Academic medicine and the public.

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A S Relman

Abstracts

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Abstracts

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Thrombokinetics in man

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Platelet production, distribution, and destruction have been quantitated in normal man and in selected patients with platelet disorders. In most instances, total production as calculated from the megakaryocyte mass agreed with production estimated from platelet turnover. In patients with megaloblastosis, a discrepancy between these two measurements indicated the presence of ineffective thrombopoiesis.

Authors

Laurence A. Harker, Clement A. Finch

Effective plasma volume in cirrhosis with ascites. Evidence that a decreased value does not account for renal sodium retention, a spontaneous reduction in glomerular filtration rate (GFR), and a fall in GFR during drug-induced diuresis

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A reduction in effective (nonportal) plasma volume is considered the basis for renal sodium retention, a spontaneous reduction in glomerular filtration rate (GFR), and a fall in GFR occurring during drug-induced diuresis in patients with cirrhosis and ascites. In the present study the concept of a reduced effective plasma volume in cirrhosis is challenged by two lines of evidence, even though effective plasma volume itself could not be measured. (a) Total plasma volume failed to rise in 10 patients with the spontaneous loss of ascites, the appearance of sodium in the urine, and a rise in GFR. Portal pressure remained constant in these patients as ascites left, suggesting that effective plasma volume had not increased while portal plasma volume decreased. (b) Reduction of GFR could not be prevented in five patients with cirrhosis and ascites while total plasma volume was prevented from falling with albumin infusions during drug-induced diuresis. Reduction of GFR during drug-induced diuresis in 15 patients with cirrhosis and ascites was completely reversed with saline infusion despite continued diuresis with the identical drugs, excluding drug nephrotoxicity as the cause for the reduced GFR.

Authors

Fred L. Lieberman, Sosuke Ito, Telfer B. Reynolds

Distribution and turnover of cholesterol in humans

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The relationships between some parameters of cholesterol metabolism and body weight were studied in 22 subjects. Cholesterol-4-14C, complexed with plasma lipoprotein, was injected intravenously and from the resultant specific activity-time curves a number of indexes of cholesterol turnover were calculated. These were based on the two-pool model previously described by Goodman and Noble and included estimates of the sizes of the two pools, the production rate of cholesterol in the system, the rate constants for cholesterol removal from the two pools and transfer between the pools, and the metabolic clearance of cholesterol.

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Paul J. Nestel, H. Malcolm Whyte, DeWitt S. Goodman

Altered permeability of the peritoneal membrane after using hypertonic peritoneal dialysis fluid

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Previous work has shown that use of hypertonic peritoneal dialysis fluid (7% glucose) results in ultrafiltration and enhanced urea transfer across the peritoneal membrane. Simultaneous creatinine studies showed a similar enhancement with hypertonic fluid which persisted in lesser degree during subsequent isotonic exchanges. The mechanism of solvent drag has been shown to contribute significantly to the increased urea removal with ultrafiltration. In the present study, the role of altered diffusive permeability of the peritoneal membrane as suggested by the creatinine data was evaluated as a possible additional mechanism. Hypertonic exchanges were bracketed by isotonic (1.5% glucose) exchanges during 11 studies in four patients. During six other studies in four patients, isotonic exchanges only were performed. A mathematical model for peritoneal solute transport by diffusion was developed and a method to distinguish alterations in peritoneal membrane permeability from changes in membrane area proposed. The method incorporates the determination and comparison of transport characteristics for two test solutes of widely different molecular weights. Alterations in inulin and urea transperitoneal transport characteristics in the above studies indicate a significant increase in membrane permeability after exposure to hypertonic solutions that persists during subsequent isotonic exchanges. Varying patterns of membrane area and permeability changes occurred during repeated exposure to only isotonic exchanges. The findings are discussed in regard to recent concepts of passive transcapillary transport.

Authors

Lee W. Henderson, Karl D. Nolph

Mechanism of change in the excretion of sodium per nephron when renal mass is reduced

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As the population of nephrons is reduced, sodium excretion per nephron must increase if sodium balance is to be maintained. The mechanism of this adjustment was studied in rats in which 50% and approximately 85% of renal tissue was excised. Although glomerular filtration per remaining nephron rose after uninephrectomy, it did not rise further when more renal tissue was removed, even though sodium excretion per nephron mounted. Hyperfiltration does not, therefore, account for the stepwise increase in sodium excretion per nephron with progressive renal ablation. Proximal tubular absorption, estimated by reabsorption half-time, was unchanged by renal insufficiency, indicating that “third factor” did not produce the observed changes in sodium excretion per nephron. It seems likely that the earliest adjustments in sodium excretion in renal failure take place in the distal tubules of healthy nephrons, and that they are conditioned by changes in the osmotic load per nephron.

Authors

John P. Hayslett, Michael Kashgarian, Franklin H. Epstein

Mechanism of exaggerated natriuresis in hypertensive man: impaired sodium transport in the loop of henle

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To evaluate the effects of saline loading on distal sodium reabsorption in hypertensive man, studies were performed during both water deprivation and water diuresis in eight hypertensive subjects, and the results were compared to data obtained from similar studies in normal subjects. All hypertensive patients exhibited an enhanced excretion of filtered sodium (CNa/CIn) at any level of distal delivery of sodium compared to normal controls. Free water reabsorption (TcH2O) during hypertonic saline loading was quantitatively abnormal in the hypertensives at high levels of osmolar clearance (COsm), and also the curve of TcH2O vs. COsm leveled off above a COsm of 18 ml/min per 1.73 m2 in the hypertensive group in contrast to the normal controls in whom TcH2O showed no evidence of achieving an upper limit. Sodium depletion exaggerated the abnormality in TcH2O in hypertensives, and resulted in a positive free water clearance (CH2O) during hydropenia.

Authors

Vardaman M. Buckalew Jr., Jules B. Puschett, James E. Kintzel, Martin Goldberg

Refsum's disease: characterization of the enzyme defect in cell culture

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Refsum's disease (heredopathia atactica polyneuritiformis, HAP) is an inherited neurological disorder associated with storage of the branched-chain fatty acid, phytanic acid (3,7,11,15-tetramethylhexadecanoic acid). Cultured fibroblasts derived from skin biopsies of HAP patients did not contain elevated levels of phytanate, yet showed rates of phytanate-C-14C oxidation less than 3% of those seen in cells from control subjects. Cells of control subjects converted phytanate to α-hydroxyphytanate, to pristanate (the [n-1] homologue of phytanate) and to 4,8,12-trimethyltridecanoate, compounds previously identified as intermediates on the major pathway for phytanate metabolism in animals, providing the first direct evidence that this same oxidative pathway is operative in human cells. None of these breakdown products could be found after incubation of phytanate with HAP cells. Labeled α-hydroxyphytanate and labeled pristanate were oxidized at normal rates by HAP cells. Oxidation of the latter proceeded at normal rates both when added to the medium at very low tracer levels and at levels 100 times greater. Phytanate was incorporated into and released from lipid esters at normal rates by HAP cells. Elevated levels of free phytanate in the medium were no more toxic to HAP cells than to control cells over the 48- to 72-hr exposures involved in these studies, as evidenced by morphologic criteria and by ability to oxidize labeled palmitate. These findings are consistent with the hypothesis that the cells from HAP patients are deficient in a single enzyme involved in the α-hydroxylation of phytanate, while the enzymes involved in later steps are present at normal or near-normal levels.

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James H. Herndon Jr., Daniel Steinberg, B. William Uhlendorf, Henry M. Fales

Localization of the oxidative defect in phytanic acid degradation in patients with refsum's disease

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The rate of oxidation of phytanic acid-U-14C to 14CO2 in three patients with Refsum's disease was less than 5% of that found in normal volunteers. In contrast, the rate of oxidation of α-hydroxyphytanic acid-U-14C and of pristanic acid-U-14C to 14CO2, studied in two patients, while somewhat less than that in normal controls, was not grossly impaired. These studies support the conclusion that the defect in phytanic acid oxidation in Refsum's disease is located in the first step of phytanic acid degradation, that is, in the alpha oxidation step leading to formation of α-hydroxyphytanic acid.

Authors

Charles E. Mize, James H. Herndon Jr., John P. Blass, G. W. A. Milne, Charlotte Follansbee, Philippe Laudat, Daniel Steinberg

Binding of digitoxin and some related cardenolides to human plasma proteins

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Tritium-labeled digitoxin, digitoxigenin, digoxin, and digoxigenin of established purity and chemcal authenticity were used to study the binding of these compounds to human plasma proteins. 97% of digitoxin in plasma was nondialyzable. Continuous flow paper electrophoresis of plasma containing digitoxin and dialysis experiments in which human serum albumin competed for the glycoside with plasma or plasma protein fractions demonstrated that digitoxin was almost exclusively bound by albumin. Equilibrium dialyses revealed that the interaction was characterized by a single binding site on the albumin molecule and an association constant of 9.62 × 104 liter/mole at 37°C. At 1°C the association constant was 4.64 × 104 liter/mole. The interaction therefore was endothermic; the gain in enthalpy of 3.5 kcal/mole and the free energy change of - 7.06 kcal/mole was derived from a large change in entropy of 33.8 cal/mole per °K. The direction of these thermodynamic changes suggested the formation of a hydrophobic bond between digitoxin and albumin. Quenching of the fluorescence of albumin by digitoxin indicated that the conformation of albumin was altered by the binding process.

Authors

Daniel S. Lukas, Anthony G. De Martino

Diagnostic and genetic studies on fibrin-stabilizing factor with a new assay based on amine incorporation

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Fibrinoligase, the fibrin cross-linking enzyme, transiently appearing during the course of coagulation in normal blood, was shown to catalyze the incorporation of a fluorescent amine, monodansylcadaverine [or N-(5-aminopentyl)-5-dimethylamino-1-naphthalene-sulfonamide] into casein. The reaction provided the basis of a sensitive fluorimetric method for measuring the activity of the enzyme (and also of similar other transpeptidases, such as transglutaminase).

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L. Lorand, T. Urayama, J. W. C. de Kiewiet, H. L. Nossel

Effect of sex hormones on bone in primary osteoporosis

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The effect of sex hormones on bone tissue was studied in 12 osteoporotic patients. Surfaces of bone undergoing formation and resorption were determined by quantitative microradiography of iliac crest biopsy samples before and after treatment with estrogens in 11 postmenopausal women and with testosterone in one gonadally competent man. Before treatment, bone resorption was greater than normal in all but one patient and bone formation was normal. After treatment, bone resorption decreased to within the normal range in all patients, and bone formation did not change significantly. Biochemical studies showed significant decreases in serum calcium, phosphorus, and alkaline phosphatase levels and in urinary excretion of calcium and hydroxyproline. These changes are believed to be the consequence of the effect of the hormones on bone. The data indicate that the major effect of sex hormones in osteoporosis is an inhibition of bone resorption.

Authors

B. Lawrence Riggs, Jenifer Jowsey, Patrick J. Kelly, James D. Jones, Frank T. Maher

Heterogeneity of human Platelets: I. Metabolic and kinetic evidence suggestive of young and old platelets

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Human platelets have been separated into two extreme density populations by centrifugation in specific density media. A large-heavy platelet population with specific gravity > 1.055 and a light-small population with specific gravity < 1.046 were obtained, each representing approximately 15-20% of the total population volume. The average volume per platelet of the separated large-heavy and light-small platelet populations was 12 and 5 μ3 respectively. When data are expressed per milliliter platelets or per gram wet weight, the large-heavy platelet population had a 2-fold greater glycogen content, 1.3-fold greater orthophosphate content, 1.3-fold greater total adenine nucleotide content, 4.2-fold greater rate of glycogenolysis, 2.6-fold greater rate of glycolysis, 2.9-fold greater rate of protein synthesis, and 5.7-fold greater rate of glycogen synthesis. Significant differences were not obtained with respect to total lipid content or total lipid synthesis. The large-heavy platelet had a 2.5-fold greater resistance to osmotic shock as measured by adenosine triphosphate (ATP) or adenosine diphosphate (ADP) release.

Authors

Simon Karpatkin, Arthur Charmatz

Heterogeneity of human platelets: II. Functional evidence suggestive of young and old platelets

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In the previous communication, suggestive evidence was presented for large-heavy platelets being “young” platelets and light-small platelets being “old” platelets. Large-heavy, light-small, and total human platelet populations were compared with respect to their platelet function. After addition of adenosine diphosphate (ADP), thrombin, or epinephrine, platelet aggregation time was 3.0-, 4.5-, and 3.3-fold shorter with large-heavy platelets compared with light-small platelets, and large-heavy platelets released 3.7-, 7.6-, and 8.1-fold greater adenosine triphosphate (ATP) into the medium, respectively, than did light-small platelets. After platelet aggregation by thrombin or epinephrine, large-heavy platelets released 6.0- and 3.8-fold more ADP into the medium than did light-small platelets. After platelet aggregation by ADP, light-small platelets consumed 5.9-fold greater added extracellular ADP than did large-heavy platelets.

Authors

Simon Karpatkin

Regulation of glutamine metabolism in vitro by bicarbonate ion and pH

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The effect of variations of medium pH and bicarbonate concentration on glutamine oxidation was studied in slices and mitochondria from dog renal cortex. Decreasing pH and bicarbonate concentration increased the rate of oxidation of glutamine-U-14C to 14CO2 in both slices and mitochondria, an effect comparable to the acute stimulation of glutamine utilization produced by metabolic acidosis. Decreases in the concentration of glutamate and α-ketoglutarate, which accompany metabolic acidosis in the intact animal, also occurred in tissue slices when pH and [HCO3-] were lowered; decrease in α-ketoglutarate but not in glutamate content occurred in mitochondria under these conditions. Study of independent variations of medium pH and [HCO3-] showed that simultaneous changes in both pH and [HCO3-] produced a greater effect on glutamine metabolism than did change in either of these parameters alone.

Authors

David P. Simpson, Donald J. Sherrard

Frequency dependence of compliance as a test for obstruction in the small airways

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We selected five bronchitics and four asthmatics in remission, whose routine lung function tests were not significantly abnormal. Dynamic compliance was measured at different respiratory frequencies and the results compared with those obtained from a normal control group. In all patients compliance was frequency dependent and remained so after the administration of bronchodilator aerosols. Compliance was frequency dependent in only one normal subject, and this was completely reversed by bronchodilators. Because the elastic properties of the patients' lungs were normal, and because pulmonary resistance was normal or only minimally increased, we interpret these results as indicating obstruction in peripheral airways.

Authors

Ann J. Woolcock, N. J. Vincent, Peter T. Macklem

Failure to demonstrate a hormonal inhibitor of proximal sodium reabsorption

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Recently, it has been reported that a humoral inhibitor of proximal sodium reabsorption could be detected in plasma, and dialysates of plasma, of rats and dogs undergoing saline diuresis. We have repeated these studies using similar techniques and protocols. Fractional sodium reabsorption by the proximal tubule (as estimated in free-flow micropuncture studies from tubule fluid-to-plasma inulin ratios) was found not to be lower during infusion of “natriuretic” plasma than during subsequent infusion of “hydropenic” plasma. Similarly, infusion of natriuretic plasma failed to prolong reabsorptive half-time of the shrinking drop beyond that seen during hydropenic plasma infusion. No increase in urine volume or rate of sodium excretion was observed during the period of natriuretic plasma infusion, nor did natriuretic plasma result in an increase in these measures in rats undergoing water diuresis.

Authors

Fred S. Wright, Barry M. Brenner, Cleaves M. Bennett, Robert I. Keimowitz, Robert W. Berliner, Robert W. Schrier, Pierre J. Verroust, Hugh E. De Wardener, Heinz Holzgreve

Effect of epinephrine on the peripheral metabolism of thyroxine

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10 normal young men received repository epinephrine repeatedly for 4 days during the course of a radiothyroxine (radio-T4) disappearance curve. During epinephrine administration, serum radio-T4 disappearance rate (k) slowed abruptly, fecal clearance decreased, urinary clearance was initially unchanged but later decreased slightly, volume of thyroxine distribution decreased, and external radioactivity over the liver remained unchanged. Beginning on day 2 of epinephrine and persisting at least 1 day after epinephrine was discontinued, serum thyroxine-binding globulin (TBG) maximal binding capacity increased, thyroxine-binding prealbumin (TBPA) maximal binding capacity decreased, and free T4 iodine decreased. Stable serum T4 iodine decreased during the experiment. Three indexes, namely the free T4 iodine, the reciprocal of TBG capacity, and the urinary radio-T4 “clearance” changed in parallel, suggesting that the increase in TBG capacity was responsible for a delayed decrease in radio-T4 metabolism. However, these changes were temporally dissociated from the decrease in k, which began and ended abruptly with initiation or discontinuing of epinephrine administration. This dissociation is unexplained, but may be caused by alterations in T4 binding in tissue sites.

Authors

Marguerite T. Hays, David H. Solomon

Drug effect in acute leukemia

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The in vivo therapeutic effect of vincristine, cytosine arabinoside, and corticosteroids on leukemic blast cells in the bone marrow was evaluated. 24 studies were done in 21 children with acute leukemia. 19 children had acute lymphoblastic leukemia, and two children had acute myeloblastic leukemia. Direct cytotoxicity or lysis of blast cells after drug administration was looked for by serial measurements of the volume of marrow buffy coat. Changes in proliferative capacity were evaluated by serial measurements of number of cells in mitosis and the per cent of cells in deoxyribonucleic acid (DNA) synthesis, as indicated by tritiated thymidine incorporation. Corticosteroid administration caused lysis of leukemic blast cells. Each drug affected the proliferative capacity of the leukemic cells by an action at a different part of the mitotic cycle. Corticosteroids suppressed the entry of cells into DNA synthesis. Vincristine arrested cells in mitosis. Cytosine arabinoside inhibited DNA synthesis. After the inhibitory effect of cytosine arabinoside, an increased number of cells began to synthesize DNA, a phenomenon indicating that partial synchronization of the mitotic cycle had been achieved in the leukemic cell population. The action of these drugs at different parts of the mitotic cycle might be important in designing treatment regimens where in two or more of these drugs are used.

Authors

Beatrice C. Lampkin, Takeshi Nagao, Alvin M. Mauer

A study of folate absorption and metabolism in man utilizing carbon-14—labeled polyglutamates synthesized by the solid phase method

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The absorption and metabolism of synthetic polyglutamates of folic acid have been compared with free pteroylglutamic acid in four subjects having chronic lymphatic leukemia and one with Hodgkin's granuloma. Pteroylpolyglutamates containing either three or seven glutamate residues were prepared by the solid-phase method permitting placement of carbon-14 labels in either the pteridine ring or in a selected glutamate unit of the gamma peptide chain. Complete dissociation was observed between biological folate activity and radioactivity of plasma after ingestion of pteroyltriglutamate labeled in the middle glutamate. This indicates cleavage to the monoglutamate form at the time of absorption from the intestine or very soon thereafter. A large portion of radioactivity liberated from the middle glutamate is recoverable as carbon dioxide in the exhaled air.

Authors

C. E. Butterworth Jr., C. M. Baugh, Carlos Krumdieck

Studies with ¹⁵N-labeled ammonia and urea in the malnourished child

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Investigations using ammonium citrate-15N and urea-15N showed that children in the acute stage of kwashiorkor and marasmus receiving a diet of adequate protein content retained a considerable percentage of the label from both compounds. Excretion of both total 15N and urea-15N was subnormal and elimination was virtually completed 36 hr after administration of the isotope. During recovery from kwashiorkor total 15N excretion had approached normal a month after commencement of rehabilitation. Urea-15N excretion was still slightly subnormal after 3 months. In marasmus urea-15N formed a normal proportion of total 15N excretion after 1 month, although total 15N excretion then was still low. Ammonia nitrogen was retained to a greater extent than urea nitrogen in all cases. As it is known that a considerable amount of urea is degraded to ammonia in the gastrointestinal tract, it seems probable that urea nitrogen became available for use after this degradation. Examination of blood from one marasmic child after feeding ammonia-15N and from another after intravenous injection of urea-15N showed incorporation of the label into blood cells and plasma proteins. This did not occur in well nourished controls. It is concluded that ammonia and urea as sources of nonessential nitrogen may play an important part in protein metabolism in the malnourished child.

Authors

W. W. C. Read, D. S. McLaren, Marie Tchalian, Siham Nassar

Determination of triiodothyronine concentration in human serum

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A simplified method has been described for the measurement of triiodothyronine (T3) in human serum. The sensitivity was sufficient for determinations on hypothyroid as well as normal and thyrotoxic sera. The values obtained have been in reasonable agreement with a double isotope derivative assay.

Authors

Kenneth Sterling, Diego Bellabarba, Edward S. Newman, Milton A. Brenner

Maximum expiratory flow rates in induced bronchoconstriction in man

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We evaluated changes of maximum expiratory flow-volume (MEFV) curves and of partial expiratory flow-volume (PEFV) curves caused by bronchoconstrictor drugs and dust, and compared these to the reverse changes induced by a bronchodilator drug in previously bronchoconstricted subjects. Measurements of maximum flow at constant lung inflation (i.e. liters thoracic gas volume) showed larger changes, both after constriction and after dilation, than measurements of peak expiratory flow rate, 1 sec forced expiratory volume and the slope of the effort-independent portion of MEFV curves. Changes of flow rates on PEFV curves (made after inspiration to mid-vital capacity) were usually larger than those of flow rates on MEFV curves (made after inspiration to total lung capacity). The decreased maximum flow rates after constrictor agents are not caused by changes in lung static recoil force and are attributed to narrowing of small airways, i.e., airways which are uncompressed during forced expirations. Changes of maximum expiratory flow rates at constant lung inflation (e.g. 60% of the control total lung capacity) provide an objective and sensitive measurement of changes in airway caliber which remains valid if total lung capacity is altered during treatment.

Authors

A. Bouhuys, V. R. Hunt, B. M. Kim, A. Zapletal