1972 PROGRAM AMERICAN SOCIETY FOR CLINICAL INVESTIGATION, INC. 64TH ANNUAL MEETING

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Alterations in the Baroreceptor Reflex in Conscious Dogs with Heart Failure

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The effectiveness of the baroreceptor reflex in conscious dogs with experimental cardiac hypertrophy and heart failure was compared with that in a group of normal conscious dogs. Cardiac hypertrophy and heart failure were produced by tricuspid avulsion and progressive pulmonary stenosis. The sensitivity of the baroreceptor reflex to transient hypertension was assessed by determining the slope of the regression line relating the prolongation of the R-R interval to the rise in systolic arterial pressure during the transient elevation of arterial pressure induced by an intravenous injection of 1-phenylephrine. The mean slope averaged 22.4±2.3 msec/nm Hg in 16 normal animals. 23.1 ±1.5 in five sham-operated animals, and was significantly reduced to 8.3 ±0.8 in 10 dogs with hypertrophy alone (P < 0.001), and to 3.3±0.5 in nine dogs with heart failure (P < 0.001). The response to baroreceptor hypotension was compared during bilateral carotid artery occlusion (BCO) in six normal and six heart failure dogs previously instrumented with Doppler flow transducers on the superior mesenteric and renal arteries. During BCO, in normal dogs arterial pressure increased 52±4 mm Hg, heart rate 33±2 beats/min, mesenteric resistance 0.17±0.03 mm Hg/ml per min, and renal resistance 0.37±0.10 mm Hg/ml per min. In the heart failure group all of these variables increased significantly less (P < 0.01); arterial pressure rose 25 ±3 mm Hg, heart rate 13 ±4 beats/min, mesenteric resistance 0.04±0.007 mm Hg/ml per min, and renal resistance 0.18±0.09 mm Hg/ml per min.

Authors

Charles B. Higgins, Stephen F. Vatner, Dwain L. Eckberg, Eugene Braunwald

Ontogeny of the Human Complement System: In Vitro Biosynthesis of Individual Complement Components by Fetal Tissues

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The human fetal liver is capable of synthesizing the biologically active form of the second (C2) and fourth (C4) components of complement as early as 8 wk after conception, and the inhibitor of C1 (C1 INH) as early as 11 wk after conception. Biologically active C3 was produced in vitro by fetal liver obtained at 14 wk gestation. These conclusions were based on the observations that isolated fetal livers produced biologically active C2, C3, C4, and C1 INH, that this production was temperature dependent and reversibly inhibited by well-known inhibitors of protein synthesis, and that 14C-labeled amino acids were incorporated into proteins immunochemically identical with these proteins. The data suggested that a large mononuclear cell was the cell type in the fetal liver that synthesized C2 and C4.

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Harvey R. Colten

Properties of Adenyl Cyclase from Human Jejunal Mucosa during Naturally Acquired Cholera and Convalescence

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The enterotoxin of Vibrio cholerae causes copious fluid production throughout the lenght of the small intestine. As this is thought to be mediated by stimulation of adenyl cyclase, a study has been made of the activity and properties of this enzyme in jejunal biopsy tissue taken from patients during the diarrheal phase of cholera and after recovery. Adenyl cyclase activity during cholera was increased more than twofold relative to the enzyme in convalescence. Under both conditions stimulation by prostaglandin E1 (PGE1) and by fluoride was observed. The responsiveness to PGE1 was not altered in cholera; the total activity of the fluoride-stimulated enzyme was similar, a finding that suggests cholera toxin stimulates pre-existing enzyme in the intestinal cell. The enzymes during cholera and convalescence were similar in all other properties examined. Optimal Mg++ concentration was 10 mM; Mn++ at 5 mM stimulated the enzyme but could not replace Mg++ except in the presence of 10 mM fluoride. Calcium was markedly inhibitory at concentrations greater than 10-4 M. The pH optimum was 7.5 and the Michaelis constant (Km) for ATP concentration approximated 10-4 M. Thus the interaction of cholera toxin with human intestinal adenyl cyclase does not alter the basic properties of the enzyme. When biopsy specimens were maintained intact in oxygenated Ringer's solution at 0°C, no loss of activity was observed at 1½ and 3 hr. In contrast, when the cells were homogenized, rapid loss of activity, with a half-life of 90 min was seen even at 0°C. Consequently for comparative assays of human jejunal adenyl cyclase, strict control of the experimental conditions is required. It was under such conditions that a twofold increase in basal adenyl cyclase activity during cholera was observed.

Authors

Lincoln C. Chen, Jon E. Rohde, Geoffrey W. G. Sharp

Phenobarbital-Induced Alterations in Vitamin D Metabolism

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The metabolic fate of intravenously injected vitamin D3-1,2-3H (D3-3H) was studied in two normal individuals on chronic phenobarbital therapy. Silicic acid column chromatography of lipid-soluble plasma extracts obtained serially for 96 hr after D3-3H injection demonstrated a decreased plasma D3-3H half-life and increased conversion to more polar metabolites. The polar metabolites formed included several with chromatographic mobility similar to known biologically inactive vitamin D metabolites and one with chromatographic mobility identical to 25-hydroxycholecalciferol. Disappearance of this latter material was also accelerated. A child with rickets and a normal volunteer studied before and after a 2 wk course of phenobarbital therapy demonstrated similar alterations in D3-3H metabolism. When liver microsomes from 3-wk-old Sprague-Dawley rats treated with phenobarbital were incubated with D3-3H, polar metabolites were produced with chromatographic mobility similar to the plasma D3-3H metabolites from phenobarbital-treated humans. Similar incubations employing 25-hydroxy-cholecalciferol-26-27-3H as the substrate also demonstrated an increased conversion to polar metabolites. The data suggest that the reported increased incidence of osteomalacia observed in patients on chronic anticonvulsant therapy may be the result of an accelerated conversion of vitamin D and its active metabolite, 25-hydroxycholecalciferol, to polar metabolites by druginduced liver microsomal enzymes.

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T. J. Hahn, S. J. Birge, C. R. Scharp, L. V. Avioli

25-Hydroxycholecalciferol. A COMPARATIVE STUDY IN DEFICIENCY RICKETS AND DIFFERENT TYPES OF RESISTANT RICKETS

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The effects of 25-hydroxycholecalciferol were studied in 4 children with deficiency rickets and 22 children with D-resistant rickets, including patients with hereditary hypophosphatemic D-resistant rickets, “pseudo-deficiency” rickets, and rickets secondary to cystinosis or to tyrosinosis. Three protocols were used. (a) 8 days after a single oral dose of 16,000 IU of 25-hydroxycholecalciferol, normalization of all biological parameters was observed in all cases of deficiency rickets. A complete lack of response was observed in the different types of resistant rickets. (b) Under prolonged administration of 2,640 IU/day for 2 months, clinical-biological symptoms and X-ray lesions disappeared, and a catch-up growth pattern was observed in deficiency rickets; no relapse of rickets occurred up to 5 months after therapy was stopped. The same dose had no significant effect in 10 patients with hereditary hypophosphatemic D-resistant rickets. A bone biopsy performed in one case showed the persistence of characteristic lesions. (c) With increasing doses of 25-hydroxycholecalciferol varying from 6,000 to 30,000 IU/day and a follow-up of 6 months up to 2 yr duration, clinical-biological-radiologic recovery and catch-up growht was obtained in all cases of “pseudo-deficiency” rickets. In hypophosphatemic hereditary D-resistant rickets, 5 out of 13 patients' serum concentration of phosphorus reached at least 30 mg/liter, but a catch-up growth pattern was not observed. These results indicate that (a) 25-hydroxycholecalciferol is highly active in deficiency rickets; (b) a defect in the conversion of vitamin D3 to its active 25-hydroxy metabolite is probably not the metabolic defect in any of the different types of vitamin D-resistant rickets studied.

Authors

Sonia Balsan, Michele Garabedian

The Development of Macrophages from Large Mononuclear Cells in the Blood of Patients with Inflammatory Disease

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The origin and function of the increased of “atypical lymphocytes” which appear in the blood of patients with many inflammatory diseases is not known. Leukocyte suspensions from eight patients with systemic lupus erythematosus (SLE), five patients with other rheumatic diseases, and five patients with infectious diseases were pulse-labeled with tritiated thymidine (Tdr-3H) and sampled after 5 and 72 hr in vitro. Radioautographs indicated that 35% of the total large, nonphagocytic mononuclear leukocytes incorporated Tdr-3H during the initial 5 hr of culture. Tdr-3H-labeled large phagocytic or glass-adherent cells were observed only infrequently. After 72 hr one-third of the original number of Tdr-3H-labeled cells from patients with SLE developed the morphology of macrophages and the capacity to phagocytose latex particles. Similar findings were observed in patients with other rheumatic diseases and bacterial infections. In contrast, the thymidine-labeled cells from patients with infectious hepatitis and infectious mononucleosis were poorly viable in culture and rarely became macrophages. Tdr-3H-labeled small lymphocytes were uncommon. The present experiments suggest that in patients with certain inflammatory diseases large, proliferating “lymphocytelike” cells are very immature monocyte precursors which appear in response to tissue injury. These DNA-synthesizing cells together with mature monocytes may serve as the circulating source of macrophages.

Authors

David A. Horwitz

Complete Deficiency of Leukocyte Glucose-6-Phosphate Dehydrogenase with Defective Bactericidal Activity

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A 52 yr old Caucasian female (F. E.) had hemolytic anemia, a leukemoid reaction, and fatal sepsis due to Escherichia coli. Her leukocytes ingested bacteria normally but did not kill catalase positive Staphylococcus aureus, Escherichia coli, and Serratia marcescens. An H2O2-producing bacterium, Streptococcus faecalis, was killed normally. Granule myeloperoxidase, acid and alkaline phosphatase, and beta glucuronidase activities were normal, and these enzymes shifted normally to the phagocyte vacuole (light and electron microscopy). Intravacuolar reduction of nitroblue tetrazolium did not occur. Moreover, only minimal quantities of H2O2 were generated, and the hexose monophosphate shunt (HMPS) was not stimulated during phagocytosis.

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M. Robert Cooper, Lawrence R. DeChatelet, Charles E. McCall, Mariano F. La Via, Charles L. Spurr, Robert L. Baehner

Plasma Catecholamines in Long-Term Diabetics with and without Neuropathy and in Hypophysectomized Subjects

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Employing a precise and sensitive double-isotope derivative technique, plasma catecholamine concentration (PCA) was measured in four groups of subjects: (a) long-term diabetics with neuropathy, (b) long-term diabetics without neuropathy, (c) hypophysectomized long-term diabetics with neuropathy, and (d) nondiabetic control subjects. Blood samples were obtained from subjects in the supine and in the standing position.

Authors

Niels Juel Christensen

Evidence for Enhanced Cellular Uptake and Binding of Thyroxine In Vivo during Acute Infection with Diplococcus pneumoniae

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Previous work has demonstrated that acute pneumococcal infections in man and in the rhesus monkey are accompanied by accelerated metabolic disposal of L-thyroxine (T4). In order to study the influence of acute pneumococcal infection on the kinetics of hormone distribution, the early cellular uptake of T4 (CT4), reflecting the net effect of plasma and cellular binding factors, was assessed in rhesus monkeys from the differences in instantaneous distribution volumes of T4-131I and albumin-125I during the first 60 min after their simultaneous injection. Hepatic and renal uptakes of 131I were also determined. Plasma binding of T4 was assessed by measuring the per cent of free T4 (% FT4) in serum. Six monkeys were studied 12 hr (INF-12) and seven 24 hr (INF-24) after intravenous inoculation with Diplococcus pneumoniae; seven controls were inoculated with a heat-killed culture. CT4 at 60 min as per cent administered dose was 31.5 ±2.0 (mean ±SE) in INF-12 and 33.0±0.8 in INF-24, values significantly greater than control (22.4±1.3). By contrast, mean% FT4 was identical in control and INF-12 (0.028 ±0.002 and 0.028 ±0.001) and variably increased in INF-24 (0.034 ±0.003). Thus, in the infected monkeys CT4 and% FT4 were not significantly correlated. The increased CT4 in the infected monkeys could not be ascribed to an increase in vascular permeability and did not correlate with the magnitude of fever. Although the increased CT4 could not be accounted for by increased hepatic or renal uptake of hormone, hepatic and renal T4 spaces were increased, results consistent with increased binding by these tissues. Our data indicate that the cellular uptake of T4 is increased early in acute pneumococcal infection and suggest that this results from a primary enhancement of cell-associated binding factors for T4.

Authors

Frederick R. DeRubertis, Kenneth A. Woeber

Effect of Cholera Enterotoxin on Ion Transport across Isolated Ileal Mucosa

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The effects of cholera enterotoxin on intestinal ion transport were examined in vitro. Addition of dialyzed filtrate of Vibrio cholerae (crude toxin) to the luminal side of isolated rabbit ileal mucosa caused a delayed and gradually progressive increase in transmural electric potential difference (PD) and shortcircuit current (SCC). A similar pattern was observed upon addition of a highly purified preparation of cholera toxin, although the changes in PD and SCC were smaller. Na and Cl fluxes across the short-circuited mucosa were determined with radioisotopes 3-4 hr after addition of crude toxin or at a comparable time in control tissues. The toxin caused a net secretory flux of Cl and reduced to zero the net absorptive flux of Na. Similar flux changes were observed when either crude or purified toxin was added in vivo and tissues were mounted in vitro 3-4 hr later. Additon of D-glucose to the luminal side of toxin-treated mucosa produced a large net absorptive flux of Na without altering the net Cl and residual ion fluxes.

Authors

Michael Field, David Fromm, Qais Al-Awqati, William B. Greenough III

Food Iron Absorption Measured by an Extrinsic Tag

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The paper describes the use of an extrinsic tag of inorganic radioiron to determine the total absorption of nonheme iron from a complete meal. The method was developed by measuring the iron absorbed from vegetable foods containing biosynthetically incorporated 55Fe (intrinsic tag) and from 59Fe added as a small dose of inorganic iron to the same meal (extrinsic tag). In studies with maize, black bean, and wheat, a consistent extrinsic: intrinsic radioiron absorption ratio averaging 1.10 was observed. Similar results were obtained with either ferrous or ferric iron as the extrinsic tag, and with doses of the latter ranging from 0.001 to 0.5 mg iron added to a test meal containing 2-4 mg of food iron. Adding the radioiron at different stages in preparation of the test meal also had little effect. Separate administration of the extrinsic tag was less satisfactory when small portions of a single food were employed, but with a complete meal, the separate dose was preferable. The extrinsic tag provided a valid measure of absorption despite marked differences in the iron status of the subject, and with wide changes in absorption imposed by adding desferrioxamine or ascorbic acid to the test meal. These findings indicate that there is a common pool of nonheme iron, the absorption of which is influenced by various blocking or enhancing substances present in the meal.

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J. D. Cook, M. Layrisse, C. Martinez-Torres, R. Walker, E. Monsen, C. A. Finch

Effects of Dibutyryl Cyclic Adenosine 3′,5′-Monophosphate and Parathyroid Extract on Calcium and Phosphorus Metabolism in Hypoparathyroidism and Pseudohypoparathyroidism

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It has been proposed previously that the metabolic defect in pseudohypoparathyroidism which accounts for parathyroid hormone unresponsiveness is an absence or abnormal form of the adenyl cyclase system in kidney and presumably in bone. To determine whether there is an associated defect in the response mechanism to cyclic adenosine 3′,5′-monophosphate (cyclic AMP), the effects of parathyroid extract (PTE), and dibutyryl cyclic AMP were compared in patients with either surgical hypoparathyroidism or pseudohypoparathyroidism. PTE and dibutyryl cyclic AMP both increased serum and urinary calcium, lowered the serum phosphorus, and increased urinary phosphorus in patients with hypoparathyroidism. PTE also increased urinary cyclic AMP in these patients. PTE increased serum and urinary calcium and urinary phosphorus but did not alter serum phosphorus or urinary cyclic AMP in the patients with pseudohypoparathyroidism. Dibutyryl cyclic AMP increased the serum and urinary calcium, lowered the serum phosphorus, and increased urinary phosphorus in all the patients with pseudohypoparathyroidism. The results indicate that (a) dibutyryl cyclic AMP can reproduce the effects of parathyroid hormone on calcium and phosphorus metabolism in man, (b) the response mechanism to cyclic AMP appears to be intact in pseudohypoparathyroidism, and (c) PTE apparently produces some of its characteristic effects on calcium and phosphorus metabolism in pseudohypoparathyroidism in the absence of an increase in urinary cyclic AMP.

Authors

Norman H. Bell, Susan Avery, Tushar Sinha, Charles M. Clark Jr., Donald O. Allen, Conrad Johnston Jr.

Estradiol and Testosterone Secretion by Human, Simian, and Canine Testes, in Males with Hypogonadism and in Male Pseudohermaphrodites with the Feminizing Testes Syndrome

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The role of the human testis in the production of 17β-estradiol (E2) was investigated by determining the concentration of E2 and testosterone in peripheral and spermatic vein plasma samples. Specimens were obtained from eight normal men, three men with hypogonadism, and two patients with the incomplete form of the feminizing testes syndrome. For comparison, similar studies were performed in four monkeys, 10 mongrel dogs, and 4 additional dogs who were given 1000 IU of human chorionic gonadotropin/day for 5 days. Plasma E2 was measured by radioimmunoassay utilizing sheep anti-E2 serum preceded by ether extraction and thin layer chromatographic separation of plasma steroids. Procedural blanks, which were subtracted from all reported values were 14.1±0.74 (SEM) pg for deionized water and 13.1±0.66 pg for charcoaladsorbed pooled male plasma. Pooled male and pooled female control plasmas averaged 17±0.71 pg/ml and 95±6.9 pg/ml, respectively; individual adult male specimens ranged between 8 and 28 with a mean of 18±1.4 pg/ml. In the eight normal men, the mean peripheral vein E2 concentration was 20±1.6 pg/ml, while the spermatic vein concentration was 50 times as great, 1049±57 pg/ml. All three patients with testicular abnormalities had low spermatic vein E2 concentrations (160, 280, and 416 pg/ml). Lesser E2 gradients were found across the simian (3-fold) and canine (approximately 12-fold) testes. Testicular testosterone gradients (human 110-, simian 10-, and canine 77-fold) were greater than the E2 gradients in all three species. In four dogs, HCG treatment elicited a 6-fold increase in peripheral and a 9-fold increase in spermatic vein testosterone concentrations; however, peripheral and spermatic vein E2 concentrations did not differ from control values. Spermatic vein E2 concentrations were > 4600 and 2210 pg/ml (post-HCG) in two patients with the incomplete form of the feminizing testes syndrome. Postorchiectomy, peripheral E2 and testosterone concentrations fell precipitously in both patients, confirming the major contribution of the testes, in this syndrome, to circulating E2 and testosterone. These studies provide direct evidence that the human testic secretes estradiol.

Authors

R. P. Kelch, M. R. Jenner, R. Weinstein, S. L. Kaplan, M. M. Grumbach

The Effect of Calcium and Other Salts upon the Release of Glucagon-Like Immunoreactivity from the Gut

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It has been suggested that glucagon-like immunoreactivity (GLI) of gastrointestinal tissues might, like pancreatic glucagon, have calcium-lowering activity. Studies were designed, therefore, to determine if calcium absorption was associated with GLI release from the gut. The intraduodenal administration of 4.5 mmoles of calcium chloride per kg of body weight to conscious dogs was associated with a prompt rise in plasma GLI from a base line of 2.2 ng/ml (SEM ±0.2) to a peak of 4.3 ng/ml (SEM ±0.3) at 45 and 60 min, in association with a rise of plasma calcium from 8.6 to 10.4 mg/100 ml. Neither pancreatic glucagon, insulin, nor glucose changed. Smaller calcium loads had progressively diminishing effects on GLI release. Calcium lactate also appeared to stimulate effectively GLI release. Both magnesium chloride and sodium chloride given intraduodenally were associated with a significant though modest increase in GLI.

Authors

Ingolf Böttger, Gerald R. Faloona, Roger H. Unger

Subhuman Primate Pregnancy Complicated by Streptozotocin-Induced Diabetes Mellitus

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Polydipsia, polyuria, polyphagia, and glucosuria followed the administration of streptozotocin to 6 nonpregnant and 15 pregnant monkeys (Macaca mulatta) in the first trimester of pregnancy. The diabetogenic action of the drug was also reflected in an induced but variable deterioration in maternal intravenous glucose tolerance and a marked attenuation of maternal plasma insulin responsiveness to intravenous glycemic stimuli. The products of conception were examined in 29 pregnancies. The neonates and the placentas of the streptozotocin-treated pregnant animals were significantly heavier than average for the period of gestation, polyhydramnios was consistently present, and there was an increase in the incidence of third trimester stillbirths.

Authors

Daniel H. Mintz, Ronald A. Chez, Donald L. Hutchinson

Study of Four New Kindreds with Inherited Thyroxine-Binding Globulin Abnormalities POSSIBLE MUTATIONS OF A SINGLE GENE LOCUS

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Five families with inherited thyroxine-binding globulin (TBG) abnormalities were studied. On the basis of serum thyroxine (T4)- binding capacity of TBG in affected males, three family types were identified: TBG deficiency, low TBG, and high TBG capacity. In all families evidence for X-linked inheritance was obtained and in one family all criteria establishing this mode of inheritance were met. Only females were heterozygous, exhibiting values intermediate between affected males and normals. Overlap in heterozygotes was most commonly encountered in families with low TBG.

Authors

Samuel Refetoff, Noel I. Robin, Chester A. Alper

Metabolism of Human C1q STUDIES IN HYPOGAMMAGLOBULINEMIA, MYELOMA, AND SYSTEMIC LUPUS ERYTHEMATOSUS

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The in vivo metabolism of radioiodinelabeled C1q was determined in patients with hypogammaglobulinemia, multiple myeloma, systemic lupus erythematosus (SLE), and in healthy controls. Marked differences in metabolic behavior were observed with a much more rapid disappearance of plasma radioactivity in patients as compared with controls. Estimated plasma volumes at 10 min after injection (time 0) were normal in controls and the SLE patient, mean 40 ml/kg, whereas they were grossly elevated, 57-82 ml/kg, in the hypogammaglobulinemic and myeloma patients, indicating significant loss of C1q-125I during the initial mixing period. Absence of a distinct initial equilibration phase of radioactivity loss from the plasma suggested significant reversible interaction of the labeled C1q with plasma proteins and density gradient studies provided evidence for in vivo uptake into the circulating trimolecular first component complex (C1q, r, s). In controls and the SLE patient 0.51-0.75 of the C1q was retained in the plasma space while only 0.28 or less was in the others. The daily plasma pool fractional C1q catabolism was 0.65-0.67 in controls compared with 0.95-4.80 in the patients. C1q synthetic rates in controls were 4.64 and 4.34 mg/kg per day while higher rates, 4.94-37.40 occurred in the patients.

Authors

Peter F. Kohler, Hans J. Müller-Eberhard

The Role of Intraluminal Sodium in Glucose Absorption In Vivo

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Active glucose absorption is thought to depend on a gradient of sodium ion concentration across the brush border membrane of intestinal epithelial cells. This concept is generally accepted, although its validity has never been adequately evaluated in the human small intestine in vivo. According to this hypothesis, the rate of glucose absorption should decrease markedly if the luminal sodium concentration is markedly reduced, and glucose absorption against a concentration gradient should cease entirely if luminal sodium is lower than intracellular sodium concentration. In the present series of experiments we were not able to show an important role of intraluminal sodium concentration in the active absorption of glucose from the human, rat, and dog ileum in vivo. Specifically, glucose absorption was minimally reduced or not reduced at all when intraluminal sodium concentration was reduced from 140 to as low as 2.5 mEq/liter. The discrepancy between our results and those of previous workers whose data suggest that removal of intraluminal sodium should markedly inhibit active glucose absorption is not entirely clear, but there are a number of differences in experimental design between most previous studies and our own. Although our data show that active glucose absorption proceeds at a near normal rate even when lumen sodium concentration is reduced below 3 mEq/liter, our results do not disprove the sodium gradient theory because of the theoretic possibility that the microclimate adjacent to the brush border has a high concentration of sodium even when luminal sodium concentration is markedly reduced. The validity of the sodium gradient hypothesis would appear to be critically dependent on such a microclimate.

Authors

David A. Saltzman, Floyd C. Rector Jr., John S. Fordtran

Effect of Magnesium Depletion on Responsiveness to Parathyroid Hormone in Parathyroidectomized Rats

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Hypocalcemia and resistance to exogenous parathyroid hormone have been reported in several clinical states associated with magnesium deficiency. On the basis of such observations, it has been suggested that magnesium depletion per se may result in impaired responsiveness of the adenyl cyclase-adenosine 3′,5′-monophosphate (3′,5′-AMP) system. To test this hypothesis, 4 wk old male parathyroidectomized rats were maintained on normal or magnesium-deficient diets for 4 wk and their responses to parathyroid hormone compared.

Authors

T. J. Hahn, L. R. Chase, L. V. Avioli

Erythropoietic Protoporphyria: Lipid Peroxidation and Red Cell Membrane Damage Associated with Photohemolysis

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The mechanism by which long wavelength ultraviolet light hemolyzes red cells obtained from patients with erythropoietic protoporphyria (EPP) was investigated. Previous studies had suggested that irradiation of these red cells with wavelengths of light capable of eliciting dermatological manifestations led to oxygen-dependent colloid osmotic hemolysis through the formation of peroxides. In the present report, lipid peroxidation during in vitro irradiation of EPP red cells with long ultraviolet light was demonstrated by: (a) the formation of 2-thiobarbituric acid reactants; (b) the presence of conjugated diene bonds in red cell lipid; and (c) the selective loss of unsaturated fatty acids proportional to the number of carbon-carbon double bonds in each. Irradiation of EPP red cells was also shown to result in the formation of hydrogen peroxide.

Authors

Bernard D. Goldstein, Leonard C. Harber

Increase in Fibrinogen and Fibrin-Related Antigen in Human Serum Due to In Vitro Lysis of Fibrin by Thrombin

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In vitro lysis of fibrin, as indicated by increased fibrinogen-fibrin-related antigen (FR-antigen) in serum is usually seen when whole blood, or plasma, or highly purified fibrinogen prepared by several different procedures is clotted and kept at temperatures above 0°C. This increase is both time and temperature dependent, occurs despite the addition of various plasmin and cathepsin inhibitors, and is probably caused by thrombin evolved during clotting and/or added in vitro. In these experiments, the FR-antigen was measured by a sensitive, reproducible hemagglutination inhibition immunoassay adapted to the AutoAnalyzer. Serum from whole blood contained more than serum from plasma, and fibrin rather than fibrinogen proved to be essential for the in vitro lysis. The phenomenon was also caused by Arvin or Reptilase, suggesting that splitting of one or more arginine or lysine bonds in fibrin may be at least partially responsible. To obtain minimal levels of FR-antigen (< 0.5 μg/ml), plasma is clotted for 4 hr at 0°C with 1.0-5.0 U/ml thrombin, CaCl2 (0.0125 mole/liter), and epsilon aminocaproic acid (0.05 mole/liter). Slightly higher levels, probably adequate for clinical diagnosis, are obtained by 10-30 min clotting at room temperature. Since endogenous and/or exogenous thrombin is essential for the collection of serum FR-antigen, all the FR-antigen found in normal serum probably results from an irreducible amount of in vitro lysis rather than from continuous intravascular clotting and fibrinolysis.

Authors

Clarence Merskey, Alan J. Johnson, Parviz Lalezari

The Metabolism of Proinsulin and Insulin by the Liver

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The removal of bovine proinsulin by the isolated perfused rat liver has been studied and the results compared with the removal of insulin. At high concentrations of insulin (> 180 ng/ml) the removal process was saturated and the t½ varied between 35 and 56 min. With low initial insulin levels the disappearance followed first-order kinetics, the mean regression coefficient being — 0.022, t½ 13.8 min, and the hepatic extraction 4.0 ml/min. The results with proinsulin were in striking contrast to these findings. At both high and low concentrations the hepatic removal of proinsulin was considerably slower, averaging 10-15 times less than that of insulin. Specific immunoassay techniques and gel filtration of samples taken from perfusions to which both labeled and unlabeled proinsulin had been added did not show conversion to either insulin or the C-peptide.

Authors

A. H. Rubenstein, L. A. Pottenger, M. Mako, G. S. Getz, D. F. Steiner

Effects of Acute Volume Expansion and Altered Hemodynamics on Renal Tubular Function in Chronic Caval Dogs

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It is well established that dogs with chronic partial constriction of the thoracic inferior vena cava develop sodium retention, ascites, and respond poorly to acute saline loading. A group of such chronic caval dogs, and a group of normal controls were studied during hydropenia, and again after acute saline loading by clearance and recollection micropuncture techniques. After volume expansion, the caval dogs excreted 52 μEq/min per kidney of sodium compared with 370 μEq/min per kidney for the normal controls. During hydropenia and after the saline infusions, single nephron filtration rates, fractional reabsorption of sodium within the proximal tubule, and proximal delivery of filtrate to the distal nephron were comparable in both groups of dogs.

Authors

Mortimer Levy

Effects of Catecholamines and their Interaction with Other Hormones on Cyclic 3′,5′-Adenosine Monophosphate of the Kidney

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Catecholamines have several physiological effects on the kidney. These include: (a) stimulation of renin synthesis in the cortex: (b) antidiuresis by beta adrenergic agents; and (c) diuresis by alpha adrenergic stimulation. The role of cyclic 3′,5′-adenosine monophosphate (cyclic AMP) in the renal actions of catecholamines was evaluated by measuring the effects of several adrenergic agents on cyclic AMP concentration in the dog kidney.

Authors

Nama P. Beck, Sarah W. Reed, H. V. Murdaugh, Bernard B. Davis

Changes in Serum and Urinary Calcium during Treatment with Hydrochlorothiazide: Studies on Mechanisms

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Studies were undertaken in man to evaluate the roles of volume depletion and of the parathyroid glands in mediating the changes in serum and urinary calcium which follow the administration of hydrochlorothiazide, 100 mg twice daily, for 4 days, 42 studies were carried out in 16 normal subjects, 9 patients with hyperparathyroidism, and 7 vitamin D-treated subjects with hypoparathyroidism. In six studies in normal subjects, daily sodium losses during thiazide administration were quantitatively replaced, and in six other studies the effect of equivalent sodium losses produced by furosemide was evaluated.

Authors

Arnold S. Brickman, Shaul G. Massry, Jack W. Coburn

Naturally Occurring Human Antiglobulins with Specificity for γE

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Human sera have been examined for antibodies with specific reactivity for γE using the tanned cell hemagglutination test. Cells tanned with three different γE myeloma proteins provided a reproducible test system. Inhibition of agglutination reactions by γE proteins, but not by γG, γA, γM, or γD confirmed the specificity of these reactions. 8.5% of 304 serial serum samples obtained from miscellaneous hospitalized patients showed clear-cut anti-γ-globulins with specificity for γE. In most of these instances no definite clinical history of concomitant allergic disorders could be obtained. 53% of 73 patients with well-established allergic disorders (hay fever, extrinsic asthma) showed serum anti-γ-globulins with reactivity for γE. Some patients studied before and after desensitization to Bermuda grass allergen showed an increase in titer or a conversion from negative to positive reactions for anti-γE antibodies following several month courses of progressive desensitization. Gradient and gel filtration studies indicated that anti-γE globulins were 19S γM in all instances. No clear correlation was noted between quantitative serum γE levels and titer of anti-γE antibodies.

Authors

Ralph C. Williams Jr., Robert W. Griffiths, Jean D. Emmons, Richard C. Field

Measurement of Regional Myocardial Perfusion in Man with ¹³³Xenon and a Scintillation Camera

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Abstract

A method was devised to quantitate regional capillary perfusion in the human heart by measuring the clearance constants (k) of Xenon-133 washout from multiple areas of the myocardium with a multiple-crystal scintillation camera. In 17 subjects, 133Xe was injected into the right or left coronary artery or both and counts per second (cps) were recorded simultaneously on magnetic tape from each of 294 scintillation crystals viewing the precordium through a multichannel collimator. Data were processed by a digital computer. Crystals detecting the myocardial washout of 133Xe were distinguished from those monitoring pulmonary excretion by positioning radioactive markers at the cardiac margins, and by a computer printout of the peak cps recorded by each crystal and its time after isotope injection into the coronary artery. The slopes of the initial segment of the multiple 133Xe curves obtained in each study were calculated by the method of least squares using a monoexponential model. Myocardial blood flow rates in the cardiac regions viewed by the individual crystals were calculated (assuming a blood to myocardium partition coefficient of 0.72) along with the SD of every flow measurement. The pattern of myocardial perfusion rates so obtained was superimposed over a tracing of the subject's coronary arteriogram. Scintiphotographs showing the arrival and washout of isotope from various regions of myocardium and the area of tissue perfused by each coronary artery were obtained by replaying the data tape on an oscilloscope. Significant regional variations in local myocardial perfusion rates were observed in hearts with normal coronary arteries. When capillary flow measurements from crystals overlying the various cardiac chambers were averaged in each subject, the mean myocardial blood flow rate of the left ventricle in 17 patients, 64.1 ±13.9 (SD) ml/100 g·min, significantly exceeded that of the right ventricle, 47.8 ±10.9 ml/100 g·min, and of the right atrial region, 33.6 ±10.3 ml/100 g·min. The approach may facilitate more objective assessment of: myocardial capillary perfusion in patients with angina pactoris, the pharmacology of antianginal drugs, and the efficacy of surgical procedures to revascularize ischemic myocardium.

Authors

Paul J. Cannon, Ralph B. Dell, Edward M. Dwyer Jr.

Regional Myocardial Perfusion Rates in Patients with Coronary Artery Disease

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Abstract

Regional myocardial perfusion rates were estimated from the myocardial washout of 133Xenon in 24 patients with heart disease whose coronary arteriograms were abnormal and 17 similar subjects whose coronary arteriograms were judged to be normal. Disappearance rates of 133Xe from multiple areas of the heart were monitored externally with a multiple-crystal scintillation camera after the isotope had been injected into a coronary artery and local myocardial perfusion rates were calculated by the Kety formula.

Authors

Paul J. Cannon, Ralph B. Dell, Edward M. Dwyer Jr.

Extent of Carotid Sinus Regulation of the Myocardial Contractile State in Conscious Dogs

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Abstract

The effects of bilateral carotid artery occlusion (BCO) and carotid sinus nerve stimulation (CSNS) on left ventricular (LV) pressure (P), diameter (D), velocity of contraction (V), rate of change of pressure (dP/dt), and cardiac output were studied in conscious dogs instrumented with ultrasonic diameter gauges, miniature pressure gauges, and aortic electromagnetic flow transducers. The effects of BCO and CSNS were also studied after automatic blockade and were compared to similar alterations in pressure produced by norepinephrine, methoxamine, and nitroglycerin. When heart rate was maintained constant with atrial stimulation, BCO had little effect on ventricular contractility, increasing isolength systolic pressure (LV Piso) by 36% while isolength velocity of myocardial shortening (Viso) decreased by 12% and (dP/dt)/P fell by 8%. These effects could be explained largely by vasoconstriction, since elevating systolic pressure with methoxamine produced similar results, while norepinephrine increased Viso by 36% and (dP/dt)/P by 56%. CSNS produced directionally opposite results from BCO; it decreased Piso by 15%, Viso increased by 11%, while (dP/dt)/P remained almost constant. These effects may be explained largely by vasodilatation since reducing systolic pressure to the same level with nitroglycerin produced similar results. When peripheral vasoconstriction was minimized by phenoxybenzamine pretreatment. BCO produced a slight positive inotropic effect (Piso increased by 8%, Viso by 4%, and (dp/dt)/P by 10%), while CSNS produced a slight negative inotropic effect (Piso decreased by 3%, Viso decreased by 5%, and (dP/dt)/P by 7%).

Authors

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

Evidence for a Specific Seminiferous Tubular Factor Affecting Follicle-Stimulating Hormone Secretion in Man

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Abstract

The interaction of the testis and gonadotropin secretion was studied in 15 men surviving chemotherapy for lymphoma. Azoospermia and complete destruction of all testicular germinal elements were present in 10 of the 15 men; however, Sertoli cells and Leydig cells were present. In these 10 men plasma follicle-stimulating hormone (FSH) levels were fourfold higher than in normal men of similar age whereas luteinizing hormone (LH) levels were normal. In contrast, both FSH and LH were normal in the remaining five men. Three had a full complement of spermatogenic tissue on biopsy and normal sperm concentrations. The other two men were azoospermic; one demonstrated full spermatogenesis in 30% of his tubules; the other had only a few spermatogonia in all tubules. In those patients with lower levels of gonadotropins pituitary insufficiency was excluded by the demonstration of appropriate responsiveness of FSH and LH to clomiphene administration. Similarly, Leydig cell function was normal since plasma testosterone was within the normal range in 13 of the 15 men and only slightly decreased in two. Thus, following chemotherapy, testicular damage was restricted to the germinal tissue, and this in turn was associated with a selective increase in FSH. The source of the FSH inhibitor is either the Sertoli cell or early germinal elements. However, since FSH levels are only half as high as those reported for castrate men, other testicular factors may modify FSH secretion.

Authors

David H. Van Thiel, Richard J. Sherins, George H. Myers Jr., Vincent T. De Vita Jr.

Estrone Sulfate: Production Rate and Metabolism in Man

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Abstract

Since estrone sulfate (E1S) is present at high concentration in plasma, we have examined the parameters of the plasma estrone, estradiol, E1S system. The metabolic clearance rate of E1S was 157 liter/day (range 70-292) in men and women. Estimated plasma production rates of E1S were (μgrams per day): men, 77; women, early follicular phase, 95; women, early luteal phase, 182. The conversion of plasma estrone and estradiol to E1S was measured and from these data and the metabolic clearance rates of the estrogens, the transfer factors were ρE1E1S = 0.54 and ρE2E1S = 0.65. Using average production rates, all plasma E1S could be shown to be derived from plasma estrone and estradiol.

Authors

Henry J. Ruder, Lynn Loriaux, M. B. Lipsett

Cystathionine Synthase Activity in Human Lymphocytes: Induction by Phytohemagglutinin

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Abstract

Uncultured human leukocytes contain no detectable cystathionine synthase activity. A method is described in which the addition of phytohemagglutinin (PHA) to short-term lymphocyte cultures results in a significant induction of enzymatic activity. This PHA-stimulated activity has characteristics that resemble those previously described for cystathionine synthase of normal liver and cultured fibroblasts. Lymphocyte cystathionine synthase activity is completely dependent on the presence of homocysteine and is absent or severely deficient in extracts from individuals with the syndrome of homocystinuria. This system for induction of cystathionine synthase in lymphocytes thus provides a simple in vitro technique for (a) diagnosing homocystinuria, (b) studying the mechanism of enzyme regulation and differentiation, and (c) examining the nutritional and hormonal control of cystathionine synthase activity both in normal subjects and homocystinuric patients.

Authors

Joseph L. Goldstein, Barbara K. Campbell, Stanley M. Gartler

Thyrotropin Increases Prostaglandin Levels in Isolated Thyroid Cells

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Abstract

We have shown that two unrelated prostaglandin antagonists block both thyrotropin (TSH) and prostaglandins E (PGE1, PGE2) stimulation of thyroidal adenyl cyclase activation and cyclic 3′,5′-adenosine monophosphate (cAMP) formation, suggesting that prostaglandins play an important role in regulating thyroid function. To further explore this postulate, we measured prostaglandin content by radioimmunoassay in homogeneous bovine thyroid cell preparations in the presence and absence of TSH. Antibodies to albumin-conjugated PGE1 and PGF2α showed specificity for prostaglandins E and F, respectively, but reacted, albeit far less effectively, with heterologous prostaglandins. A double antibody system was used to separate free from antibody-bound PGE1-3H and PGF2α-3H. Thyroid cells were extracted with ethanol/ethyl acetate and the various prostaglandins separated on silicic acid columns. Recoveries of added PGE1-3H and PGF2α-3H through the extraction and separation procedures ranged from 50-80%. The sensitivity of the method was 10-50 pg. Basal thyroid cell content of PGE1 and PGF2α “equivalents” varied between cell preparations (range = 2-6 ng/0.2 ml cell suspension) but, in each instance, remained constant during 5-30-min incubations at 37°C. TSH, 10-100 mU/ml, increased the levels of cell PGE1 and PGF2α “equivalents” 30-80% above basal during 5-15-min incubations. The stimulatory effect was specific for TSH, no increase in PGE1 or PGF2α “equivalent” levels being seen with luteinizing hormone (LH), human growth hormone (HGH), adrenocorticotropic hormone (ACTH), or glucagon. These data support the thesis that prostaglandins may mediate TSH effects on thyroid.

Authors

S.-C. Yu, L. Chang, G. Burke