Clofibrate-Induced Antidiuresis

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Abstract

Normal subjects and patients with antidiuretic hormone (ADH) deficiency were studied to determine the mechanism of the antidiuretic action of clofibrate. Before clofibrate treatment, the patients' ability to concentrate urine with a standardized dehydration procedure correlated with the amount of ADH which was excreted. During clofibrate administration all six patients with ADH deficiency developed an antidiuresis which was like that of ADH, since there was no change in sodium, potassium, total solute, or creatinine excretion. There was a correlation between the patients' ability to concentrate urine during dehydration and the subsequent response to clofibrate, and the excretion of ADH during dehydration correlated with the excretion of ADH on clofibrate therapy. Clofibrate-induced antidiuresis in these patients was partially overcome by ethanol and by water loading. Clofibrate interfered with the ability of patients and subjects to excrete a water load and prevented the water load from inhibiting ADH excretion in the normal subjects. These studies suggested that clofibrate was acting through endogenous ADH and this thesis was supported by the failure of clofibrate to produce an antidiuresis when injected into rats with total ADH deficiency (Brattleboro strain) although an antidiuresis was produced in water-loaded normal rats. When the drug was injected into Brattleboro rats with exogenous ADH, clofibrate either did not alter or it inhibited the action of the ADH. The data demonstrate that clofibrate has a significant ADH-like action. This action appears to be mediated through the release of endogenous ADH.

Authors

Arnold M. Moses, Joan Howanitz, Marcia Van Gemert, Myron Miller

The Stimulation of 1,25-Dihydroxycholecalciferol Metabolism in Vitamin D-deficient Rats by 1,25-Dihydroxycholecalciferol Treatment

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Abstract

Daily oral administration of 1,25-dihydroxycholecalciferol to vitamin D-deficient rats increases the rate of disappearance of [3H]1,25-dihydroxycholecalciferol and increases the rate of appearance of metabolites both less polar and more polar than 1,25-dihydroxycholecalciferol in the intestine, bone, liver, kidney, plasma, and muscle. Since 1,25-dihydroxycholecalciferol is believed to be the metabolically active form of vitamin D in the stimulation of intestinal calcium transport and bone calcium mobilization, these results provide an explanation for the fact that daily oral administration of 1,25-dihydroxycholecalciferol is relatively ineffective in the maintenance of serum calcium and in the calcification of bone in rats.

Authors

C. A. Frolik, H. F. DeLuca

Immunopathologic Studies in Relapsing Polychondritis

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Abstract

Serial studies have been performed on three patients with relapsing polychondritis in an attempt to define a potential immunopathologic role for degradation constituents of cartilage in the causation and/or perpetuation of the inflammation observed. Crude proteoglycan preparations derived by disruptive and differential centrifugation techniques from human costal cartilage, intact chondrocytes grown as monolayers, their homogenates and products of synthesis provided antigenic material for investigation. Circulating antibody to such antigens could not be detected by immunodiffusion, hemagglutination, immunofluorescence or complement mediated chondrocyte cytotoxicity as assessed by 51Cr release. Similarly, radiolabeled incorporation studies attempting to detect de novo synthesis of such antibody by circulating peripheral blood lymphocytes as assessed by radioimmunodiffusion, immune absorption to neuraminidase treated and untreated chondrocytes and immune coprecipitation were negative.

Authors

Jerome H. Herman, Marie V. Dennis

Hyperoxia: Influence on Lung Mechanics and Protein Synthesis

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Abstract

We studied the time-course of the influence of in vivo hyperoxia on lung mechanics and on protein synthesis. After 24 h of exposure to greater than 98% O2 at 1 atm there were no alterations in descending pressure-volume curves (air or saline) of lungs excised from O2-exposed rats compared to control rats. After 48 h of hyperoxia there was a decrease in lung compliance.

Authors

Gerardo Gacad, Donald Massaro

Hyperoxia: A Stereologic Ultrastructural Examination of Its Influence on Cytoplasmic Components of the Pulmonary Granular Pneumocyte

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Abstract

We used the technique of lineal analysis to study the influence of 48 h of hyperoxia on cytoplasmic organelles of pulmonary granular pneumocytes with particular reference to their lamellar bodies. We undertook this study because lamellar bodies are considered to be storage granules for pulmonary surfactant and because we had found that hyperoxia decreased [14C]leucine incorporation into protein of a surface-active lung fraction.

Authors

Gloria D. Massaro, Donald Massaro

Studies on Mechanisms of Cerebral Edema in Diabetic Comas. EFFECTS OF HYPERGLYCEMIA AND RAPID LOWERING OF PLASMA GLUCOSE IN NORMAL RABBITS

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Abstract

To investigate the pathophysiology of cerebral edema occurring during treatment of diabetic coma, the effects of hyperglycemia and rapid lowering of plasma glucose were evaluated in normal rabbits. During 2 h of hyperglycemia (plasma glucose=61 mM), both brain (cerebral cortex) and muscle initially lost about 10% of water content. After 4 h of hyperglycemia, skeletal muscle water content remained low but that of brain was normal. Brain osmolality (Osm) (343 mosmol/kg H2O) was similar to that of cerebrospinal fluid (CSF) (340 mosmol/kg), but increases in the concentration of Na+, K+, Cl-, glucose, sorbitol, lactate, urea, myoinositol, and amino acids accounted for only about half of this increase. The unidentified solute was designated “idiogenic osmoles”. When plasma glucose was rapidly lowered to normal with insulin, there was gross brain edema, increases in brain content of water, Na+, K+, Cl- and idiogenic osmoles, and a significant osmotic gradient from brain (326 mosmol/kg H2O) to plasma (287 mosmol/kg). By similarly lowering plasma glucose with peritoneal dialysis, increases in brain Na+, K+, Cl-, and water were significantly less, idiogenic osmoles were not present, and brain and plasma Osm were not different. It is concluded that during sustained hyperglycemia, the cerebral cortex adapts to extracellular hyperosmolality primarily by accumulation of idiogenic osmoles rather than loss of water or gain in solute. When plasma glucose is rapidly lowered with insulin, an osmotic gradient develops from brain to plasma. Despite the brain to plasma osmotic gradient, there is no net movement of water into brain until plasma glucose has fallen to at least 14 mM, at which time cerebral edema occurs.

Authors

Allen I. Arieff, Charles R. Kleeman

Effect of Alcohol on Serum Folate Level

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Abstract

Alcohol was given orally and intravenously to normal and chronic alcoholic volunteers to study its effect on folate metabolism. Oral alcohol, given to nine subjects on a low folate diet, caused a greater fall in serum Lactobacillus casei folate levels than that seen in eight subjects on a low folate diet alone. This alcohol-induced fall in serum folate level occurred largely during the 1st day of the protocol. Although brief infusions of intravenous ethanol had no effect on serum folate level, a 13 h infusion caused a striking fall in serum folate level between the 8th and 10th h. When ethanol was stopped, the serum folate level returned rapidly to normal. Two chronic alcoholic subjects with different basal levels of serum folate were studied for several weeks on a low folate diet plus alcohol. The serum folate level fell promptly in each subject, rose when alcohol was temporarily stopped, and fell when alcohol was resumed. Folate-deficient megaloblastic anemia developed in 3 wk in the subject with initially marginal serum folate levels, but failed to develop in almost 7 wk in the subject with normal folate stores, as reflected by initially high serum folate levels. Thus, the alcohol-induced fall in serum folate level was apparently not a result of depletion of folate stores. In vitro experiments ruled out an assay artifact as an explanation for the alcohol-induced fall in serum L. casei folate level. It seems likely that alcohol interferes with the delivery of n-5-methyltetrahydrofolic acid from storage areas.

Authors

Edward R. Eichner, Robert S. Hillman

Chemotherapy of Experimental Streptococcal Endocarditis. I. COMPARISON OF COMMONLY RECOMMENDED PROPHYLACTIC REGIMENS

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The effectiveness of various antibiotics commonly recommended for the prophylaxis of bacterial endocarditis has been evaluated in experimental streptococcal endocarditis in rabbits. High doses of penicillin G did not prevent the development of this infection. The only consistently successful prophylactic regimens using penicillin alone were those which provided for both an early high serum level and more than 9 h of effective antimicrobial action. Vancomycin was the only other drug which proved uniformly successful when given alone, even though the duration of its antimicrobial action in the blood was only 3 h. However, combined therapy using penicillin G or ampicillin with streptomycin was always effective in prophylaxis. Treatment with single injections of ampicillin, cephaloridine, cephalexin, clindamycin, cotrimoxazole, rifampicin, streptomycin, erythromycin, and tetracycline failed to prevent infection.

Authors

David T. Durack, Robert G. Petersdorf

Reduction of Experimental Myocardial Infarct Size by Corticosteroid Administration

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Abstract

The influence of the administration of pharmacologic doses of hydrocortisone on the extent and severity of acute myocardial ischemic injury and on subsequent necrosis after acute coronary occlusion was investigated in 28 dogs. In order to study acute myocardial injury, repeated epicardial electrocardiograms were recorded from 10 to 15 sites on the anterior surface of the left ventricle. Average ST segment elevation (S̄T̄) and the number of sites in which ST segment elevation exceeded 2 mV (NST), indices of the magnitude and extent of myocardial injury, respectively, were analyzed at 30 and 60 min after coronary occlusion. In the control group S̄T̄ and NST did not change significantly in this time interval while in the treated group, which received 50 mg/kg hydrocortisone just after the 30 min recording, S̄T̄ fell from 3.5±0.8 to 1.1±0.4 mV (P<0.01) and NST was reduced from 6.7±1.1 to 1.4±0.8 (P<0.01). In order to study the influence of hydrocortisone on necrosis, epicardial ST segment elevation 15 min after coronary occlusion was compared to myocardial creatine phosphokinase activity (CPK) and histologic appearance 24 h later in each site. In a control group (14 dogs) a relationship was established between ST segment elevation at 15 min (in millivolts) and CPK activity (in international units per milligram of protein) 24 h later: log CPK = -0.0611ST + 1.26 (N = 102 specimens, r = -0.79). In the treated groups, hydrocortisone (50 mg/kg i.v.) was given either at 30 min after occlusion (seven dogs) or at 6 h after occlusion (six dogs). Both groups received supplementary doses of hydrocortisone (25 mg/kg) 12 h after occlusion. The two treated groups exhibited less CPK depression than that expected from ST segment elevation at each site, with slopes of the regression lines which were significantly less steep: log CPK = -0.0288ST + 1.26 (N = 48, r = -0.71) and log CPK = -0.0321ST + 1.31 (N = 48, r = -0.76) in the ½ h and 6 h groups, respectively. Histologically, sites with ST segment elevations of less than 2 mV at 15 min after occlusion exhibited normal appearance 24 h later. Sites with ST segment elevations (> 2 mV) in the control group showed histologic changes compatible with early myocardial infarction in 96% of specimens, while this occurred only in 61% and 63% of specimens, respectively, in the treated groups, showing that over one third of the sites were protected from undergoing necrosis due to the intervening hydrocortisone treatment. Thus pharmacological doses of hydrocortisone prevent myocardial cells from progressing to ischemic necrosis even when administration is initiated 6 h after coronary occlusion.

Authors

Peter Libby, Peter R. Maroko, Colin M. Bloor, Burton E. Sobel, Eugene Braunwald

Glucose Utilization and Production by the Dog Kidney In Vivo in Metabolic Acidosis and Alkalosis

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Abstract

Using D-[1-14C]glucose as a tracer, renal glucose utilization and production was measured in chronic metabolic acidosis and alkalosis in dog kidney in vivo. In six experiments in acidosis, mean total renal glucose production was 4.447±1.655 SE μmol/min and glucose utilization was 4.187±0.576 SE μmol/min. In five alkalotic experiments it was found that mean total glucose production was 12.227±2.026 SE μmol/min and glucose utilization was 18.186±2.054 SE μmol/min. Renal glucose utilization and production are therefore significantly higher in alkalosis than in acidosis in vivo. Since glucose production is maximal under conditions when glutamine extraction is minimal (i.e. alkalosis), it is apparent that in alkalosis glutamine is not a major precursor of glucose.

Authors

J. Costello, J. M. Scott, P. Wilson, E. Bourke

Sodium Chloride and Water Transport in the Medullary Thick Ascending Limb of Henle. EVIDENCE FOR ACTIVE CHLORIDE TRANSPORT

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Abstract

Transport of NaCl and water was examined in the rabbit medullary thick ascending limb of Henle (ALH) by perfusing isolated segments of these nephrons in vitro. Osmotic water permeability was evaluated by perfusing tubules against imposed osmotic gradients. In these experiments the net transport of fluid remained at zero when segments of thick ALH were perfused with isotonic ultrafiltrate in a bath of rabbit serum in which the serum osmolality was increased by the addition of either 239±8 mosmol/liter of raffinose or 232±17 mosmol of NaCl indicating that the thick ascending limb of Henle is impermeant to osmotic flow of water. When these tubules were perfused at slow rates with isosmolal ultrafiltrate of same rabbit serum as used for the bath, the effluent osmolality was consistently lowered to concentrations less than the perfusate and the bath. That this decrease in collected fluid osmolality represented salt transport was demonstrated in a separate set of experiments in which it was shown that the sodium and chloride concentrations decreased to 0.79±0.02 and 0.77±0.02 respectively when compared with the perfusion fluid concentrations. In each instance the simultaneously determined transtubular potential difference (PD) revealed the lumen to be positive with the magnitude dependent on the perfusion rate. At flow rates above 2 nl·min-1, the mean transtubular PD was stable and equal to 6.70±0.34 mv. At stop-flow conditions this PD became more positive. Ouabain and cooling reversibly decreased the magnitude of this PD. The transtubular PD remained positive, 3.3±0.2 mV, when complete substitution of Na by choline was carried out in both the perfusion fluid and the bathing media. These results are interpreted to indicate that the active transport process is primarily an electrogenic chloride mechanism. The isotopic permeability coefficient for Na was 6.27±0.38 × 10-5 cm·s-1 indicating that the thick ALH is approximately as permeable to Na as the proximal convoluted tubule. The chloride permeability coefficient for the thick ALH was 1.06±0.12 × 10-5 cm·s-1 which is significantly less than the chloride permeability of the proximal tubule.

Authors

Antonino S. Rocha, Juha P. Kokko

The Action of Cathepsin D in Human Articular Cartilage on Proteoglycans

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Abstract

In recent years the lysosomal cathepsins have been implicated as important agents in the physiological degradation of various cartilages. In the present study, the nature of cathepsin present in human articular cartilage was investigated by microtechniques and a possible role for cathepsins in the cartilage degradation observed in osteoarthritis was sought. The results of this study indicated that the hemoglobin and proteoglycan-digesting activity in the human cartilage observed is predominantly that of a cathepsin D-type enzyme. This cathepsin D-type enzyme activity was present in two to three times greater amounts in yellowish or ulcerated articular cartilage from patients with primary osteoarthritis than in control “normal” human cartilages. The human cathepsin D-type enzyme, as well as a highly purified cathepsin D from bovine uterus degraded proteoglycan subunit (PGS) maximally at pH 5. Both enzyme preparations were inactive on hemoglobin at pH 6-8, but degraded PGS considerably at neutral pH. The activity of the human cathepsin extract was not affected by reagents which inhibit or activate cathepsins A and B. Neutral proteases which are active on hemoglobin or are inhibited by diisopropylfluorophosphate (DFP) were not detected in these preparations, but contamination by another type of neutral protease cannot be excluded. Chloroquine inhibited the degradation of PGS at neutral pH by the human cartilage enzyme extract.

Authors

Asher I. Sapolsky, Roy D. Altman, J. Frederick Woessner, David S. Howell

Properdin and C3 Proactivator: Alternate Pathway Components in Human Glomerulonephritis

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Abstract

Serological and immunopathological studies of human glomerulonephritis have suggested that alternate pathways of activation of the third component of complement may be important in some forms of glomerulonephritis. We have investigated the role of two alternate pathway proteins, properdin and C3 proactivator, in 22 patients with chronic membranoproliferative glomerulonephritis, 21 patients with systemic lupus erythematosus, 20 patients with acute poststreptococcal glomerulonephritis, and 19 patients with other forms of renal disease. C3 (measured at β1A), properdin, and C3 proactivator were assayed by single radial immunodiffusion.

Authors

Robert H. McLean, Alfred F. Michael

Gastric Acid Secretion Rate and Buffer Content of the Stomach after Eating. RESULTS IN NORMAL SUBJECTS AND IN PATIENTS WITH DUODENAL ULCER

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Abstract

New methods are described by which the buffer content and the rate and pattern of net gastric acid secretion in human subjects fed normal meals can be measured by use of sodium bicarbonate infusion to control intragastric pH. With these techniques, it was shown that the rate of acid secretion in response to a steak meal in seven duodenal ulcer patients was twice the rate achieved in six control subjects and that the amount of acid secreted after eating exceeded the peak histamine response in the ulcer patients but not in the controls. Meal-stimulated acid secretion, expressed as a function of the peak histamine response, was roughly correlated with the serum gastrin concentration (r = 0.45), but it was concluded that other factors must also contribute to the higher than normal secretory responses to a meal found in duodenal ulcer patients. Measurement of buffer content of the stomach revealed that the duodenal ulcer patients emptied the meal buffer at a much more rapid rate than the normal subjects. By 2 h after eating, the ulcer subjects had less than half as much buffer in their stomachs as the controls. The combination of acid hypersecretion and rapid buffer emptying leads to abnormally high gastric acidity after a meal in duodenal ulcer patients. These results suggest that, in addition to a large parietal cell mass, parietal cell responsiveness to a meal and the rate of buffer emptying may be important in the pathogenesis of duodenal ulcer.

Authors

John S. Fordtran, John H. Walsh

Ouabain-Uninhibited Sodium Transport in Human Erythrocytes. EVIDENCE AGAINST A SECOND PUMP

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Abstract

Others have concluded that a second Na “pump” (active Na outflux) exists in human erythrocytes. This second pump was said to be ouabain-insensitive, unlike the classic ouabain-sensitive Na-K pump. An alternative explanation is that “pump II” is Na exchange diffusion. These hypotheses were examined in the present experiments, utilizing 22Na influx and outflux measurements, net Na fluxes, and ATPase determinations. Ouabain-uninhibited Na outflux was reduced 0.58±0.05 mmol/liter cells per h when extracellular Na (Nao) was replaced by Mg. Ethacrynic acid or furosemide produced similar decrements of outflux (0.50 mmol) in the presence of ouabain and Nao. However, these diuretics had minimal inhibitory effects on outflux in the absence of Nao suggesting that they inhibited principally the Nao-dependent outflux. Whereas this ouabain-uninhibited portion of outflux was dependent on Nao, it was independent of Ko. Contrary to expectations, Na influx did not change when intracellular Na was altered. No uphill, net Na transport (ouabain-uninhibited) could be demonstrated under a variety of circumstances. Furosemide at high concentrations inhibited ATPase, reducing both ouabain-sensitive and ouabain-insensitive enzyme at 1.0 mM concentration while showing no effect on ATPase at 0.05-0.1 mM concentration. The effects of furosemide on ATPase and on Na flux were dissociable on a dose-response curve. Energy depletion for 22 h practically eliminated the Nao-dependent, diuretic-inhibited Na outflux. Activation energies and temperature coefficients for the diuretic-inhibited outflux were one-half the values for the classic ouabain-inhibited pump. These data are interpreted as evidence against a second Na pump. Exchange diffusion accounts adequately for most of these observations; however, the ouabain-insensitive fluxes may be complex and composed of several processes.

Authors

Michael J. Dunn

Maturation of the Human Complement System. I. ONSET TIME AND SITES OF FETAL C1q, C4, C3, AND C5 SYNTHESIS

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The onset times and sites of human C1q, C4, C3, and C5 synthesis were determined by culturing tissues from 23 fetuses, 8-25 wk old, in the presence of [14C]lysine and isoleucine. In parallel, IgG and IgM production was followed. Liver, spleen, placenta, peritoneal and bone marrow cells, thymus, and colon were cultured for 48 h and the concentrated media studied by immunoelectrophoresis and subsequent autoradiography using adult human serum as carrier and specific antisera. The quantitative synthesis was approximated by scoring the intensity of the labeled precipitin lines using uniform conditions. C5 production was detected earliest at 8 wk gestation and by 11 wk and thereafter, C3, C4, and C5 synthesis was uniformly present in multiple tissues. C1q synthesis, however, was limited almost exclusively to the spleen, began at 14 wk, and was not uniformly present. In contrast IgG and IgM production did not occur in three fetuses synthesizing complement and while detected as early as 11 wk. was inconstant, occurred predominantly in the spleen, and was quantitatively much less compared to C3, C4, and C5. These findings suggest that developmentally the complement system is a more primative biological defense mechanism than antibody.

Authors

Peter F. Kohler

The Effect of Keto-analogues of Essential Amino Acids in Severe Chronic Uremia

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Alpha keto-analogues of valine, leucine, isoleucine, methionine, phenylalanine, and (in one instance) tryptophan and histidine, along with the remaining essential amino acids, were administered orally to 10 patients with severe chronic uremia fed a diet low in protein but adequate in calories. Ketoacid dosage varied from 6 to 14 g daily, as sodium or calcium salts. Net nitrogen intake, calculated as intake minus urinary protein nitrogen, averaged 1.8 g/day. The urea space was either estimated or measured with [14C]urea and daily changes in the body urea pool were calculated. Urea appearance was measured as the sum of urea excretion and the change in urea pool. If these ketoacids were converted to amino acids and utilized for protein synthesis, a fall in urea nitrogen appearance should occur. In five subjects, ketoacids were given for 15-18 days and then withdrawn. Urea nitrogen appearance increased 1.55 g/day on withdrawing ketoacids, and corrected nitrogen balance decreased by 1.73 g/day. In two other subjects ketoacid administration was followed, on two occasions each, by a period of administration of nine essential amino acids. In three of these four instances, urea appearance rose significantly with amino acids. In four patients studied at high blood urea levels, ketoacid treatment was relatively ineffective; two of these patients responded more favorably when studied again after peritoneal dialysis. One of these improved enough clinically to be managed as an out-patient for short intervals, despite virtual anuria. No accumulation of ketoacids in plasma or urine could be detected, and no toxicity was identified.

Authors

Mackenzie Walser, A. Will Coulter, Shrikant Dighe, Frank R. Crantz

Effects of Cholera Toxin on In Vitro Models of Immediate and Delayed Hypersensitivity. FURTHER EVIDENCE FOR THE ROLE OF CYCLIC ADENOSINE 3′,5′-MONOPHOSPHATE

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Abstract

Cholera enterotoxin inhibits the antigen-induced. IgE-mediated release of histamine from human leukocytes and the lysis of allogeneic mastocytoma cells by splenic lymphocytes from specifically immunized mice. This effect requires a prolonged preincubation time of the toxin with the lymphocyte/leukocyte preparations: a demonstrable inhibition requires about 30 min of pre-incubation and the toxin activity is still increasing at 90-180 min. Cholera enterotoxin also stimulates adenyl cyclase and leads to increased levels of cyclic AMP in the lymphocyte/leukocyte preparations. The concentration of toxin required for both cyclic AMP accumulation and inhibition of the biologic responses is about the same (ca. 1 ng/ml), and the time course of cyclic AMP accumulation parallels the development of inhibitory activity. Both activities, inhibition of the in vitro hypersensitivity reactions and cyclic AMP accumulation, are blocked by cholera antitoxin and by a toxoid prepared from the toxin (choleragenoid). These are specific antagonists in that they do not block the inhibiting activity or rise in cyclic AMP levels caused by other adenyl cyclase stimulators. Because cholera enterotoxin has no known activity other than the stimulation of adenyl cyclase and because of its unusual time course and the availability of specific antagonists, this data considerably strengthens the hypothesis that the cyclic AMP system influences the expression of these two forms of hypersensitivity phenomena.

Authors

L. M. Lichtenstein, C. S. Henney, H. R. Bourne, W. B. Greenough III

Effects of Cholera Enterotoxin on Adenosine 3′,5′-Monophosphate and Neutrophil Function. COMPARISON WITH OTHER COMPOUNDS WHICH STIMULATE LEUKOCYTE ADENYL CYCLASE

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Abstract

Cholera enterotoxin caused a delayed accumulation of adenosine 3′,5′-monophosphate (cyclic AMP) in human leukocytes, associated with an increase in leukocyte adenyl cyclase activity. The action of cholera enterotoxin contrasted with that of other agents which stimulate adenyl cyclase: (a) the effects of the toxin were delayed in onset, while prostaglandin-E1 (PGE1) and isoproterenol acted rapidly; (b) removal of the soluble toxin from the extracellular medium did not abolish its effects on cyclic AMP and inhibition of antigenic histamine release, while removal of PGE1 did prevent its effects; (c) PGE1, but not cholera enterotoxin, stimulated adenyl cyclase activity when added directly to broken cell preparations. Binding of the toxin to leukocytes was rapid and irreversible, and was followed by a gradual increase in cyclic AMP which was not prevented by cycloheximide.

Authors

Henry R. Bourne, Robert I. Lehrer, Lawrence M. Lichtenstein, Gerald Weissmann, Robert Zurier

Synthesis of Globin Chains in Sickle β-Thalassemia

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Abstract

In five patients with sickle β-thalassemia there was balanced α- and β-globin synthesis in the bone marrow and decreased total β-chain synthesis relative to that of α-chain in the peripheral blood. These findings are similar to those in patients with simple β-thalassemia trait. Despite a range of hemoglobin concentrations from 6.8 to 12.5 g/100 ml in the patients with sickle thalassemia, there was no evidence of a significant excess of α-chains in the red cells of the bone marrow which could contribute to the hemolysis and anemia.

Authors

Frances M. Gill, Elias Schwartz

Triketocholanoic (Dehydrocholic) Acid. HEPATIC METABOLISM AND EFFECT ON BILE FLOW AND BILIARY LIPID SECRETION IN MAN

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Abstract

[24-14C]Dehydrocholic acid (triketo-5-β-cholanoic acid) was synthesized from [24-14C]cholic acid, mixed with 200 mg of carrier, and administered intravenously to two patients with indwelling T tubes designed to permit bile sampling without interruption of the enterohepatic circulation. More than 80% of infused radioactivity was excreted rapidly in bile as glycine- and taurine-conjugated bile acids. Radioactive products were identified, after deconjugation, as partially or completely reduced derivatives of dehydrocholic acid. By mass spectrometry, as well as chromatography, the major metabolite (about 70%) was a dihydroxy monoketo bile acid (3α,7α-dihydroxy-12-keto-5β-cholanoic acid); a second metabolite (about 20%) was a monohydroxy diketo acid (3α-hydroxy-7,12-di-keto-5β-cholanoic acid); and about 10% of radioactivity was present as cholic acid. Reduction appeared to have been sequential (3 position, then 7 position, and then 12 position) and stereospecific (only α epimers were recovered).

Authors

Roger D. Soloway, Alan F. Hofmann, Paul J. Thomas, Leslie J. Schoenfield, Peter D. Klein

Sites of Formation of the Serum Proteins Transferrin and Hemopexin

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Abstract

Sites of synthesis of hemopexin and transferrin were determined by culturing various tissues of rabbits and monkeys in the presence of labeled amino acids. Labeling of the serum proteins was examined by means of autoradiographs of immunoelectrophoretic patterns as well as by precipitation in the test tubes employing immunospecific antisera. Good correlation was seen between the results obtained by the two different methods. The liver was found to be the only site of many tissues studied that synthesized hemopexin. Transferrin production was observed in the liver, submaxillary gland, lactating mammary gland, testis, and ovary.

Authors

G. J. Thorbecke, H. H. Liem, S. Knight, K. Cox, U. Muller-Eberhard

Diurnal Patterns of Triglycerides, Free Fatty Acids, Blood Sugar, and Insulin during Carbohydrate-Induction in Man and Their Modification by Nocturnal Suppression of Lipolysis

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Previous studies have shown that carbohydrate induction of hypertriglyceridemia in normal subjects occurs at night and appears to be related to a rise of free fatty acids after diurnal feeding of high-carbohydrate formula diet. The present investigation was undertaken to observe the effect on 24-h triglyceride, free fatty acid, blood sugar, and plasma insulin profiles of inhibition of nocturnal lipolysis by glucose or nicotinic acid in normal subjects and in patients with type IV hyperlipoproteinemia.

Authors

G. Schlierf, E. Dorow

Biological Defense Mechanisms. THE PRODUCTION BY LEUKOCYTES OF SUPEROXIDE, A POTENTIAL BACTERICIDAL AGENT

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Abstract

As a highly reactive substance produced in biological systems by the one-electron reduction of oxygen, superoxide (O2-) seemed a likely candidate as a bactericidal agent in leukocytes. The reduction of cytochrome c, a process in which O2- may serve as an electron donor, was found to occur when the cytochrome was incubated with leukocytes. O2- was identified as the agent responsible for the leukocyte-mediated reduction of cytochrome c by the demonstration that the reaction was abolished by superoxide dismutase, an enzyme that destroys O2-, but not by boiled dismutase, albumin, or catalase.

Authors

Bernard M. Babior, Ruby S. Kipnes, John T. Curnutte