Conversion of blood androgens to estrogens in normal adult men and women

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Abstract

Continuous infusions of Δ4-androstenedione-7-3H and testosterone-7-3H have been used to demonstrate that these androgens are converted to estrone and 17β-estradiol, and contribute to the circulating blood levels of these estrogens in normal males and females. The conversion ratio (ratio of concentrations of radioactivity of free product steroid [χ-PRO] and free precursor steroid [χ-PRE], both corrected for recoveries, after an infusion of radioactive precursor steroid) for androstenedione (precursor) to estrone (product) is 0.013 in males and 0.007 in females, and the conversion ratio for testosterone (precursor) to estradiol (product) is 0.0018 in males and 0.005 in females. The transfer constant, [ρ]BBAE1, for androstenedione conversion to estrone ([ρ]BBAE1 = per cent of infused androstenedione, precursor, converted to estrone, product, when infusion and measurement are both in blood) is 1.35% in males and 0.74% in females, and the transfer constant, [ρ]BBTE2, for testosterone conversion to estradiol is 0.39% in males and 0.15% in females.

Authors

Christopher Longcope, Tatsuo Kato, Richard Horton

Genetic control of the phenobarbital-induced shortening of plasma antipyrine half-lives in man

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Abstract

The mean half-life of antipyrine in the plasma of four sets of identical and four sets of fraternal twins after a single oral dose of 16 mg/kg of antipyrine was 12.7 ±SD 3.3 hr. After 2 wk on sodium phenobarbital (2 mg/kg daily) the half-life of antipyrine in the plasma of these twins was reduced to 8.0 ±SD 1.5 hr. Shortening of the plasma antipyrine half-life occurred in all but one of these 16 normal, adult volunteers, but there was considerable variation in the extent of reduction which ranged from 0 to 69%. Phenobarbital administration decreased individual variations in antipyrine metabolism as indicated by the smaller standard deviation of the plasma antipyrine half-lives after phenobarbital than observed initially and by the narrowed range of variation in plasma antipyrine half-lives from 2.8-fold initially to 1.8-fold after phenobarbital. These results suggest that some inducing agents may be used to minimize individual variations in drug metabolism where such variations create therapeutic problems by exposing patients who slowly metabolize certain drugs to toxicity and other patients who rapidly metabolize some drugs to undertreatment.

Authors

Elliot S. Veseli, John G. Page

Natriuretic activity in plasma and urine of salt-loaded man and sheep

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Abstract

The present study was designed to examine the question of whether or not there is a natriuretic hormonal substance involved in the renal regulation of sodium balance.

Authors

Jean E. Sealey, J. Dianne Kirshman, John H. Laragh

Plasma insulin: fluctuations in the “big” insulin component in man after glucose and other stimuli

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Abstract

Plasma was filtered on G50 Sephadex, and two components of circulating insulin, “little” insulin and “big” insulin, were measured by immunoassay. The former component is indistinguishable from insulin, whereas the latter more closely resembles proinsulin and the other insulin-like substances isolated from the pancreas. In thin normal subjects, the fraction of plasma insulin that was big insulin (per cent “big”). 15-30 min after oral glucose, was less than 5%; per cent big rose 2- to 8-fold over the next hour and by 90-120 min represented 5-29% of the plasma insulin. In young thin subjects with idiopathic glucose intolerance associated with normal concentrations of plasma insulin, an identical pattern of big insulin was observed. In thin subjects in whom elevations of per cent big at 90-120 min during the standard test were only modest, starvation for 48 hr before the glucose administration resulted in a more pronounced rise in the per cent big insulin. Early after glucose administration to obese and acromegalic subjects, the per cent big was higher than in thin subjects. The magnitude of the elevation was roughly correlated with elevations in the fasting plasma insulin concentration. By 90-120 min, the per cent big in obese and acromegalic patients was the same range as in the thin subjects. Intravenously administered arginine and tolbutamide in a small number of subjects yielded a response that was similar to oral glucose; the per cent big was low early after stimulation and increased with time. In two patients with islet cell carcinomas, the per cent big was in the same range as in normal subjects.

Authors

Phillip Gorden, Jesse Roth

Inhibition of steady-state intestinal absorption of long-chain triglyceride by medium-chain triglyceride in the unanesthetized rat

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Abstract

Maximal steady-state intestinal absorption rates in unanesthetized rats for triolein, a long-chain triglyceride, and for trioctanoin, a medium-chain triglyceride, are known to differ. Both these lipids are hydrolyzed in the intestinal lumen but the products of hydrolysis are metabolized differently by the mucosal cell. Intraduodenal infusion of trioctanoin was found to reduce steady-state triolein absorption. Luminal lipolysis was shown not to be rate-controlling. High rates of trioctanoin infusion significantly lowered the pH of the luminal aqueous phase and altered the partition of oleic acid between aqueous and oil phases. Two possible mechanisms for the inhibition of triolein uptake are considered. In the intestinal lumen medium chain lipids might have lowered the activity of oleic acid monomers in the aqueous phase and reduced passive diffusion into mucosal cells. Alternatively, competition between long and medium chain fatty acids for some common receptor during transport into the intestinal mucosal cell may have occurred.

Authors

Susanne Bennett Clark, Peter R. Holt

Decreased myocardial adenyl cyclase activity in hypothyroidism

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Abstract

It has been suggested that hypothyroidism may alter the responsiveness of the heart to sympathetic stimulation. To define more precisely the interrelationship between hypothyroidism and catecholamine responsiveness we: (a) studied the effects of norepinephrine and fluoride on the activation of adenyl cyclase in the particulate fraction of heart homogenates from euthyroid and hypothyroid cats; and (b) assessed the contractile response of isolated right ventricular papillary muscles from the same cats to increasing concentrations of norepinephrine. It was found that maximal accumulation of cyclic 3′,5′-adenosine monophosphate (3′,5′-AMP) was significantly lower at peak norepinephrine concentrations in the hypothyroid (284 ±5 pmoles) than in the euthyroid group (326 ±10 pmoles) (P < 0.02). However, the Km for norepinephrine was similar in both groups (1-2 × 10-5 moles/liter), and there was no apparent change in the threshold concentration. Fluoride-mediated increases in Cyclic 3′,5′-AMP accumulation were also significantly lower in the hypothyroid (585 ±25 pmoles) as compared to the euthyroid group (790 ±20 pmoles) (P < 0.02). In contrast, norepinephrine produced a similar augmentation of contractility in isolated papillary muscles from the hypothyroid and euthyroid cats. It thus appears that although the hypothyroid state is associated with a decrease in the total amount of myocardial adenyl cyclase per milligram of tissue capable of being activated by norepinephrine or fluoride, there is no change in the sensitivity of the enzyme to norepinephrine stimulation. Moreover, the finding that the inotropic response to norepinephrine is unaltered in hypothyroidism is compatible with the hypothesis that only a fraction of the total intracellular cyclic 3′,5′-AMP produced by norepinephrine activation of adenyl cyclase is required to elicit the inotropic response.

Authors

Gerald S. Levey, C. Lynn Skelton, Stephen E. Epstein

Congenital dysprothrombinemia: an inherited structural disorder of human prothrombin

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Abstract

A large family has been studied, 11 of whose members have half-normal plasma concentrations of biological prothrombin activity. The pattern of inheritance is autosomal. By use of a specific immunoassay, affected family members have been shown to possess normal quantities of immunoreactive prothrombin, whose immunologic properties seem identical with those of the normal zymogen. Prothrombin isolation from the plasma of one such individual gave normal yields of protein but half-normal amounts of prothrombin activity. Activation of this material in the “intrinsic” and “extrinsic” systems, in concentrated sodium citrate, or by trypsin, gives rise to half, or less, of the thrombin clotting and esterase activities expected from a comparable normal prothrombin preparation. During the clotting of blood from an affected individual, all material with the mobility of prothrombin disappears. Immunoelectrophoresis of the serum reveals a normal nonthrombin “pro piece,” and an additional activation product with an electrophoretic mobility intermediate between that of prothrombin and of “pro piece.” These results suggest that affected individuals are heterozygotes in whom half the prothrombin molecules synthesized are structurally abnormal, since they undergo some alterations during activation, but are incapable of releasing the active enzyme, thrombin.

Authors

Sandor S. Shapiro, Jose Martinez, Ruth R. Holburn

Carbohydrate metabolism in pregnancy: VI. Plasma fuels, insulin, liver composition, gluconeogenesis, and nitrogen metabolism during late gestation in the fed and fasted rat

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Abstract

The effects of late pregnancy on metabolic fuels, liver composition, gluconeogenesis, and nitrogen metabolism have been examined in fed and fasted rats.

Authors

Emilo Herrera, Robert H. Knopp, Norbert Freinkel

Amino acid balance across tissues of the forearm in postabsorptive man. Effects of insulin at two dose levels

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Abstract

Amino acid balance across skeletal muscle and across subcutaneous adipose tissue plus skin of the forearm has been quantified in postabsorptive man before and after insulin infusion into the brachial artery.

Authors

Thomas Pozefsky, Philip Felig, Jordan D. Tobin, J. Stuart Soeldner, George F. Cahill Jr.

Structural polymorphism of the fourth component of human complement

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Abstract

The fourth component of human complement (C4) in 102 individual plasma samples has been examined by the technique of antigen-antibody crossed electrophoresis (AACE). Electrophoretic heterogeneity of C4 was manifested by the repeated occurrence of seven different precipitin patterns. These patterns were formed by varying combinations of three subtypes of C4, differing in electrophoretic mobility. The subtypes were designated C, A, and A1, in order of increasing electrophoretic mobility toward the anode. The evidence that the observed electrophoretic heterogeneity of the C4 molecule represents structural polymorphism rests on five points: the pattern obtained from the plasma of a given individual was reproducible in different runs and with different bleedings; all seven patterns could be demonstrated on the same electrophoretic run; C4 of a given subtype retained its characteristic mobility after purification, when run alone or mixed with plasma containing C4 of other subtypes; the subtypes A1 and C comprising pattern 6 could be separated chromatographically as well as electrophoretically; and the characteristic relative mobilities of different C4 subtypes, in plasma or after purification, were retained even after the rather large shift in mobility associated with conversion to C4i. The ratio of C4 hemolytic activity to protein concentration varied according to the subtype composition of individual samples, with highest ratios occurring with patterns composed of subtype C alone, intermediate values with patterns consisting of A and C, and lower values occurring with patterns containing subtype A alone. Although the mechanism of inheritance of this polymorphism is not yet clear, the data suggest that subtypes A and A1 are inherited as autosomal codominant characteristics, independent of the inheritance of subtype C.

Authors

Stephen I. Rosenfeld, Shaun Ruddy, K. Frank Austen

Inheritance of human α₁-acid glycoprotein (orosomucoid) variants

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Although variants of sialic acid-free α1-acid glycoprotein have been described in human beings, the mode of inheritance of these types has not been reported previously. With the use of a new technique of immunofixation after agarose gel electrophoresis of neuraminidase-treated whole serum, the present study demonstrates that the types of α1-acid glycoprotein variants in family members are consistent with inheritance as autosomal traits with codominant expression. Gene frequencies have been determined for several ethnic groups. Of a total of 11 maternal-cord serum pairs, seven were discordant types, indicating that the fetus synthesizes α1-acid glycoprotein and confirming a previous report that there is no significant transplacental passage of this protein.

Authors

A. Myron Johnson, Karl Schmid, Chester A. Alper

Dopamine (3-Hydroxytyramine) metabolism in parkinsonism

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Abstract

Three patients with idiopathic parkinsonism and six normal subjects were infused over a 4 hr period with 104.6 μc of dopamine-2-14C (3,4-dihydroxyphenylethylamine, 3-hydroxytyramine),1 the immediate precursor in the synthesis of the sympathetic neurohormone, noradrenaline (norepinephrine). Urine was collected during the infusion period, 0-2 hr, 2-4 hr, 4-8 hr, 8-24 hr, and thereafter for 4 additional days. Using a technique herein described, the various metabolic and biosynthetic products of dopamine, including noradrenaline and its metabolic products, were separated, identified, and their radioactivity measured.

Authors

McC. Goodall, Harold Alton

Insulin responses to glucose: evidence for a two pool system in man

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Abstract

Four rapid glucose injections of 5 g each were administered to normal young adult subjects before, during, and after an infusion of glucose. After the first glucose pulse, insulin responses measured immunologically reached a peak between 3 and 5 min and rapidly returned to base line. A short glucose infusion of 300 mg/min decreased the rapid insulin response to a second glucose pulse (- 58%), but after a longer infusion (20 hr) the acute insulin response to a third pulse was restored to normal. Stopping the infusion was followed by return of glucose and insulin levels to prestudy base line within 1 hr, but a fourth glucose pulse was followed by a supernormal acute insulin response (+ 200%). Other observations during these studies showed that a short glucose infusion of either 100 mg/min or 300 mg/min produced a parallel rise in glucose and insulin, but continuation of the infusion for 20 hr was associated with a “paradoxical” fall in glucose and continued rise in insulin. These observations are considered incompatible with a simple linear model often used to describe the relation between plasma glucose and serum insulin. Instead, a two pool system—one for acute insulin release, and the other a time-dependent compartment for long term insulin responses—is suggested.

Authors

D. Porte Jr., A. A. Pupo

Phospholipases in arterial tissue: IV. The role of phosphatide acyl hydrolase, lysophosphatide acyl hydrolase, and sphingomyelin choline phosphohydrolase in the regulation of phospholipid composition in the normal human aorta with age

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Abstract

The role of phospholipases in the regulation of the changing phospholipid composition of normal human aortae with age was studied. Portions of grossly and histologically lesion-free ascending aortae from 16 females and 29 males obtained at autopsy, were analyzed for deoxyribonucleic acid (DNA), phospholipid, and cholesterol content and phospholipid composition. Enzymic activity toward four substrates, lecithin (LE), phosphatidyl ethanolamine, lysolecithin, and sphingomyelin (SP), was determined on portions of the same homogenate. By regression analysis for correlation between all determinations and age the following results were obtained: (a) total phospholipids and choleserol increased linearly with age; (b) the increase in sphingomyelin accounted for about 70% of the phospholipid increment; (c) hydrolysis of lecithin and phosphatidyl ethanolamine increased markedly with age, that of lysolecithin only moderately; (d) hydrolysis of sphingomyelin decreased with age; and (e) an inverse relation between the SP/LE ratio and age and sphingomyelinase/lecithinase activity and age was obtained. These results were interpreted to indicate that a causal relation exists between the fall in sphingomyelinase activity, both absolute and relative to lecithinase activity, and the accumulation of sphingomyelin with age.

Authors

S. Eisenberg, Y. Stein, O. Stein

Micropuncture study of hypertonic mannitol diuresis in the proximal and distal tubule of the dog kidney

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Abstract

Fractional reabsorption of water, sodium, and potassium at proximal and distal tubular sites within the nephron was studied by recollection-micropuncture experiments on dogs undergoing hypertonic mannitol diuresis. After an initial control hydropenic phase, 16% mannitol in modified Ringer's solution was administered intravenously, resulting in marked increases in fractional excretion of water (28.7%), sodium (12.6%), and potassium (63.9%). Inulin clearance decreased significantly from 35.1 to 25.2 ml/min. Analysis of paired micropuncture data revealed a significant decrease in tubule fluid to plasma (TF:P) inulin ratios in both the proximal tubule (1.63-1.45) and distal tubule (5.38-1.94). There was also a significant decrease in proximal TF:P sodium ratios (0.99-0.93) and potassium ratios (1.05-0.98). Distal TF:P sodium ratios, in contrast, rose significantly (0.38-0.59), while TF:P potassium ratios tended towards unity whether initially greater or less than one. Fractional reabsorption of sodium and water decreased by 5% and 10% respectively in the proximal tubule, but to a lesser extent than the resulting increases in fractional urinary excretion. The nonreabsorbed fraction, however, had increased sharply at the point of distal puncture for water (32%), sodium (26%), and potassium (26%), indicating a large inhibitory effect within the loop of Henle in addition to the smaller proximal effects.

Authors

John F. Seely, John H. Dirks

Hemoglobin Yoshizuka (G10(108)β asparagine→aspartic acid): a new variant with a reduced oxygen affinity from a Japanese family

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Abstract

During the course of a survey, a new hemoglobin, designated hemoglobin Yoshizuka, has been encountered in a Japanese family. Clinically, mild anemia was noted in five of six heterozygous individuals but no other significant abnormalities were found. Hemoglobin Yoshizuka is characterized by the substitution of aspartic acid for asparagine at the tenth residue of the G helix in the β-chain. Reduced oxygen affinity with almost normal heme-heme interaction was found to be a property of this abnormal hemoglobin.

Authors

Takashi Imamura, Shigeru Fujita, Yoshiro Ohta, Motosuke Hanada, Toshiyuki Yanase

Metabolic clearance and production rates of human growth hormone

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Abstract

The metabolic clearance rate (MCR) of human growth hormone (HGH) was determined by the constant infusion to equilibrium technique utilizing HGH-125I. 22 control subjects had a MCR of 229 ±52 ml/min (mean ±SD). No difference was evident between sexes, or between various age groups. Patients with acromegaly demonstrated normal MCR's. Moreover, acute elevations of plasma growth hormone concentrations in normal subjects did not alter the MCR of HGH. The MCR was relatively constant from day to day and within the day when subjects were evaluated in the supine position. In contrast, the assumption of the upright position was associated with a mean 24% decrease in the MCR.

Authors

Andrew L. Taylor, Joseph L. Finster, Daniel H. Mintz

Cori cycle activity in man

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Abstract

12 subjects have been studied after an overnight fast with trace amounts of pyruvate-3-14C and glucose-6-14C. Blood disappearance curves and incorporation of the pyruvate-3-14C label into blood glucose have been determined. By the use of transfer functions which allow processes with many different chemical steps to be examined as a unit, we have determined the per cent of pyruvate and presumably lactate which is regenerated into glucose. 8 of the 12 subjects showed that 7-23 mg/kg per hr are recycled, while 4 subjects fell well outside this range. Correlation of increased activity was not good with any demonstrated metabolic abnormality (diabetes or obesity), and it is suggested from clinical observation of the subjects that anxiety may play a role.

Authors

Christine Waterhouse, Julian Keilson

Very low density lipoproteins in intestinal lymph: role in triglyceride and cholesterol transport during fat absorption

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Abstract

The role of nonchylomicron very low density lipoproteins (VLDL, Sf 20-400) in the transport of triglyceride and cholesterol was studied during lipid absorption. Various long chain fatty acids were infused intraduodenally in the form of mixed fatty acid—mono-olein-taurocholate micelles; control animals received saline or taurocholate.

Authors

Robert K. Ockner, Faith B. Hughes, Kurt J. Isselbacher

Immunochemical studies in four cases of alpha chain disease

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Abstract

Studies of a number of properties of the pathological γA-proteins in the first four cases of the recently recognized alpha-chain disease demonstrate that, as in γ-heavy-chain disease, the abnormal protein is devoid of light chains and represents a portion of the α-heavy chain related to the Fc-fragment. In two patients, serum electrophoresis showed a broad abnormal band, whereas in the two others the pathological protein was not noticeable on the electrophoretic pattern. The diagnosis of α-chain disease can be established without purification of the protein by immuno-electrophoresis and gel diffusion experiments using selected antisera to γA and a reference α-chain disease protein. All four proteins belonged to the α1-subclass, displayed electrophoretic heterogeneity, and showed a strong tendency to polymerize. The polymers occurred in vivo and were held together both by disulfide bonds and by strong noncovalent forces. Two of the three purified proteins had a very high carbohydrate content. The abnormal protein was always found in concentrated urines in variable but generally low amounts. It was not detected in parotid saliva but was present in significant amounts in jejunal fluid of all four patients. The α-chain disease protein was shown to be associated with the secretory piece in external secretions of two patients.

Authors

Maxime Seligmann, Edith Mihaesco, Daniel Hurez, Constantin Mihaesco, Jean-Louis Preud'homme, Jean-Claude Rambaud

Galactose-1-phosphate uridyltransferase and galactokinase activity in cultured human diploid fibroblasts and peripheral blood leukocytes: I. Analysis of transferase genotypes by the ratio of the activities of the two enzymes

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Abstract

The specific activities of galactokinase and galactose-1-phosphate uridyltransferase were determined in peripheral blood leukocytes directly after separation from whole blood, and in cultured skin fibroblasts at various times during the subculture growth period. Growth curves were obtained for fibroblasts based on three different parameters: direct cell counts, total protein, and total deoxyribonucleic acid (DNA) content. At the time in culture when the specific activity of both enzymes was maximal and least variable, the ratio of transferase to galactokinase correlated well with the transferase genotypes of the original tissue donors. Leukocyte transferase: galactokinase ratios gave a similar distribution pattern.

Authors

Thomas A. Tedesco, William J. Mellman

Failure of bile acids to control hepatic cholesterogenesis: evidence for endogenous cholesterol feedback

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Abstract

Studies were undertaken to define the role of bile acids in the control of hepatic cholesterogenesis from acetate. Both biliary diversion and biliary obstruction increase the rate of sterol synthesis by the liver 2.5- to 3-fold. After biliary diversion, however, the bile acid content of the liver is decreased, whereas after biliary obstruction, it is markedly increased. Thus, there is no relationship between the tissue content of bile acid and the rate of hepatic cholesterol synthesis. Furthermore, restoration of the enterohepatic circulation of bile acid in animals with biliary diversion fails to prevent the rise in synthetic activity seen after this manipulation. These data indicate that bile acid plays no direct inhibitory role in the regulation of cholesterol synthesis by the liver.

Authors

Hans J. Weis, John M. Dietschy

Two distinct groups of immunoglobulin A(IgA) revealed by peptic digestion

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Abstract

Serum IgA M-components, secretory IgA separated from colostrum, and IgA from serum of patients with cirrhosis of the liver were digested with pepsin at pH 4.1. The IgA M-components segregated into two groups on the basis of their relative rates of peptic digestion. Serum and colostral IgA were digested at a total rate intermediate to that of the two groups of IgA myeloma proteins. It appeared, however, that colostral IgA may have been initially more resistant to peptic digestion than serum IgA. The variability in the rate of peptic digestion was not related to electrophoretic mobility, light-chain type, or IgA subclass. Experimental conditions related to enzyme to substrate ratio or to the pH of the reaction mixture did not appear to explain the differences found.

Authors

I. Dodd Wilson, R. C. Williams Jr.