We studied the role of the direction of intrahepatic blood flow upon the location of hepatocyte formation in regenerating liver. Single liver lobes in the dog were autotransplanted to the region of the neck with the blood supply reestablished in a manner to perfuse the hepatic lobule from portal tract to central vein or, in a reverse direction, from central vein to portal tract. Partial resection of the nontransplanted liver was later performed to induce regeneration in the grafts by humoral means. Tritiated thymidine was administered, and radioautographs were prepared from excised graft and nontransplanted liver. In the “straight” blood flow grafts, as well as in all nontransplanted livers, labeled hepatocytes indicating DNA synthesis were found predominantly in the vicinity of the portal tracts. In the “reverse” blood flow grafts, labeled hepatocytes were more prevalent about the central veins. Thus, the localization of hepatocyte formation in the lobule during active liver regeneration cannot be attributed to an inherently greater capacity of periportal liver cells to divide but is probably related to their preferential exposure to blood constituent changes (humoral mechanisms). Hepatocyte regeneration in the presence of abnormal directional circulation might lead to lobular disorganization resulting in consequent biochemical aberrations despite the formation of new cells.
Bernard Sigel, Liveo B. Baldia, Signe A. Brightman, Marvin R. Dunn, Raphael I. M. Price
Antiserum against purified human urokinase was produced by immunization of Hartley strain guinea pigs. The antiserum was capable of neutralizing the plasminogen activator activity of the antigen and of native urokinase in human urine. The antiserum did not inhibit plasminogen activators of bacterial origin, i.e., streptokinase and staphylokinase; neither did it inhibit urokinase from nonprimate mammals, i.e., dog, pig, rabbit, guinea pig, nor tissue activator or tissue culture supernatants from porcine sources. Partial cross-reactivity against urokinase from primates, i.e., rhesus monkey and baboon, was noted as well as with supernatant from rhesus kidney tissue culture. In vitro studies showed lack of immunologic identity between human urokinase and human milk activator or human tissue activator from adrenal sources but demonstrated immunologic identity between human urokinase and the supernatant from human kidney tissue culture. In vivo studies in man failed to show detectable levels of urokinase activity in peripheral venous or renal venous blood under a variety of clinical states and when stimuli such as exercise, electroshock therapy, or nicotinic acid were used to enhance plasminogen activator activity in the plasma. The results establish that human plasma activator, milk activator, and tissue activator from the adrenals are immunologically distinct from human urokinase.
Chester S. Kucinski, Anthony P. Fletcher, Sol Sherry
The plasma levels of the urate-binding α1-α2-globulin, as determined by its urate-binding capacity, have been recorded in 19 individuals from two gouty kindreds. A significantly reduced binding capacity, accounting for 13-30% of the mean value obtained in healthy, unrelated control subjects, was found in all cases of gout and in the single case of essential hyperuricemia included in the present study. In addition, six apparently healthy members of one of these kindreds also exhibited this characteristic. The distribution of the characteristic in three subsequent generations from this kindred further supported the hypothesis that the reduced binding capacity was inherited as an autosomal trait for which affected subjects were heterozygous.
J. O. Alvsaker
In a series of experiments on the human forearm, preparation designed to examine the effects of variations in immunologically determined endogenous serum insulin levels and of blood glucose concentrations on muscular glucose uptake, the following results were obtained: (a) A highly significant correlation between muscular glucose uptake and simultaneous arterial serum insulin concentration. (b) No correlation between glucose uptake and simultaneous arterial blood glucose concentration during hyperglycemia. (c) A maximal insulin effect on muscular glucose uptake at arterial serum insulin concentrations at about 200 μU/ml. This observation is, however, based on only a few experiments.
Niels Juel Christensen, Hans Ørskov
Auditory detection thresholds for sinusoidal tones and various tests of auditory perception were determined in 12 patients with adrenal cortical insufficiency (seven with Addison's disease and five with panhypopituitarism) and compared to those in normal volunteers. In adrenal cortical insufficiency auditory detection sensitivity was significantly more acute than normal, and judgments of loudness and of the contralateral threshold shift were made at levels more than 20 db below those of normal subjects. Thus both the lower and the upper limits of the dynamic auditory range are significantly decreased in these patients. Speech discrimination ability of the patients was significantly impaired as was their difference limens, their alternate binaural loudness balances, and their ability to localize tones in space.
Robert I. Henkin, Robert L. Daly
The early labeled bilirubin consists of two primary components. The more rapidly synthesized of the two is independent of erythropoiesis (nonerythropoietic), whereas the second fraction is related to red cell production (erythyropoietic). The present studies concern the origin of the nonerythropoietic component.
M. Levitt, B. A. Schacter, A. Zipursky, L. G. Israels
Bradykinin is a potent constrictor of the human umbilical artery and vein and the ductus arteriosus of the lamb in vitro at oxygen tensions above 40 mm Hg (comparable to those in the newborn infant). Bradykinin is also capable of producing remarkable dilatation of the pulmonary vasculature of the lamb. Theoretically, kinins are capable of effecting some of the rapid circulatory changes required of the neonate. The present study was undertaken to investigate the role of kinins as mediators of such changes.
Kenneth L. Melmon, Martin J. Cline, Trevor Hughes, Alan S. Nies
Through a series of controlled experiments in volunteers, quantitative aspects of infection, illness, and immunity to ECHO-11 virus were studied. ECHO-11 is a transmissable viral infection in man and equally infectious to the upper respiratory and the intestinal tracts. The rate of infection was directly related to the dose of virus exposure, but any infectious dose of virus produced illness in only about one-third of the infected subjects. The infectious dose for man varied over a billionfold range. Larger challenge doses caused no difference in the local symptoms at the portal of entry or in the peak severity of illness, but symptoms were more diverse and prolonged after a higher dose. Persons with asymptomatic infections became just as heavily infected as ill persons.
Gilbert S. Saliba, Sylvia L. Franklin, George Gee Jackson
Studies were carried out to test the hypothesis that abnormal bile salt metabolism (interruption of the enterohepatic circulation) is responsible for steatorrhea in patients with ileal disease and (or) ileectomy.
B. W. Van Deest, J. S. Fordtran, S. G. Morawski, J. D. Wilson
A case of xanthinuria is briefly described, and the results of in vivo studies with 14C-labeled oxypurines are discussed. The data demonstrate that the rate of the turnover of uric acid is normal, despite an extremely small uric acid pool. Xanthine and hypoxanthine pools were measured and their metabolism evaluated. The bulk of the daily pool of 276 mg of xanthine, but only 6% of the 960 mg of hypoxanthine, is excreted. Thus, xanthine appears to be a metabolic end product, whereas hypoxanthine is an active intermediate. Biochemical implications of this finding are discussed.
Michael J. Bradford, Irwin H. Krakoff, Robert Leeper, M. Earl Balis
The mechanical properties of left ventricular contraction were described in terms of tension, velocity, length, and time in closed-chest, sedated dogs in which a large aorto-caval fistula had resulted in circulatory congestion, and the results were compared with those in normal dogs. Instantaneous contractile element velocity was calculated from left ventricular pressure and its first derivative during isovolumic left ventricular contractions produced by sudden balloon occlusion of the ascending aorta during diastole. A range of ventricular end-diastolic volumes was induced and heart rate was controlled at 150 beats/min. Wall tension (stress) was derived from ventricular pressure and volume, the latter being obtained from the pressure-volume relation of the passive ventricle. Extrapolated velocity at zero tension, Vmax, averaged 3.0 circ/sec in the normal dogs and 2.9 circ/sec in the seven dogs with an aorto-caval fistula and fluid retention; in only one of these seven animals was Vmax below the lower limit of normal of 2.7 circ/sec. Isovolumic tension (Po) in dogs with aorto-caval fistulas tended to be slightly greater than normal at low ventricular filling pressures, and there was no difference in Po between the two groups of animals at high ventricular filling pressures. Time to peak pressure averaged 151 ± 6 (SE) msec (normal 139 ± 3). Left ventricular weight averaged 6.32 ± 0.23 g/kg of initial body weight (normal 5.25 ± 0.56 g/kg) (P < 0.001), which reflected moderate ventricular hypertrophy, and ventricular internal volume at a given filling pressure was increased proportionally. Therefore, the ventricular contractile state usually was normal in the dog with a large aorto-caval fistula, and it is proposed that mechanisms for fluid retention that results in circulatory congestion were activated because of the large hemodynamic burden despite normal myocardial contractile properties.
Roger R. Taylor, James W. Covell, John Ross Jr.
Active glycogen metabolism has been demonstrated in both normal and glycogen-rich erythrocytes taken from patients with type III glycogen storage disease. Activity of all enzymes catalyzing the reactions required for the synthesis and degradation of glycogen have been demonstrated in the mature erythrocytes. Uniformly labeled glucose-14C is incorporated into glycogen in intact cells of both types during incubation. Replacement of the glucose-14C by unlabeled glucose in the medium resulted in a significant loss of radioactivity from cellular glycogen. In the absence of the substrate a progressive shortening of outer branches occurred during incubation of intact glucogen-rich cells. Using cells from patients with type III glycogen storage disease, which have sufficient glycogen content to be analyzed by β-amylolysis, we demonstrated that the glucosyl units are first incorporated in the outer tiers, then transferred to the core where they tend to accumulate due to the absence of amylo-1,6-glucosidase.
Shimon W. Moses, Reuben Chayoth, Stanley Levin, Ela Lazarovitz, David Rubinstein
Multiple indices of thyroid hormone binding have been studied in sera obtained from patients with thyrotoxic Graves' disease, before and after treatment, and in sera from a group of carefully matched normal controls. Specimens from patients with thyrotoxicosis displayed a decrease in the thyroxine (T4)-binding capacities of T4-binding globulin (TBG) and T4-binding prealbumin (TBPA), an increase in serum protein-bound iodine (PBI), and an increase in both the proportion and absolute concentration of free T4. In addition, a smaller than normal proportion of 131I-labeled T3 was associated with TBG during filter paper electrophoresis. After treatment of thyroxicosis, the only residual abnormality detected was a very slight persistent decrease in the T4-binding capacity of TBPA, which did not appear to influence the overall thyroid hormone-plasma protein interaction significantly, regardless of whether this was assessed under basal conditions or after enrichment of specimens with stable T4. It is concluded that the persistent abnormalities in the peripheral metabolism of T4, previously reported to occur in some patients with treated Graves' disease, probably do not stem from residual abnormalities in the transport of T4 in the plasma but must arise from abnormalities in T4 accumulation or metabolism within the tissues themselves.
Lewis E. Braverman, Angela E. Foster, Sidney H. Ingbar
We have tested two of the hypotheses proposed to explain the adjustment in sodium reabsorption in the proximal tubule that follows a change in the rate of glomerular filtration (glomerulotubular balance). Using the recollection micropuncture technique, we were able to measure the immediate and late changes in reabsorptive rate after an acute alteration in filtration rate produced by aortic constriction and release of constriction. It was found that fractional reabsorption, as measured by the inulin tubule fluid to plasma (TF/P) ratio, increased after aortic constriction and decreased after release, but that in most instances, absolute reabsorptive rate changed in parallel to glomerular filtration rate. The change was similar whether the collections were made less than 1 or more than 5 min after the change in blood pressure. The rapid time course of this adjustment in reabsorptive rate is viewed as evidence against an intrarenal humoral feedback mechanism.
Barry M. Brenner, Cleaves M. Bennett, Robert W. Berliner
A hemolytic disorder with mild hyperbilirubinemia and reticulocytosis of 6 to 15% was documented in eight members of a large family from the Dominican Republic and was presumed to be present in eight other members. The disorder appeared to be inherited as an autosomal dominant characteristic.
Ernst R. Jaffé, Eugene L. Gottfried
In three unrelated patients with hereditary fructose intolerance (HFI), but in none of five normal subjects, the experimental administration of fructose invariably induced a reversible dysfunction of the renal tubule with biochemical and physiological characteristics of renal tubular acidosis. During a state of ammonium chloride-induced acidosis, (a) urinary pH was greater than six and the rate of excretion of net acid (titratable acid plus ammonium minus bicarbonate) was inappropriately low, (b) the glomerular filtration rate remained unchanged or decreased modestly, and (c) urinary excretion of titratable acid increased briskly with diuresis of infused phosphate, although urinary pH changed little. The tubular dysfunction, which also includes impaired tubular reabsorption of alpha amino nitrogen and phosphate, persisted throughout administration of fructose and disappeared afterward. The tubular dysfunction was not causally dependent on hypoglucosemia, ammonium chloride-induced acidosis or osmotic diuresis. Rather, it appeared causally related to the fructose-induced metabolic abnormality of patients with HFI. The causal enzymatic defect, the virtual absence of fructose-1-phosphate aldolase, occurs in the kidney as well as in the liver of patients with HFI.
R. Curtis Morris Jr.
Administration of phenobarbital to rats in a dosage schedule previously demonstrated to increase hepatocellular binding of thyroxine results in increased hormonal turnover, due both to increased deiodination and to fecal disposition of thyroxine iodine. The rate of biliary excretion of thyroxine iodine is roughly proportional to the hepatic content of exchangeable thyroxine. The enhanced peripheral disposition of thyroxine appears to lead to increased thyroidal function, as measured by isotopic iodine studies, and the maintenance of a normal nonradioactive serum PBI. On the other hand, thyroidectomized animals maintained on a constant replacement dose of L-thyroxine and treated with phenobarbital exhibit a marked fall in serum PBI. These findings suggest that increased thyroxine flux in phenobarbital-treated animals is secondary to primary stimulation of hepatocellular binding. Exchangeable intracellular thyroxine may thus be an important determinant of hormone turnover and, possibly, of hormonal action.
Jack H. Oppenheimer, Gerald Bernstein, Martin I. Surks
The influence of catecholamines on growth hormone secretion has been difficult to establish previously, possibly because of the suppressive effect of the induced hyperglycemia on growth hormone concentrations. In this study, an adrenergic receptor control mechanism for human growth hormone (HGH) secretion was uncovered by studying the effects of alpha and beta receptor blockade on insulin-induced growth hormone elevations in volunteer subjects.
William G. Blackard, Sylvia A. Heidingsfelder
Detailed clinical and genetic studies have been performed in a Negro family, which segregated for sex-linked sideroblastic anemia and glucose-6-phosphate dehydrogenase (G-6-DP) deficiency. This is the first such pedigree reported. Males affected with sideroblastic anemia had growth retardation, hypochromic microcytic anemia, elevated serum iron, decreased unsaturated iron-binding capacity, increased 59Fe clearance, low 59Fe incorporation into erythrocytes, normal erythrocyte survival (51Cr), normal hemoglobin electrophoretic pattern, erythroblastic hyperplasia of marrow with increased iron, and marked increase in marrow sideroblasts, particularly ringed sideroblasts. Perinuclear deposition of ferric aggregates was demonstrated to be intramitochondrial by electron microscopy. Female carriers of the sideroblastic gene were normal but exhibited a dimorphic population of erythrocytes including normocytic and microcytic cells. The bone marrow studies in the female (mother) showed ringed marrow sideroblasts.
Ananda S. Prasad, Liborio Tranchida, Edward T. Konno, Lawrence Berman, Samuel Albert, Charles F. Sing, George J. Brewer
Secretion of cortisol, corticosterone, and aldosterone was measured in vivo in normal and sodium-depleted hypophysectomized dogs. Biogenesis of steroids was then measured in vitro with outer slices of the adrenals of the same dogs. In some studies, metyrapone or puromycin was added.
Warren W. Davis, Lawrence R. Burwell, Alfred G. T. Casper, Frederic C. Bartter
A series of experiments were performed on anesthetized dogs in which varying quantities of normal canine erythrocytes damaged by incubation with N-ethylmaleimide were injected into the circulation. Cell sequestration and catabolism of hemoglobin to carbon monoxide remained normal after injections that contained from 0.058 to 0.154 g of hemoglobin per kg of body weight.
Ronald F. Coburn, Peter B. Kane
Non-Newtonian viscosity of blood, i.e., the rise in apparent viscosity at low flow, was believed to be a result of reversible aggregation of red cells at low velocity gradients (shear rate). By making a cone-plate viscometer transparent, direct observation was made possible of the blood flowing under defined shear rates. Red cell aggregates, occurring in all cases at low flow, were reversibly dispersed by increasing the shear rate. This behavior was independent of the addition of anticoagulants, but it could be altered by changing the plasma protein composition. Red cells in serum did not form aggregates; such nonaggregating samples did show an increase in viscosity at low shear rates. Since the sedimentation rate can be influenced by many parameters, it is not reliable in describing red cell aggregation. Aggregation of red cells is linked with a marked separation of plasma and cells. Such a separation is of considerable influence on cone-plate viscometry.
H. Schmid-Schönbein, P. Gaehtgens, H. Hirsch
Total respiratory, pulmonary, and chest wall flow resistances were determined by means of forced pressure and flow oscillations (3-9 cps) superimposed upon spontaneous breathing in a group of patients with varying degrees of obstructive lung disease. Increased total respiratory and pulmonary resistances were found, whereas the chest wall resistance was normal or subnormal. The total respiratory and pulmonary resistances decreased with increasing frequencies. Static compliance of the lung was measured during interrupted slow expiration, and dynamic compliance was measured during quiet and rapid spontaneous breathing. Compliance was found to be frequency-dependent. The frequency dependence of resistance and compliance are interpreted as effects of uneven distribution of the mechanical properties in the lungs. The practical application of the oscillatory technique to the measurement of flow resistance in patients with lung disease is discussed. Measurements of total respiratory resistance by the forced oscillatory technique at frequencies less than 5 cps appear to be as useful for assessing abnormalities in airway resistance as either the plethysmographic or esophageal pressure techniques.
Gunnar Grimby, Tamotsu Takishima, William Graham, Peter Macklem, Jere Mead