were used to measure the effects of feeding a low phosphorus diet to intact and thyroparathyroidectomized rats on several processes of bone mineralization and turnover. In severely hypophosphatemic animals, the matrix formation rate was decreased, the osteoid maturation rate was decreased, which indicated a delay in the onset of mineralization, the initial rate of mineralization was decreased, and the endosteal osteoclastic bone resorption rate was increased. In moderately hypophosphatemic animals, there was a substantial increase in bone resorption but no change in formation or in mineralization. The increase in endosteal bone resorption was due to an increase in the linear rate of bone resorption and particularly to an increase in the length of the endosteal resorbing surface. The magnitude of the increase in bone resorption was similar in thyroparathyroidectomized and intact rats indicating that neither parathyroid hormone nor calcitonin is involved in this change. This, together with the finding that there was a strong negative correlation (r = -0.99) between the per cent endosteal resorbing surface and the serum phosphorus, supports the view that the increased resorption was due to hypophosphatemia. This inverse relationship between endosteal resorbing surface and serum phosphorus appeared to hold for values of serum phosphorus above normal. The resorptive response to hypophosphatemia, as previously shown for the resorptive response to excess endogenous parathyroid hormone, was partially inhibited by vitamin D deficiency. Increased resorption occurred at levels of serum phosphorus where no changes were observed in bone formation, mineralization, or growth, suggesting that this resorptive response functions as a homeostatic mechanism to maintain serum and intracellular phosphorus concentrations.

Authors

D. Baylink, J. Wergedal, M. Stauffer

Fecal excretion of bile acids: a new technique for studying bile acid kinetics in patients with ileal resection

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The fecal elimination and enterohepatic circulation of bile acid was studied in 11 patients. 10 patients with varying degrees of ileal disease or resection and 1 patient with pancreatic insufficiency and no ileal disease. A new technique was employed which involved the nearly simultaneous administration of cholic acid-14C and a nonabsorbable marker. 51CrCl3. Each individual stool specimen was collected for 36-96 hr and analyzed separately. Assay of the radioactivity of each isotope allowed the accurate determination of an excretion rate for both cholic acid and 51Cr. The difference between these rates was used to calculate an absorption coefficient for cholic acid. In addition, bile acid concentration measured by the steroid dehydrogenase technique, and the water content of each stool was determined.

Authors

James F. Woodbury, Fred Kern Jr.

Chemotaxis of polymorphonuclear leukocytes from patients with rheumatoid arthritis

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Abstract

Using a new in vitro method of measuring the chemotaxis of polymorphonuclear leukocytes from peripheral blood, a chemotactic index has been calculated. The mean chemotactic index of 320 in 24 patients with definite rheumatoid arthritis, was significantly less (P < 0.0005) than the mean of 555 in 24 normal controls matched for age and sex.

Authors

Alastair G. Mowat, John Baum

Sites of pulmonary vasomotor reactivity in the dog during alveolar hypoxia and serotonin and histamine infusion

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Abstract

In order to evaluate separately changes in vascular tone occurring in arteries and veins, we measured pulmonary capillary red blood cell (RBC) concentration under zone II (waterfall) conditions in isolated dog lungs rapidly frozen with Freon 12. The lungs were frozen while being perfused from artery to vein and from vein to artery breathing normal and hypoxic gas mixtures and during infusions of serotonin and histamine. Changes in capillary RBC concentration which occurred during the experimental conditions indicated an alteration in vascular resistance upstream from the capillaries. Alveolar hypoxia caused a significant decrease in capillary RBC concentration during forward perfusion, but no change from the control values during reverse perfusion. Serotonin infusion caused a decrease in RBC concentration during forward perfusion comparable with that of hypoxia and a small but significant decrease during reverse perfusion. Histamine infusion caused no change in RBC concentration from control values during forward perfusion, but a large decrease during reverse perfusion. We conclude that vasoconstriction occurs (a) exclusively in arteries during alveolar hypoxia, (b) predominantly in arteries but to a lesser extent in veins during serotonin infusion, and (c) exclusively in veins during histamine infusion.

Authors

Jon B. Glazier, John F. Murray

Immunologic responses to bacteriophage ϕX 174 in immunodeficiency diseases

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Abstract

Immunologic responses to bacteriophage ϕX 174 were studied in 26 patients with immunodeficiency diseases. In eight cases of infantile X-linked agammaglobulinemia, there was prolonged circulation of phage and no detectable antibody response. The remaining 18 patients cleared phage normally and produced antibodies. 10 of these patients made only IgM antibody in spite of repeated immunization; all of these have recurrent respiratory tract infections and require treatment with gamma globulin and antibiotics. Eight patients made both IgM and IgG antibody; they experience either milder or no infections, and only one requires treatment with gamma globulin.

Authors

Hans D. Ochs, Starkey D. Davis, Ralph J. Wedgwood

Intestinal transport of water and electrolytes during extracellular volume expansion in dogs

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The effects of extracellular fluid volume expansion on intestinal transport of salts and water were studied in dogs by perfusing loops of bowel in vivo. Saline loading caused depression of duodenal and jejunal absorption with net secretion of salt and water into the lumen. Studies of unidirectional transport of 22Na+ revealed that the negative net sodium flux was due primarily, and perhaps exclusively, to increased serosal to mucosal transport, for mucosal to serosal sodium transport was not changed during volume expansion. Net transport of water and potassium paralleled net sodium flux. Administration of deoxycorticosterone did not affect the intestinal response to saline loading. Hemodilution, accomplished by equilibrating the dogs' blood with a reservoir of saline, did not affect intestinal absorption, but isotonic, iso-oncotic expansion of the extracellular fluid produced by reinfusing the saline-blood mixture from the reservoir resulted in negative net transport of water, sodium, and potassium by the duodenum. It is suggested that the small bowel is capable of secreting salts and water through intercellular spaces, and that this process is stimulated by extracellular fluid volume expansion.

Authors

James T. Higgins Jr., Norman P. Blair

Studies on antibiotic synergism against enterococci: II. Effect of various antibiotics on the uptake of ¹⁴C-labeled streptomycin by enterococci

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The mechanism by which agents that inhibit bacterial cell wall synthesis produce a synergistic effect against enterococci when combined with aminoglycoside antibiotics has not been elucidated. Using 14C-labeled streptomycin, it could be shown that uptake of this aminoglycoside antibiotic was markedly enhanced in enterococci growing in the presence of penicillin or other agents which inhibit the synthesis of bacterial cell walls. There was no enhancement of streptomycin uptake when the cells were incubated with antibiotics which primarily affect the bacterial cell membrane or inhibit protein synthesis. Increased streptomycin uptake was produced by penicillin only in actively growing bacteria. These observations are consistent with the hypothesis that enterococci exhibit a natural barrier to the entry of streptomycin which can be overcome by agents which inhibit cell wall synthesis, thus producing a synergistic effect.

Authors

Robert C. Moellering Jr., Arnold N. Weinberg

Effects of cardiac depression and of anesthesia on the myocardial action of a cardiac glycoside

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Abstract

The effects of ouabain (G-strophanthin) 20 μg/kg, on left ventricular (LV) pressure (P), diameter (D), velocity of contraction (dD/dt), and dP/dt were studied in conscious dogs instrumented with ultrasonic diameter gauges and miniature pressure gauges. The effects of ouabain were compared on separate occasions in the same dogs after cardiac depression with propranolol, 3.0 mg/kg, and also after general anesthesia with Na pentobarbital, 30 mg/kg. Maximal pressor effects were observed in the first 10 min, but maximal effects on the contractile state occurred at 30 min after ouabain. At this time, in conscious dogs, ouabain had increased LV isolength systolic pressure by 5%, LV isolength velocity by only 9%, and LV (dP/dt)/P by 21%, while end systolic diameter (ESD) decreased slightly and end diastolic diameter (EDD) and heart rate (HR) were unchanged. After anesthesia, ouabain increased LV systolic pressure by 8%, velocity 32%, (dP/dt)/P by 47%, and ESD decreased by 1.2 mm while EDD rose slightly and HR fell by 26 beats/min. Returning HR to control with atrial pacing decreased EDD 0.9 mm below control. After cardiac depression with propranolol, ouabain caused responses similar to those observed in the anesthetized dogs. Thus, the cardiac glycoside was found to exert only minor inotropic effects on the nonfailing heart of conscious dogs but far more striking inotropic responses in the anesthetized state.

Authors

Stephen F. Vatner, Charles B. Higgins, Thomas Patrick, Dean Franklin, Eugene Braunwald

Plasma insulin disturbances in primary hyperparathyroidism

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Abstract

Plasma insulin dynamics were evaluated in 10 patients with primary hyperparathyroidism before and after parathyroidectomy and correction of hypercalcemia. Before surgery fasting plasma insulin concentrations and insulin responses to administered glucose, tolbutamide, and glucagon were significantly greater than postoperative values. Hyperinsulinemia was not associated with altered glucose curves during glucose or glucagon tolerance tests, but a relatively greater insulin response to tolbutamide resulted in an increased hypoglycemic effect following its administration. The glucose-lowering action of intravenous insulin was slightly impaired before treatment. Intramuscular injections of parathormone to six normal men for 8 days induced mild hypercalcemia and hypophosphatemia and reproduced augmented plasma insulin responses to oral glucose and intravenous tolbutamide. 4-hr intravenous infusions of calcium to another group of six normal men raised serum calcium concentrations above 11 mg/100 ml. This did not alter glucose or insulin curves during oral glucose tolerance but markedly accentuated insulin responses to tolbutamide and potentiated its hypoglycemic effect. When highly purified parathormone was incubated with isolated pancreatic islets of male rats, glucose-stimulated insulin secretion was unaffected.

Authors

Hakjoong Kim, Ronald K. Kalkhoff, Nicholas V. Costrini, James M. Cerletty, Mitchell Jacobson

Bilirubin excretion in rats with normal and impaired bilirubin conjugation: effect of phenobarbital

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Abstract

The effect of phenobarbital on bilirubin excretion was studied in rats with different capacities for bilirubin conjugation. Drug treatment induced substantial increases in bilirubin UDP-glucuronyl transferase activity in the liver of both normal and heterozygous Gunn rats, but not homozygous Gunn rats in which enzyme activity is completely absent. However, enhancement of bilirubin excretion in vivo was observed only in heterozygous Gunn rats. In these animals the maximum capacity to excrete bilirubin into bile (Tmax), like the activity of the conjugating enzyme, was half normal; phenobarbital caused an increase in Tmax to levels characteristic of normal animals, with a twofold rise in the excretion of conjugated pigment. This appeared to be largely unrelated to enhancement of bile flow, and there was no stimulation of alternate pathways of bilirubin excretion.

Authors

Stephen H. Robinson, Claudine Yannoni, Susumu Nagasawa

Quantitative assessment of the extent of myocardial infarction in the conscious dog by means of analysis of serial changes in serum creatine phosphokinase activity

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Abstract

This study was designed to develop a method for quantitative assessment of infarct size in the conscious animal based on serial changes of serum creatine phosphokinase (CPK) activity. From 11 experiments in which myocardial CPK was injected intravenously in conscious dogs, the average CPK distribution space and average CPK fractional disappearance rate from serum were found to be 11.4% of body weight and 0.48% min respectively. In other experiments, myocardial infarction was produced in 22 conscious dogs by constriction of a left coronary artery snare and serum CPK activity was determined at frequent intervals for 24 hr. Since myocardial CPK depletion reflects infarct size, infarct size was determined directly by analysis of myocardial CPK content in the same animals 24 hr after coronary artery occlusion. CPK released from the infarct was determined from observed changes in serum CPK activity analyzed according to a model taking into account the fraction of CPK released from an infarct and the rates of appearance and disappearance of CPK activity from serum. Infarct size was calculated on the basis of observed changes in serum CPK and compared to infarct size determined directly by analysis of myocardial CPK depletion. Agreement was close and results from all experiments fit the equation: [infarct size (g) determined from serum CPK] = 1.13 × [infarct size (g) determined from myocardial CPK] - 1.3, r = 0.96, n = 22. The method described is useful for accurate assessment of infarct size in the conscious animal and for detection of modification of infarct size produced by pharmacologic interventions.

Authors

William E. Shell, John K. Kjekshus, Burton E. Sobel

Interruption of the enterohepatic circulation of digitoxin by cholestyramine: I. Protection against lethal digitoxin intoxication

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Abstract

Previous studies have demonstrated that considerable amounts of parenterally administered cardiac glycosides are excreted in the bile and reabsorbed across the intestinal mucosa in several species. It is currently believed that the more prolonged action of nonpolar digitalis glycosides is due to their retention and recycling in the enterohepatic circulation. This report describes studies carried out to evaluate the effects of pharmacologic interruption of this enterohepatic cycle with the intraluminal sequestering agent cholestyramine.

Authors

James H. Caldwell, Norton J. Greenberger

Interruption of the enterohepatic circulation of digitoxin by cholestyramine: II. Effect on metabolic disposition of tritium-labeled digitoxin and cardiac systolic intervals in man

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Abstract

Previous studies of digitalis glycoside metabolism and excretion have indicated that these compounds undergo a significant enterohepatic cycle in some species. It has been suggested that the existence of such a cycle in man contributes to the prolonged action of certain cardiac glycosides. Previous studies have demonstrated that cholestyramine binds digitoxin and digoxin in vitro and accelerates the metabolic disposition of digitoxin in rats and guinea pigs, presumably by interrupting the enterohepatic circulation.

Authors

James H. Caldwell, Charles A. Bush, Norton J. Greenberger

Defective granulocyte chemotaxis in the Chediak-Higashi syndrome

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In vivo and in vitro studies of granulocyte chemotaxis were performed in three patients with the Chediak-Higashi syndrome. Rebuck skin windows showed a decreased accumulation of leukocytes at an inflammatory site. Studies in Boyden chambers documented a cellular defect in granulocyte chemotaxis. The chemotactic response of Chediak-Higashi cells by this technique averaged approximately 40% of normal and was consistently reduced using several different chemotactic stimuli. This deficit was magnified by shortening the chamber incubation time or by decreasing the pore size of the micropore filter and was independent of granulocytopenia. No abnormalities of passive motility, adhesiveness, viability, or pH optimum for migration were found in these cells. Chediak-Higashi serum contained no inhibitors of chemotaxis and was capable of generating normal amounts of chemotactic factors with the exception of one patient with the accelerated phase of the disease. Heterozygotes for the Chediak-Higashi trait had normal chemotactic function. This cellular defect in chemotaxis may contribute to the marked susceptibility to pyogenic infections which is so characteristic of patients with the Chediak-Higashi syndrome.

Authors

Robert A. Clark, Harry R. Kimball

Pressure-flow studies in man: effect of atrial systole on ventricular function in mitral stenosis

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The effect of atrial contraction on left ventricular function in six patients with varying degrees of mitral stenosis was determined by utilizing the pressure gradient technique to measure instantaneous aortic blood flow and pressure. Aortic flow was measured as ventricular rate was controlled by right ventricular pacing to create A-V (atrioventricular) dissociation at varying rates (90-150 beats/min). At each heart rate, beats with preceding P waves, effective atrial systole, were grouped according to the duration of the P-R interval. Beats without P waves served as controls. There was always a significant increase in stroke volume, created by effective atrial systole, but the P-R interval at which it took place was different for each patient. There was no difference in the stroke volume for beats preceded by P waves having a P-R interval within the range of 0.05-0.20 sec. These beats were grouped for each patient, subjected to regression analysis, and compared to control beats. The absolute and percent change created by effective atrial systole was inversely proportional to the severity of the disease as determined by mitral valve orifice size.

Authors

M. Eugene Kendall, Abe Walston II, Frederick R. Cobb, Joseph C. Greenfield Jr.

Studies of the secretion of monkey placental lactogen

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A radioimmunoassay for monkey placental lactogen (MPL) was developed to study the factors controlling the secretion of MPL. The sensitivity of the assay was 1 ng MPL per ml. Human and monkey growth hormone, and human placental lactogen (HPL) showed minimal cross-reactions with MPL. Maternal MPL concentrations as measured in 40 rhesus monkeys increased progressively throughout pregnancy to a mean of 5000 ng/ml at term while umbilical vein MPL was less than 50 ng/ml. After term delivery maternal MPL concentrations decreased rapidly with a t½ of 20 min.

Authors

C. Belanger, B. Shome, H. Friesen, R. E. Myers

Pathogenesis of hypocalcemia in magnesium depletion: Normal end-organ responsiveness to parathyroid hormone

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Hypocalcemia in the hypomagnesemic state in man is usually attributed to refractoriness of end-organs to the calcemic action of parathyroid hormone. We studied the responsiveness of end-organs to bovine parathyroid extract (PTE) in magnesium-depleted and control dogs by the following three methods after thyroparathyroidectomy: (a) assessment of the calcemic response to a set dose of PTE (0.3 U/kg per hr); (b) assessment of PTE dose required to attain normocalcemia; (c) evaluation of regression lines of plasma calcium concentration on PTE dose. The calcemic response of magnesium-depleted thyroparathyroidectomized puppies to a set dose of PTE was similar to that of control puppies. There was no significant difference in the dose of PTE required to attain normocalcemia nor in the dose-response relations between the plasma calcium concentration and the PTE dose. In a group of magnesium-depleted puppies with intact thyroid and parathyroid glands, the dose of PTE required to attain normocalcemia was similar to that required in thyroparathyroidectomized animals, indicating calcitonin was not a factor contributing to hypocalcemia. We conclude that hypocalcemia in magnesium-depleted puppies is not due to refractoriness of end-organs to the calcium-mobilizing action of parathyroid hormone. Defective synthesis or diminished secretion of parathyroid hormone is suggested as an explanation.

Authors

Se Mo Suh, Adele Csima, Donald Fraser

Serum triiodothyronine: measurements in human serum by radioimmunoassay with corroboration by gas-liquid chromatography

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Abstract

Serum triiodothyronine (T3) has been measured by radioimmunoassay and corroborated by analysis of the identical samples with a previously described gas-liquid chromatographic technique. Special features of the radioimmunoassay procedure which permit determinations in unextracted serum include the use of a T3-free serum preparation for the construction of the standard curve and of tetrachlorothyronine to inhibit binding of T3 to thyroxine-binding globulin.

Authors

Terunori Mitsuma, Noriyuki Nihei, Marvin C. Gershengorn, Charles S. Hollander

Renal effects of calcitonin and parathyroid extract in man: Studies in hypoparathyroidism

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To clarify the controversial renal action of calcitonin (CT) and a possible interrelationship between CT and parathyroid hormone, eight patients with untreated surgical hypoparathyroidism were studied. Various calcitonins, i.e. extracted porcine, synthetic porcine, synthetic human, and synthetic salmon CT in doses of 150 Medical Research Council U or 1.5 mg were infused over a 3 hr period. Subsequently, six of the same subjects received 500 USP U parathyroid extract (PTE) (Eli Lilly & Co., Indianapolis, Ind.) in 3 hr and later a combination of CT and PTE. In addition, two patients were given an infusion of ammonium phosphate with the aim of producting a phosphaturia of comparable degree as seen after CT and PTE, thus differentiating hormonal from nonhormonal influences on cation excretion. A protocol of serial clearance (C) studies using the patients as their own controls was followed. Serum and urinary inorganic phosphate (P), calcium (Ca), magnesium (Mg), sodium (Na), potassium (K), and creatinine (Cr) were determined and the clearance values calculated.

Authors

Heinrich G. Haas, Maximilian A. Dambacher, Jan Gunčaga, Thierry Lauffenburger

Amino acid metabolism in exercising man

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Abstract

Arterial concentration and net exchange across the leg and splanchnic bed of 19 amino acids were determined in healthy, postabsorptive subjects in the resting state and after 10 and 40 min of exercise on a bicycle ergometer at work intensities of 400, 800, and 1200 kg-m/min. Arterio-portal venous differences were measured in five subjects undergoing elective cholecystectomy.

Authors

Philip Felig, John Wahren

Glucose metabolism during leg exercise in man

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Abstract

Arterial concentrations and net substrate exchange across the leg and splanchnic vascular bed were determined for glucose, lactate, pyruvate, and glycerol in healthy postabsorptive subjects at rest and during 40 min of exercise on a bicycle ergometer at work intensities of 400, 800, and 1200 kg-m/min.

Authors

John Wahren, Philip Felig, Gunvor Ahlborg, Lennart Jorfeldt

A hereditary immunoglobulin A abnormality: absence of light-heavy—chain assembly: Study of immunoglobulin synthesis in tonsillar cells

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A new immunoglobulin A abnormality, absence of assembly of α-chain and light-chain, was found in an adult female suffering from recurrent upper respiratory infection and tonsillitis since childhood, but otherwise healthy. The IgA abnormality was manifest in her serum by the presence of free α-chains, in her saliva by the presence of α-chains bound to secretory piece, and in her urine by the presence of free α-chains and free light-chains. The serum IgG and IgM were found to be complete, containing both heavy-chains and light-chains.

Authors

Chaya Moroz, Jacob Amir, Andre De Vries

Decreased noradrenaline (norepinephrine) synthesis in familial dysautonomia

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Abstract

Noradrenaline synthesis and metabolism of dopamine was evaluated in three patients with familial dysautonomia and compared with that of six normal subjects. Each patient and subject was infused with 104.8 μCi of dopamine-2-14C dissolved in 1000 ml of physiological saline. The urine was collected during the infusion period and at intervals thereafter. Using a specially designed flow monitor system, the various biosynthetic and metabolic products of dopamine were separated, identified, and their radioactivity measured. The results indicate that in familial dysautonomia the synthesis of noradrenaline is significantly decreased; this is reflected by a decrease in recovery of radioactive noradrenaline as well as various metabolic products of noradrenaline, i.e. 3-methoxy-4-hydroxymandelic acid (MOMA), normetadrenaline, and normetadrenaline conjugate. Concomitant with this decrease in noradrenaline synthesis, there was a shift towards dopamine metabolism as reflected by an increase in the recovery of primary and secondary dopamine metabolites; 3,4-dihydroxyphenylacetic acid (DOPAC), 3-methoxy-4-hydroxyphenylacetic acid (HVA), 3-methoxytyrosine, and respective conjugates, etc. Whereas all dysautonomic patients showed the same general metabolic pattern as was expected, they varied in degree.

Authors

McC. Goodall, S. E. Gitlow, H. Alton

The effect of polystyrene beads on cyclic 3′,5′-adenosine monophosphate concentration in leukocytes

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Abstract

After incubation with polystyrene latex beads for 5 min. the cyclic 3′,5′-adenosine monophosphate (cyclic AMP) content of human peripheral blood leukocyte suspensions was increased severalfold. Preparations enriched in mononuclear cells and containing only 0-20% polymorphonuclear leukocytes (PMN) and no visible platelets exhibited a quantitatively similar response. Purified fractions of cells containing 85-90% PMN responded to polystyrene beads with a much smaller increase in cyclic AMP content. Phagocytosis of paraffin oil emulsion in the unfractionated mixed human leukocyte preparation was associated with little or no change in cyclic AMP levels. There was no change in cyclic AMP content of rabbit alveolar macrophages or guinea pig PMN during phagocytosis of polystyrene beads. All of these observations are consistent with the view that particle uptake per se does not increase cyclic AMP levels in phagocytic cells. It seems probable that the increase in cyclic AMP concentration that results when unfractionated human blood leukocytes are incubated with polystyrene beads occurs in cells other than PMN.

Authors

Vincent Manganiello, Warren H. Evans, Thomas P. Stossel, Robert J. Mason, Martha Vaughan

Flow dependence of transtubular potential difference in isolated perfused segments of rabbit proximal convoluted tubule

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Abstract

Transmembrane potential difference (pd) was studied in isolated perfused segments of rabbit proximal convoluted tubules. At perfusion flow rates above 10 nl/min the pd was -5.80 ±0.3 mv (lumen negative) when perfusing with isosmolal ultrafiltrate of same rabbit serum as the bath. That this pd is generated by transport activity of the tubule is supported by three separate observations: (a) pd reversibly decreased with cooling from 37°C to 25°C; (b) pd decreased when 10-5 M ouabain was added to the bath and reversed to control levels when ouabain was removed; and (c) heating to 47°C irreversibly decreased pd to zero. The magnitude of the pd was related to perfusion flow rate at slower rates than 10 nl/min. A decrease in flow rate was associated with a decrease in pd. The tubular geometry and transmembrane hydrostatic pressure were ruled out as the mediating factors governing the magnitude of observed pd.

Authors

Juha P. Kokko, Floyd C. Rector

Urinary excretion of pregnanetriol and Δ⁵-pregnenetriol in two forms of congenital adrenal hyperplasia

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Although congenital adrenal hyperplasia due to 3β-hydroxysteroid dehydrogenase deficiency generally reveals a predominance of Δ5-3β-hydroxysteroids, on occasion substantial quantities of pregnanetriol have been found as well. It appears that the latter steroid more often occurs in the subjects who have survived beyond infancy. The use of the measurement of pregnanetriol alone may therefore not be relied upon as a sole determinant of the specific form of defective steroidal biogenesis. It is more characteristic of the 21-hydroxylase deficiency. However when both Δ5-pregnenetriol and pregnanetriol are measured the ratio of the former to the latter is always considerably below 1.0 in 21-hydroxylase deficiency and always above 1.0 in 3β-hydroxysteroid dehydrogenase. Furthermore, 11-ketopregnanetriol has been found only in the urine of subjects with the 21-hydroxylase deficiency. Thus, these two forms of defective steroidal biogenesis may be distinguished by the measurement of these three urinary steroidal metabolites.

Authors

Alfred M. Bongiovanni, Walter R. Eberlein, Thomas Moshang Jr.

Defect in messenger RNA for human hemoglobin synthesis in beta thalassemia

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Abstract

Functional messenger RNA for human hemoglobin synthesis was prepared from reticulocyte lysates of patients with homozygous beta thalassemia and sickle cell anemia. The messenger RNA stimulated the synthesis of human globin chains by a cell-free system derived from Krebs mouse ascites cells. In the presence of beta thalassemia messenger RNA, the system synthesized much less beta chain than alpha chain whereas in the presence of sickle cell anemia messenger RNA, nearly equal amounts of alpha and beta chains were synthesized. The beta/alpha synthetic ratios obtained in the cell-free system were similar to those obtained by incubating intact beta thalassemia and sickle cell anemia reticulocytes in the presence of radioactive leucine. The experiments provide direct evidence of a defect in messenger RNA for beta chains as a cause for the decreased synthesis of beta chains observed in beta thalassemia.

Authors

Edward J. Benz Jr., Bernard G. Forget

Mechanisms of endotoxin tolerence. The role of the Spleen

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Abstract

Authors