In Vivo Demonstration of the Cholesterol Feedback System by Means of a Desmosterol Suppression Technique

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Abstract

This report describes a “desmosterol suppression” technique with which it has been possible to demostrate the operation of the cholesterol negative feedback system in the intact animal. 0.1% triparanol in the diet causes a virtually complete block in the conversion of desmosterol to cholesterol by liver and intestine. Since desmosterol is not consumed in the diet, the level of plasma desmosterol can be employed as an index of endogenous sterol production and release into the bloodstream. With this technique it was shown that the feeding of cholesterol for 8 days to rats decreases blood desmosterol levels to less than 5% of control values. Very similar results were obtained when cholesterol synthesis was assayed in vivo with acetate-14C as a cholesterol precursor. These observations indicate that the cholesterol feedback system operates very effectively in the intact animal in suppressing the endogenous contribution to the circulating cholesterol pool. Since intestinal cholesterol synthesis is only slightly inhibited by exogenous cholesterol, these results also indicate that the intestine does not represent a significant source of plasma sterols in the rat.

Authors

Lee A. Bricker, Hans J. Weis, Marvin D. Siperstein

Loss of the Cholesterol Feedback System in the Intact Hepatoma-Bearing Rat

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Abstract

By means of the desmosterol suppression technique described in the previous paper, the influence of hepatomas on sterol metabolism has been studied in the intact rat. The major finding of this study is that all hepatoma-bearing rats demonstrate a consistent in vivo loss of the cholesterol feedback system that is characteristic of normal liver. The results also demonstrate that such tumors retain only minor amounts of the sterol they synthesize, releasing over 90% of such endogenous sterol into the circulation. Finally, the in vivo loss of cholesterol feedback control was found to occur in at least two minimal deviation hepatomas and in one highly malignant adenocarcinoma of hepatic origin. These findings indicate that even tumors that are capable of only very limited cholesterol synthesis in vitro, can contribute significant quantities of sterol to the bloodstream.

Authors

Lee A. Bricker, Harold P. Morris, Marvin D. Siperstein

The Role of the Pancreas in Vitamin B₁₂ Absorption: Studies of Vitamin B₁₂ Absorption in Partially Pancreatectomized Rats

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Abstract

The effect of partial pancreatectomy (80-90%) on vitamin B12 absorption was studied in the rat. The absorption of 5 ng of 57Co-labeled vitamin B12 was significantly reduced from 70 ±2.5% (mean ±SE) in control and sham-operated rats to 32 ±2.6% in partially pancreatectomized rats. Hog pancreatic extract (0.17 g/kg) improved vitamin B12 absorption from 30.0 to 61.0% in partially pancreatectomized rats but did not alter vitamin B12 absorption in control rats. Chloramphenicol did not enhance vitamin B12 absorption in partially pancreatectomized rats with pancreatic extract-improved vitamin B12 malabsorption. The partially pancreatectomized rats with pancreatic extract-improved vitamin B12 malabsorption were sacrificed and the stomach and small bowel studied in vitro to further define the pathogenesis of the vitamin B12 malabsorption. Rat gastric intrinsic factor stimulated vitamin B12 uptake by intestinal sacs prepared from partially pancreatectomized rats 3.1-fold. Gastric intrinsic factor prepared from partially pancreatectomized rats was as effective in promoting vitamin B12 uptake by rat intestinal sacs as intrinsic factor prepared from control rats. These data indicate that partially pancreatectomized rats develop an abnormality in the absorption of labeled vitamin B12 which can be corrected by pancreatic extract. The vitamin B12 malabsorption is due to neither an alteration in gastric intrinsic factor activity nor an impairment of the intrinsic factor-vitamin B12 receptor in the intestine. It is suggested that in the partially pancreatectomized rats the intrinsic factor-vitamin B12 complex exists in a form which is not available for absorption.

Authors

Philip P. Toskes, Julius J. Deren

The Control of Iron Absorption by the Gastrointestinal Mucosal Cell

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Abstract

Gastrointestinal mucosal factors controlling rates of iron absorption were studied utilizing an in vivo closed duodenal loop technique. Cellular distribution of newly absorbed radioiron was identified by molecular sieve and iron-exchange chromatography of the mucosal cell supernate. In the normal animal, iron rapidly appeared in ferritin, and this fraction accounted for greater than 90% of mucosal supernatant radioactivity after 60 min absorption time. The nonferritin radioiron appeared to be unbound iron salts. In the presence of increased iron absorption induced by iron depletion or hemolysis, the major difference from the normal distribution pattern was an increase in the proportion and quantity of the free iron salts. Incorporation of newly absorbed iron into ferritin did not correlate with the rate of iron absorption. No evidence was found for a specific soluble iron-chelating molecule within the mucosal cell. The nonheme iron content of the mucosal supernates from iron-deficient and hemolyzing animals were significantly lower than in the normal animal.

Authors

Richard G. Sheehan, Eugene P. Frenkel

The Stimulus-Secretion Coupling of Glucose-Induced Insulin Release. VII. A PROPOSED SITE OF ACTION FOR ADENOSINE-3′,5′-CYCLIC MONOPHOSPHATE

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Abstract

Glucose-induced insulin release is thought to result from the following sequence of events in the beta cell: glucose metabolism leading to the production of a metabolic signal, net calcium uptake by the beta cell in response to the signal, and interaction between calcium and a microtubular-microfilamentous system, leading to emiocytosis of the secretory granules. Dibutyryl-cyclic AMP (db-cAMP) and theophylline are known to potentiate glucose-induced insulin release, their insulinotropic action being most marked at high glucose concentrations. Based on the above mentioned concepts, it was considered in the present experiments that the primary site of action of cAMP in the beta cell could correspond to either a facilitation of glucose metabolism, a modification of calcium distribution, or an interaction with the microtubular-microfilamentous system.

Authors

Guy R. Brisson, Francine Malaisse-Lagae, Willy J. Malaisse

Pathophysiology of Intense Physical Conditioning in a Hot Climate. I. MECHANISMS OF POTASSIUM DEPLETION

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Abstract

Serial estimations of exchangeable 42K showed that six volunteer subjects undergoing intensive physical conditioning in a hot climate sustained a mean deficit of 517 mEq. This deficit occurred despite a daily potassium intake of 100 mEq. Simultaneous values for lean body mass rose suggesting that potassium deficiency was not the result of catabolism. Although sweating was the major avenue by which the deficit occurred, daily excretion of potassium into the urine when each subject was maximally deficient ranged from 46 to 75 mEq and thus was inappropriately high for potassium-depleted subjects. Despite high intakes of sodium and excretion of corresponding quantities into the urine, Na/K ratios in sweat were low thus indicating unsuppressed activity of aldosterone on sweat glands. Moreover, excretion and secretion of aldosterone and in many instances, plasma renin activity, appeared to be high with respect to sodium intake.

Authors

James P. Knochel, Larry N. Dotin, Richard J. Hamburger

The Simultaneous Determination of Muscle Cell pH Using a Weak Acid and Weak Base

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Abstract

Should significant pH heterogeneity exist within cells then the simultaneous calculation of intracellular pH from the distribution of a weak acid will give a value closest to the highest pH in the system, whereas calculation from the distribution of a weak base will give a value closer to the lowest pH. These two values should then differ significantly. Intact rat diaphragms were exposed in vitro to varying bicarbonate concentrations (pure metabolic) and CO2 tensions (pure respiratory), and steady-state cell pH was measured simultaneously either by distribution of the weak acid 5,5-dimethyloxazolidine-2,4-dione-14C (pH DMO) or by distribution of the weak base nicotine-14C (pH nicotine). The latter compound was found suitable to measure cell pH since it was neither metabolized nor bound by rat diaphragms.

Authors

Sheldon Adler

Long-Term Kinetics of Serum and Xanthoma Cholesterol Radioactivity in Patients with Hypercholesterolemia

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Abstract

In four patients with hypercholesterolemia (type II hyperlipoproteinemia) and xanthomatosis the decay of serum cholesterol specific activity was followed for 53-63 wk after pulse labeling. Specific activity of biopsied xanthoma cholesterol was measured four times in the course of the study. The xanthoma specific activity curve crossed and thereafter remained above the serum specific activity curve. The average ratio of xanthoma to serum specific activity was 4.7 at the end of the study. The final half-time of the xanthoma decay curves was significantly greater (average: 200 days) than the slowest half-time of serum specific activity decay (average: 93 days). The data were analyzed by input-output analysis and yielded the following results. The average value for the total input rate of body cholesterol (IT) (sum of dietary and biosynthesized cholesterol) was 1.29 g/day. The average size of the rapidly miscible pool of cholesterol (Ma) was 55.7 g. and of the total exchangeable body mass of cholesterol (M) 116.5 g. The average value of M - Ma (remaining exchangeable mass of cholesterol) was 60.8 g. The derived values for exchangeable masses of cholesterol, in the present patients with marked hypercholesterolemia, were significantly larger than in a group of patients with normal serum lipids in previous studies. One of the four patients died of a sudden acute myocardial infarction 53 wk after pulse labeling. Specific activity of aortic wall and atheroma cholesterol was 3.12 times that of serum. The ratio was close to 2 for adipose tissue and spleen, and was slightly above 1 or was close to unity in most other organs studied, with the exception of brain which showed a ratio of 0.19.

Authors

Paul Samuel, William Perl, Charles M. Holtzman, Norman D. Rochman, Sidney Lieberman

Differences in Direct Effects of Adrenergic Stimuli on Coronary, Cutaneous, and Muscular Vessels

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Abstract

Direct effects of adrenergic stimuli on coronary vessels in dogs were compared with effects on vessels to skin (hind paw) and skeletal muscle (gracilis muscle) after intravenous administration of practolol (2 mg/kg), a selective myocardial beta receptor blocker which minimized indirect effects of myocardial stimulation on coronary vascular resistance. The left circumflex coronary, cranial tibial, and gracilis arteries were perfused separately but simultaneously at constant flow. Perfusion pressures, left ventricular pressure and dP/dt. and heart rate were recorded. Changes in perfusion pressure to each bed reflected changes in vascular resistance.

Authors

Allyn L. Mark, Francois M. Abboud, Phillip G. Schmid, Donald D. Heistad, Howard E. Mayer

Effects of Elastase, Collagenase, and Papain on Structure and Function of Rat Lungs In Vitro

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Abstract

Present concepts of the roles of collagen and elastin in lung elastic behavior and maintenance of lung structure have been largely inferred from anatomical observations or from studies of isolated fibers in vitro. Based on the intimate association of elastin and collagen it has been postulated that elastin contributes little to elastic behavior and that collagen is the major determinant of lung structure. Using clostridial collagenase, pancreatic elastase, and papain we have selectively degraded these fibers and studied the resulting changes in elastic behavior and structure of rat lungs in vitro.

Authors

Waldemar G. Johanson Jr., Alan K. Pierce

The Influence of the Carbonic Anhydrase Inhibitor, Benzolamide (CL-11,366), on the Reabsorption of Chloride, Sodium, and Bicarbonate in the Proximal Tubule of the Rat

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Abstract

Benzolamide (CL-11,366), a potent carbonic anhydrase inhibitor, was used to examine the influence of carbonic anhydrase inhibition on the reabsorption of chloride, sodium, and bicarbonate in the rat proximal convoluted tubule. Administration of 2 mg/kg benzolamide was associated with a decrease in the tubular fluid/plasma (TF/P) chloride ratio from 1.19±0.10 (SEM) to 1.06±0.01, and an increase in the TF/P bicarbonate ratio from 0.181±0.02 to 0.584±0.02. This dose of benzolamide significantly reduced proximal fractional reabsorption of chloride by 29.14%, of sodium by 34.3%, and of bicarbonate by 35.64%. These results indicate that benzolamide administration inhibits the reabsorption of all three electrolytes in the proximal convoluted tubule. Although 20 mg/kg benzolamide accentuated the changes in fractional reabsorption, the differences between 2 and 20 mg/kg were not statistically significant.

Authors

Robert T. Kunau Jr.

Coagulant Activity of Leukocytes. TISSUE FACTOR ACTIVITY

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Abstract

Peritoneal leukocytes harvested from rabbits which have received two spaced doses of endotoxin have significantly greater (10-fold) coagulant activity than leukocytes from control rabbits. The coagulant activity accelerates the clotting of normal plasma and activates factor X in the presence of factor VII and calcium and is therefore regarded as tissue factor. A total of 40-80 mg tissue factor activity was obtained from the peritoneal cavity of single endotoxin-treated rabbits. In leukocyte subcellular fractions, separated by centrifugation, the specific tissue factor activity sedimented mainly at 14,500 g and above. The procoagulant activity was destroyed after heating for 10 min at 65°C but was preserved at lower temperatures. Polymyxin B, when given with the first dose of endotoxin, reduced both the number of peritoneal leukocytes and their tissue factor activity by two-thirds. When given immediately before the second dose of endotoxin, polymyxin B had no inhibitory effect.

Authors

J. Niemetz

Effect of Peritubular Protein Concentration on Reabsorption of Sodium and Water in Isolated Perfused Proximal Tubules

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Abstract

Micropuncture studies have indicated that variation in peritubular oncotic pressure influences net transport of fluid out of the proximal tubule. The present in vitro studies on isolated perfused rabbit proximal convoluted tubules were designed to examine whether protein concentration gradient must act across the peritubular capillary membrane to influence reabsorption, or whether it can exert a direct effect across the tubular basement membrane 71 proximal tubules were perfused with ultrafiltrate made isosmolal to bathing fluids, the latter having identical electrolyte composition as the perfusing ultrafiltrate, but adjusted to three oncotic pressures: hypooncotic, protein 0.0 g/100 ml; control isooncotic serum, protein 6.4 g/100 ml; and hyperoncotic, protein 12.5 g/100 ml. Net volume flux (nl/mm per min), net Na flux (nEq/mm per min), unidirectional Na flux from bath to lumen (nEq/mm per min), and passive permeability coefficient (× 10-5 cm/sec) for Na (PNa), urea (Purea), and sucrose (Psucrose) were determined using isotopic techniques. When the bath was hypooncotic, there was (as compared with isooncotic serum) a significant decrease in net volume (38%) and net sodium (40%) flux, but no change in PNa, Purea, or transtubular potential; however, Psucrose increased significantly (78%). In experiments in which hyperoncotic bath was used, there was (compared with isooncotic serum) an increase in net volume (28%) and net sodium (30%) flux, but transtubular potential difference did not change significantly.

Authors

Masashi Imai, Juha P. Kokko

Immunoglobulin E in Immunologic Deficiency Diseases. I. RELATION OF IGE AND IGA TO RESPIRATORY TRACT DISEASE IN ISOLATED IGE DEFICIENCY, IGA DEFICIENCY, AND ATAXIA TELANGIECTASIA

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Abstract

Serum immunoglobulin E concentration was studied in normal children and adults, in 25 patients with isolated IgA deficiency, and in 44 patients with ataxia telangiectasia using a double antibody radioimmunoassay. The geometric mean IgE level of the normal adult population studied was 105 ng/ml, with a broad 95% interval (5-2045 ng/ml). Individuals with concentrations less than 15 ng/ml were considered to be IgE deficient. IgE deficiency, defined in this way, was observed in 7 of 73 normal adults and was not found to be associated with respiratory tract disease.

Authors

Stephen H. Polmar, Thomas A. Waldmann, Suellen T. Balestra, Margaret C. Jost, William D. Terry

Impaired Reflex Vasoconstriction in Chronically Hypoxemic Patients

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Abstract

Acute hypoxia impairs vasoconstrictor responses in normal men. The present study was done to determine whether reflex vasoconstriction is impaired in chronically hypoxemic patients and whether correction of hypoxemia in these patients improves their cardiovascular reflexes. In eight chronically hypoxemic patients, arterial PO2 was increased from an average of 45 mm Hg while breathing room air to 161 mm Hg while breathing 40-100% oxygen, with minimal changes in arterial PCO2 or pH. Correction of hypoxemia did not cause changes in resting arterial pressure or in forearm vascular resistance, but it caused a small increase in resting heart rate. Reflex responses to lower body negative pressure, which causes pooling of blood in the lower part of the body, were observed. When the patients were hypoxemic, lower body negative pressure caused a fall in arterial pressure, slight constriction of forearm vessels, and a small increase in heart rate. When hypoxemia was corrected, the same intervention caused marked vasoconstriction and a greater increase in heart rate, and there was no decrease in arterial pressure. The results indicate that reflex vasoconstrictor responses are depressed in chronic hypoxemia, indicating that adaptive mechanisms which occur in chronic hypoxemia do not include preservation of sympathetic reflexes.

Authors

Donald D. Heistad, Francois M. Abboud, Allyn L. Mark, Phillip G. Schmid

Changes in Fatty Acid Metabolism after Erythrocyte Peroxidation: Stimulation of a Membrane Repair Process

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Abstract

To study certain membrane repair processes in human erythrocytes, vitamin E-deficient cells were incubated with hydrogen peroxide. The incorporation of exogenous fatty acid and the transfer of fatty acid from phosphatidylcholine and neutral lipid into phosphatidylethanolamine were examined using radioactive fatty acids.

Authors

Bertram H. Lubin, Stephen B. Shohet, David G. Nathan

Experimental Renal Disease Induced by DNA—Anti-DNA Immune Complexes

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Abstract

Rabbits immunized with ultraviolet-irradiated DNA (UV-DNA) produced high titers of serum antibody. This experimental model was studied to determine if injection of antigen (UV-DNA) intravenously into immunized animals would induce glomerulonephritis and proteinuria. Proteinuria was observed several days after the start of daily intravenous injections into immunized animals and was sustained as long as injections were continued, but fell to normal values after stopping antigen administration. The kidneys showed glomerulitis sometimes associated with focal proliferative lesions, and immunofluorescence showed rabbit Ig and C3 in glomeruli. By electron microscopy, electron-dense subendothelial deposits were seen. Sucrose density gradient analyses of sera immediately after antigen injections suggested the presence of immune complexes of DNA and antibody since both heavy sedimenting and 7S Ig were detected. After digestion with deoxyribonuclease rabbit Ig could be found only in the 7S sedimenting fractions. Intravenous injection of UV-DNA into normal, nonimmune animals did not produce heavy sedimenting Ig or abnormal sedimentation patterns. These studies with an experimental model might provide insight into pathogenetic mechanisms operating in systemic lupus erythematosus where the importance of DNA—anti-DNA immune complexes have been documented. The studies suggested that gradual accumulation of DNA immune complexes in glomeruli might be one mechanism causing renal functional abnormalities.

Authors

Pier Giorgio Natali, Eng M. Tan

Fat Absorption During Inhibition of Protein Synthesis: Studies of Lymph Chylomicrons

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Abstract

The effect of protein synthesis inhibition on the absorption of oleic acid from micellar solution was studied in mesenteric lymph fistula rats. A micellar solution of oleic acid labeled with tracer doses of oleic acid-14C was administered by intraduodenal infusion to rats with indwelling mesenteric lymph cannulas. Protein synthesis was inhibited by intraperitoneal acetoxycycloheximide (ACH), 0.25 mg/kg, 1 hr before lipid infusion. Lymph chylomicrons labeled with oleic acid-14C were collected from control and protein inhibited animals at various times after lipid infusion and subjected to sucrose density gradient centrifugation to determine changes in size. In control animals there was a transient increase in chylomicron size during maximal triglyceride absorption; however, in protein-inhibited animals there was a marked and sustained increase in chylomicron size as late as 4 hr after lipid infusion.

Authors

R. M. Glickman, K. Kirsch, K. J. Isselbacher

Translation of β-Globin m-RNA in β-Thalassemia and the S and C Hemoglobinopathies

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Abstract

Genetic and biochemical evidence indicates that in β-thalassemia there is impaired synthesis of the β-globin chains of hemoglobin A. In patients heterozygous for the hemoglobinopathies, hemoglobin S and hemoglobin C, the mutant β-chain is produced in smaller amounts than normal βA. Defective m-RNA translation has been suggested as a possible cause of decreased β-globin polypeptide synthesis in thalassemia and the hemoglobinopathies. In the present study, the ribosomal assembly of β-globin chains was examined in the peripheral, nucleated red blood cells and reticulocytes of patients with Cooley's anemia, thalassemia intermedia, sickle thalassemia, sickle cell anemia, hemoglobin C disease, and in hemolytic anemias not associated with a hemoglobinopathy. The translation times of βA, βS, and βC did not differ significantly (average times; βA = 75 sec, range 43-114, βS = 69 sec, βC = 92 sec). In thalassemia, no evidence was found for a delay in translation as the cause of the marked impairment of β-globin synthesis. In several specimens of peripheral blood from thalassemic patients, the translation time of the β-chain was even shorter than in nonthalassemic specimens (average time = 45 sec, range 35-59). The results suggest that the defect in β-globin synthesis in β-thalassemia is due to impaired initiation of β-globin chain assembly or a quantitative deficiency in m-RNA.

Authors

Ronald F. Rieder

Evidence for a Direct Action of Cholecalciferol and 25-Hydroxycholecalciferol on the Renal Transport of Phosphate, Sodium, and Calcium

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Abstract

Acute clearance studies were performed in stable thyroparathyroidectomized dogs to evaluate the possibility of a direct renal action of vitamin D and its biologically active 25-hydroxylated metabolite. Alterations in renal hemodynamics and serum calcium concentration were minimized and attempts at vitamin D depletion were not undertaken. Steady-state volume expansion of modest degree was employed as the control experimental situation so that an effect of the vitamin to enhance phosphate reabsorption would not go undetected because of an already maximal phosphate reabsorptive rate secondary to parathyroidectomy. Under these experimental circumstances, 10,000 U of cholecalciferol and 25-120 U of 25-hydroxycholecalciferol (25-HCC) produced significant depressions in the percentage of filtered phosphate excreted (mean declines of 39 and 47%, respectively), which were not attributable to alterations in renal hemodynamics or to changes in the levels of serum calcium or phosphate. There was an accompanying decline in sodium and calcium excretion; mean percentage excretion rates for sodium fell by 38% with vitamin D and 26% with 25HCC, and for calcium this measurement declined by 46 and 23%, respectively. Furthermore, parathyroid hormone and 25HCC produced antagonistic effects on phosphate excretion. These observations provide the first conclusive evidence for a direct (proximal) tubular action of vitamin D to promote phosphate (as well as sodium and calcium) transport.

Authors

Jules B. Puschett, Joel Moranz, Warren S. Kurnick

Plasma Aldosterone Concentration at Delivery and during the Newborn Period

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Abstract

Aldosterone concentrations in plasma of women on normal sodium intake undergoing cesarean section were 3.7±1.4 ng/100 ml (mean±1 SD). These values were significantly lower (P < 0.001) than those observed in mothers on normal sodium diet, delivered by the vaginal route (14.9±7.0 ng/100 ml). A significant elevation (P < 0.001) of the concentrations was found if the mothers had been on sodium restriction and/or diuretics (44.9±24.2 ng/100 ml). In supine position, adult nonpregnant subjects have aldosterone concentrations in plasma of 1.7±1.4 ng/100 ml on normal sodium intake and of 16.7±8.1 ng/100 ml on low sodium diet.

Authors

Inese Z. Beitins, Francis Bayard, Lynne Levitsky, Isadore G. Ances, Avinoam Kowarski, Claude J. Migeon

Metabolic Studies in the African Pygmy

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Abstract

Major metabolic effects of human growth hormone (HGH) were assessed in the African Babinga pygmy. Plasma free fatty acid (FFA) and glucose concentrations were measured in pygmies, HGH-deficient dwarfs, Bantu tribesmen, and Caucasian controls after each received 4 mg of HGH intravenously over a 20 min period. Pygmies had an early decrease of plasma FFA and glucose concentration, but did not exhibit a later lipolytic response.

Authors

T. J. Merimee, D. L. Rimoin, L. L. Cavalli-Sforza

Effect of Chronic Bile Duct Obstruction on Renal Handling of Salt and Water

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Abstract

Renal sodium reabsorption and the concentrating and diluting abilities of the kidney were evaluated in the same trained mongrel dogs before and after chronic common bile duct ligation (BDL). Glomerular filtration rate (GFR) and CPAH were not altered by BDL. The natriuretic response to a standardized infusion of 0.45% solution of NaCl was markedly blunted by BDL (P < 0.01); calculated distal sodium delivery was significantly less in experiments after BDL than in control studies. Furthermore, the fractional reabsorption of sodium at the diluting segment for any given rate of distal delivery was enhanced by BDL. Similarly, CH2O/100 ml GFR for a given sodium delivery was higher after BDL than control values. Maximal urinary concentration (Uosm-max) was lower after BDL, and the mean Uosm-max for the whole group of animals was 60% of the control value (P < 0.001). Mean maximal TH2O/100 ml GFR after BDL was not different from control values; however, TcH2O/100 ml GFR for a given Cosm/100 ml GFR was lower after BDL in three dogs only. The sodium content of the inner part of renal medulla after BDL was significantly lower than the values obtained in control animals. The excretion of an oral water load in the conscious state was impaired after BDL; although all animals excreted hypotonic urine, urinary osmolality was usually higher after BDL than in control studies. Maximal urinary concentration and the excretion of an oral water load were not affected by sham operation.

Authors

Ori S. Better, Shaul G. Massry

α-Thalassemia in the American Negro

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Abstract

In Italian and Chinese patients with the α-thalassemia syndromes the production of α-chain of normal hemoglobin is decreased relative to that of β-chain in reticulocytes. In this study the relative rates of α- and β-chain synthesis were determined in members of three Negro families with α-thalassemia. Two of the families had members with hemoglobin H disease and α-thalassemia trait, while the mother of several children with α-thalassemia trait in the third family was doubly heterozygous for α-thalassemia and an α-chain mutant. The α/β ratios of globin synthesis in the patients with hemoglobin H disease and α-thalassemia trait indicated less severe biochemical defects in the peripheral blood than those previously determined in Italian and Chinese patients. In the third family, there was a heterogeneity of expression of the gene for α-thalassemia, including patients with normal red cell indices and synthesis ratios. These findings differ from those previously described in patients with α-thalassemia from other racial groups. Hydrops fetalis due to homozygous α-thalassemia may not occur in the Negro because of the relatively mild thalassemic defect.

Authors

Elias Schwartz, Jean Atwater

The Actin and Myosin Filaments of Human and Bovine Blood Platelets

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Abstract

The contractility of platelets has been attributed to an actomyosin-like protein which has been well defined on a physicochemical basis. Moreover, platelets contain ±80 A filaments which resemble actin filaments in smooth muscle. Studies were undertaken on human and bovine platelets to better define the morphologic structures which may subserve this contractile function. In order to identify actin, the ability of the filaments to react with heavy meromyosin (HMM) was tested. Accordingly, platelets were glycerinated and treated with HMM. In addition, platelet actin was extracted, reacted with HMM, and examined by negative staining. In both instances typical arrowhead structures with clearly defined polarity and a periodicity of ±360 A formed. As is the case with purified muscle actin, the complexes were dissociable with Mg-ATP. The formation of myosin-like filaments was observed when osmotically shocked platelets were incubated with MgCl2 and excess ATP. These “thick” filaments measured 250-300 A in width, tapered at both ends and often occurred in clumps. They resembled aggregates of thick filaments described in contracted smooth muscle. Extraction of platelets by methods suitable for the demonstration of myosin showed filaments with an average length of 0.3 μ, a smooth shaft, and frayed or bulbous ends. These appeared identical to those seen in synthetically prepared myosin of striated muscle. It is suggested that the filaments described here represent the actin and myosin of platelets.

Authors

Dorothea Zucker-Franklin, George Grusky

Serum Thyrotropin Responses to Synthetic Thyrotropin-Releasing Hormone in Normal Children and Hypopituitary Patients. A NEW TEST TO DISTINGUISH PRIMARY RELEASING HORMONE DEFICIENCY FROM PRIMARY PITUITARY HORMONE DEFICIENCY

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Abstract

Synthetic thyrotropin-releasing hormone (TRH) was administered intravenously in a dose of 7 μg/kg to 20 normal children ages 4-13 yr. Serum thyroid-stimulating hormone (TSH) was measured by radioimmunoassay and rose from a mean value of 1.7 μU/ml (range = < 1.25-7.2) to a mean peak value of 21.5 μU/ml (5.2-33.2) at 15 or 30 min after administration.

Authors

Thomas P. Foley Jr., Janice Owings, John T. Hayford, Robert M. Blizzard

Quantitative Radioautography of Sugar Transport in Intestinal Biopsies from Normal Humans and a Patient with Glucose-Galactose Malabsorption

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Both galactose accumulation and phlorizin binding by columnar epithelial cells have been investigated in vitro with a recently developed technique for high-resolution, plastic-section radioautography which is particularly suited to small quantities of biopsy tissue. Grain density analysis of the radioautographs provides definitive support for the view that the cellular mechanisms underlying glucose-galactose absorption in laboratory animals are fully applicable to the small intestine of man. Even the number of sugar carriers at the microvillar membrane appears similar and the major quantitative difference, lower affinity for phlorizin in man, correlates with the finding that phlorizin is also a less potent inhibitor of uphill, galactose transport at the microvilli. In addition, radioautographs of biopsies taken 2 yr apart from a patient with glucose-galactose malabsorption provide evidence that the cellular defect in this inborn error of transport is a persistent reduction in the number of functioning sugar carriers at the microvillar membrane.

Authors

Charles E. Stirling, Albert J. Schneider, Ming-Der Wong, William B. Kinter

Peripheral Aromatic L-Amino Acids Decarboxylase Inhibitor in Parkinsonism. I. EFFECT ON O-METHYLATED METABOLITES OF L-DOPA-2-¹⁴C

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Abstract

The effects of MK-486, an inhibitor of peripheral aromatic L-amino acids decarboxylase, on the urinary metabolites derived from orally administered L-Dopa-2-14C were studied in three Parkinsonian patients. Treatment with MK-486 before L-Dopa-2-14C markedly reduced radioactivity found in catecholamines fraction by 70-80% during 48 hr, but increased 3-O-methyldopa fraction by threefold, as compared with a nonpretreated base line value. Pretreatment with MK-486 for a period of 1 wk resulted in less inhibition of O-methylated amine and acid metabolite fractions than that measured after a single dose of the inhibitor.

Authors

F. S. Messiha, T. H. Hsu, J. R. Bianchine

Prostaglandins and Their Effects on Human Placental Adenyl Cyclase

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Prostaglandins increased adenyl cyclase activity in human term placental homogenates in a dose-dependent manner during 10-min incubation periods. The potency of the prostaglandins examined was demonstrated to be in the ascending order, prostaglandin F1α < A2, F2α, B2 < A1 < E2 < E1. Although no specific trophic or regulating factors for placental function have been described as yet, it is possible that prostaglandins which are synthesized in decidual tissue could play such a physiological role.

Authors

Kazuo Satoh, Kenneth J. Ryan

The Effect of Copper on Red Cell Enzyme Activities

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Abstract

Previous studies have shown a marked effect of very high levels of copper on red cell glucose-6-phosphate dehydrogenase and glutathione. When the effect of more nearly physiological levels of copper were studied, red cell hexokinase, phosphofructokinase, phosphoglyceric kinase, pyruvate kinase, and 6-phosphogluconate dehydrogenase were found to be inhibited. Inhibition was observed both when copper was added directly to hemolysates or when hemolysates were prepared from red cells from whole blood which had been incubated with copper and washed. The inhibition of red cell enzymes by copper was completely reversed by the addition of EDTA.

Authors

M. Boulard, K.-G. Blume, E. Beutler