ATLANTIC CITY MEETINGS 1969

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Bone Matrix Turnover And Balance In Vitro: I. The effects of parathyroid hormone and thyrocalcitonin

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Labeled proline from incubation media has been shown to be incorporated into living bone matrix collagen in vitro. Hydroxyproline is released from fresh bone slices in similar systems in a characteristic curve against time. This hydroxyproline is derived from three distinct sources, each of which may be separately quantitated. Part of the total represents passive solubilization of matrix collagen, part is derived from new synthesis of soluble collagen occurring in vitro, and the remainder is released by cell-mediated resorptive action.

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Barry Flanagan, George Nichols Jr.

Bone matrix turnover and balance in vitro: II. The effects of ageing

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The rates of both formation and resorption of bone collagen may be accurately quantitated by kinetic analysis of hydroxyproline metabolism in vitro. Using this approach we have studied the changes in bone collagen turnover with age in the rat. The rates of synthesis and resorption of collagen decline with age although the resorptive activity per cell increases up to 6 months of age. The solubility of collagen declines with age. The fraction of the newly synthesized collagen which is deposited as matrix declines dramatically with age revealing a new and hitherto unsuspected aspect of the osteoporotic process. The collagen balance becomes progressively more negative over the 1st 6 months of life. These results indicate that even in an animal who is not subject to clinical osteoporosis, biochemical measurement reveals that such a trend exists. The application of this approach to human subjects is feasible and has important implications.

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Barry Flanagan, George Nichols Jr.

The role of endotoxin during typhoid fever and tularemia in man: IV. The integrity of the endotoxin tolerance mechanisms during infection

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Volunteers infected with Salmonella typhosa develop a remarkable hyperreactivity to the pyrogenic and subjective toxic activities of homologous (S. typhos) and heterologous (Pseudomonas) endotoxins. The present studies quantitate this augmented reactivity and demonstrate by three differing approaches that significant tolerance to these endotoxins can be readily induced within the framework of the hyperreactive state. Thus, (a) tolerance induced before illness by repeated daily intravenous injections of the endotoxins remained demonstrable during overt illness, (b) daily intravenous injections of the endotoxins begun during overt illness evoked progressively increasing tolerance, and (c) continuous intravenous infusions of S. typhosa endotoxin during illness rapidly induced a pyrogenic refractory state. Despite unequivocal activation of the endotoxin tolerance mechanisms by any of the above methods, the febrile and toxic course of typhoid fever proceeded unabated. Similarly, in other volunteers with Pasteurella tularensis infection, continuous intravenous infusions of S. typhosa endotoxin evoked initial hyperreactive febrile and subjective toxic responses followed by rapid appearance of a pyrogenic refractory state without modification of the underlying clinical illness. These observations suggest that circulating endotoxin plays no major role in pathogenesis of the sustained fever and toxemia during typhoid fever and tularemia in man.

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Sheldon E. Greisman, Richard B. Hornick, Henry N. Wagner Jr., William E. Woodward, Theodore E. Woodward

Demonstration of macromolecular inhibitor(s) of calcification and nucleational factor(s) in fluid from calcifying sites in cartilage

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An extracellular fluid phase (Cf1), aspirated by micropuncture techniques from the hypertrophic cell zone of calcifying epiphyseal certilage, has been characterized in a calcifying system in vitro in respect to the behavior of sedimenting and supernatant fractions after high speed ultracentrifugation. To perform these tests on the starting samples of 20 nl of Cf1, macroscopic analytical methods were scaled down for the identification of relevant organic components, including hexuronic acid and proteinpolysaccharides (PPL). The mineral accretion system was designed to simulate physiologic conditions in the calcifying cartilage septa of normal rats, and the mineral used for seeding was an immature calcium phosphate similar to native cartilage mineral. Normal Cf1 or its dilutions in synthetic lymph up to 1:4 completely prevented mineral accretion in vitro. The inhibitory action was localized to the sedimented fractions after ultracentrifugation and could be destroyed by incubation with trypsin or hyaluronidase. The sediment of Cf1 contained 2 mg of hexuronic acid per ml of Cf1 and gave a strong reaction of identification for a light fraction of PPL by fluorescent antibodies to rat PPL. PPL fractions were tested in the same mineral accretion systems as Cf1 and exhibited responses similar to those of Cf1. Also, there was evidence of a mineral phase in Cf1 of normal rats, in Cf1 of rats with healing rickets, but not in Cf1 of untreated rachitic rats. These results are interpreted to indicate that certain PPLs function as an inhibitor of crystal growth at extracellular sites premonitory to calcification. Evidence for a low density inhibitor of mineral accretion was found in normal serum but not in Cf1.

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David S. Howell, Julio C. Pita, Juan F. Marquez, Robert A. Gatter

Permeability-increasing activity in hereditary angioneurotic edema plasma: II. Mechanism of formation and partial characterization

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Plasma from persons with hereditary angioneurotic edema readily developed the capacity to increase vascular permeability and to induce the isolated rat uterus to contract. Both activities resided in a small, heat-stable molecule that was apparently a polypeptide. Crude preparations of the polypeptide were inactivated during incubation with trypsin. They also failed to produce pain and erythema, but caused markedly increased vascular permeability in human skin. These characteristics differ from those of bradykinin, from which crude preparations of the polypeptide could also be distinguished by electrophoretic mobility and paper chromatographic behavior. Proof that the polypeptide is truly different from bradykinin must await its further purification. Histamine played no role in the activities observed.

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Virginia H. Donaldson, Oscar D. Ratnoff, Wilmar Dias Da Silva, Fred S. Rosen

The effect of estrogen on bile formation in the rat

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Female rats given large doses of estrone developed increased permeability of the biliary tree as determined by an increase in the biliary clearances of sucrose and mannitol. Spontaneous bile flow and the choleretic response to dehydrocholate declined. Estrone reduced the clearance of sulfobromophthalein (BSP) at low plasma concentrations as well as the absolute rate of BSP excretion when plasma levels were above those required to saturate active transport. The findings are consistent with a postulate that estrogen cholestasis may involve enhanced diffusion of materials from bile to blood in addition to inhibition of active transport in the opposite direction.

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E. L. Forker

Ecological studies of intestinal bacteria. Relation between the specificity of fecal ABO blood group antigen-degrading enzymes from enteric bacteria and the ABO blood group of the human host

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This report presents evidence for enteric bacterial adaptation to genetically controlled environmental factors in the individual human host. Human feces contains bacterial enzymes that degrade water-soluble A, B, and H antigens, and both the presence and the specificity of ABH blood group antigens in human gut mucous secretions are genetically determined for each individual. In this study, partially purified fecal blood group antigen-degrading enzymes from 31 subjects of known blood group and secretor status were obtained and their relative specificity for A, B, and H antigen was measured.

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Lansing C. Hoskins

Alterations of red blood cell sodium transport during malarial infection

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Previous studies have suggested that malaria induces changes in erythrocytic membrane permeability and susceptibility to osmotic lysis. The present study investigated erythrocytic transport of sodium with cells from Rhesus monkeys infected with Plasmodium knowlesi. Red blood cell sodium concentration was significantly elevated in 37 parasitized animals (21.8±1.2 mM; mean ±SEM), as compared to 23 control animals (10.0±0.38 mM). The cellular sodium increased with the density of parasitemia and the cellular potassium decreased in proportion to the elevation of sodium. Nonparasitized as well as parasitized erythrocytes possessed this abnormality of cation metabolism. Effective chloroquine therapy reversed the changes over a period of 4 days.

Authors

Michael J. Dunn

Formation of iodoprotein during the peripheral metabolism of 35,3′-triiodo-l-thyronine-¹²⁵I in the euthyroid man and rat

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3,5,3′-Triiodo-L-thyronine-125I (T3-125I) metabolism was studied in nine euthyroid human subjects on blocking doses of nonradioactive iodide. After the intravenous injection of T3-125I, the fractional disappearance rate of plasma radioactivity progressively disappearance rate of plasma radioactivity progressively decreased with time. Analysis of individual plasma samples by dialysis, electrophoretic, and extraction techniques revealed three radioactive components: T3-125I, iodide-125I, and an unidentified material which was nonextractable in acid butanol (NE125I). Ne125I rose to maximal levels 24-36 hr after injection of T3-125I and then decreased with a fractional rate which approached, after 12-14 days, approximately 0.05 day-1 (t½ = 14 days). The plasma T3-125I concentration, obtained by subtraction of iodide-125I and NE125I from the plasma total 125I, declined at a constant fractional rate with time with a t½ of 1.5 days. Qualitatively similar results were obtained in rats. After 72 hr, 57% of the plasma and 40% of the liver radioactivity was NE125I. Chromatographic purification of the T3-125I before injection did not alter these results. The extrathyroidal origin of NE125I was further demonstrated by similar results in thyroidectomized rats maintained on thyroxine. NE125I from human sera separated from the other radioiodinated substances by ion-exchange chromatography was quantitatively precipitated by trichloracetic acid, not dialyzable, insoluble in CHCl3:CH2OH, and migrated with albumin during starch-gel electrophoresis. Based on these properties, NE125I was tentatively identified as iodoalbumin. Observations in rats equilibrated with 125I, as well as nonradioactive iodine determinations in human sera before and after acid butanol extraction, indicate that 10-20% of the serum organic iodine is in the form of iodoprotein. Our studies suggest that this moiety may be derived at least in part from the peripheral metabolism of the thyroid hormones.

Authors

Martin I. Surks, Jack H. Oppenheimer

Metabolism of testosterone and androstenedione in normal and ovariectomized women

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Metabolic clearance rates of testosterone (MCRT) and androstenedione (MCRA) were determined twice during the same cycle in six normal women, using a constant infusion of testosterone-3H and androstenedione-14C. Nonlabeled steroids served as internal standards. Plasma concentrations of testosterone (iT) and androstenedione (iA) were measured, and the blood production of testosterone (PBT) and of androstenedione (PBA) were calculated. The interconversions of these two steroids were also estimated. Six ovariectomized women were studied in the same manner. For testosterone, the mean iT in the normal women was not significantly different from that in the ovariectomized subjects, whereas the MCRT and PBT were significantly lower in the ovariectomized subjects. For androstenedione, the mean MCRA values of the two groups of subjects were not different, whereas the iA and PBA in the normal women were about double those in the ovariectomized subjects. In comparing the follicular and luteal phases of the menstrual cycle in four of six subjects there was no difference in iT, MCRT, or PBT, whereas iA, MCRA, and PBA were increased in the luteal phase. In one ovariectomized woman infused with testosterone and androstenedione at physiologic levels, MCRT doubled but MCRA remained the same. After six wk on estrogen, the same subject did not show any change in MCRT after infusion of testosterone. It is suggested that MCRT depends on PBT and on plasma binding of testosterone which is partly estrogen dependent.

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G. E. Abraham, J. Lobotsky, C. W. Lloyd

Deficient activity of dephosphophosphorylase kinase and accumulation of glycogen in the liver

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Low activity of phosphorylase and increased concentration of glycogen were found in liver tissue from five children with asymptomatic hepatomegaly. In vitro activation of liver phosphorylase in these patients occurred at the rate of 10% or less of normal. Elimination of the defect by the addition of kinase that activates phosphorylase demonstrated the integrity of the phosphorylase enzyme and the deficient activity of dephophophosphorylase kinase.

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George Hug, William K. Schubert, Gail Chuck

Intestinal β-galactosidases: I. Separation and characterization of three enzymes in normal human intestine

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Previous studies based on work in the rat and preliminary experiments with human intestine have suggested that two β-galactosidases are present in small intestine, and it is believed that only one of these enzymes is a lactase important for the digestion of dietary lactose. The high prevalence of intestinal lactase deficiency in man prompted more complete study of these enzymes.

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Gary M. Gray, Nilda A. Santiago

Intestinal β-galactosidases: II. Biochemical alteration in human lactase deficiency

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Despite the high prevalence of intestinal lactase deficiency in some racial groups and in patients with intestinal disease, the biochemical defect has not been characterized.

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Gary M. Gray, Nilda A. Santiago, Eugene H. Colver, Myron Genel

The role of membrane lipids in the survival of red cells in hereditary spherocytosis

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Red cells in hereditary spherocytosis (HS) have a decreased ratio of membrane surface area to cell volume and therefore a spheroidal shape. This abnormality in shape predisposes them to pooling and destruction in the spleen. Although splenectomy prevents hemolysis in HS, the red cell defect, as manifested by spheroidicity, increased autohemolysis, excesive permeability to sodium, and hypermetabolism, persists. The role of membrane lipids in these manifestations in vitro and in cell survival in vivo was examined.

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R. A. Cooper, J. H. Jandl

Effects of secretin, pancreozymin, or gastrin on the response of the endocrine pancreas to administration of glucose or arginine in man

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Intravenous administration of porcine secretin or pancreozymin or synthetic human gastrin II resulted in raised increments in serum immunoreactive insulin during intravenous infusion of glucose in normal man. Enhancement of serum immunoreactive insulin by each hormone was associated with accelerated disposal of glucose. In response to prolonged intravenous infusion of arginine with pancreozymin there was a maintained rise in immunoreactive insulin and glucagon-like immunoreactivity in the blood. These effects of pancreozymin and arginine were not reproduced with secretin and arginine, and may have been due to the stimulation of glucagon secretion together with insulin by pancreozymin.

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J. Dupre, J. D. Curtis, R. H. Unger, R. W. Waddell, J. C. Beck

Decreased 19S antibody response to bacterial antigens in systemic lupus erythematosus

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The antibody response to immunization with Brucella and the levels of natural antibody to Escherichia coli and Shigella were compared in patients with systemic lupus erythematosus and control groups. After Brucella immunization, SLE patients showed a significantly lower antibody response in whole serum and in the macroglobulin antibody fraction separated by sucrose density gradient centrifugation.

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John Baum, Morris Ziff

Effects of triiodothyronine-induced hypermetabolism on factor VIII and fibrinogen in man

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Triiodothyronine (liothyronine sodium) (400-500 μg/day for 14 days) was given to six normal subjects. Factor VIII (antihemophilic globulin) activity increased from 109 to 167% (P < 0.05); fibrinogen increased from 344 to 581 mg/100 ml (P < 0.01). To test whether the increases in factor VIII activity and fibrinogen were mediated by beta adrenergic receptors, propranolol (20 mg every 6 hr) was given orally to four other normal subjects in addition to triiodothyronine for 14 days. Factor VIII increased from 100 to 161%; fibrinogen increased from 374 to 564% (P < 0.01). Factor VIII activity did not change in a severe classical hemophiliac made hypermetabolic with triiodothyronine, but it increased from 39 to 82% in a patient with von Willebrand's disease. Triiodothyronine-induced hypermetabolism increased the incorporation of selenomethionine-75Se into plasma fibrinogen. These results suggest that the increases in clotting factor activity during triiodothyronine-induced hypermetabolism reflect an effect of increased protein synthesis rather than enhanced stimulation of beta adrenergic receptors.

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John C. Hoak, William R. Wilson, Emory D. Warner, Ernest O. Theilen, Glenna L. Fry, Fred L. Benoit

Influence of the thyroid state on left ventricular tension-velocity relations in the intact, sedated dog

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The mechanical properties of left ventricular contraction were described in terms of tension, velocity, length, and time in closed-chest, sedated normal, hypothyroid, and hyperthyroid dogs. Heart rate was controlled at 150 beats/min, and 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. Wall tension was derived from ventricular pressure and volume, the latter being obtained from the pressure-volume relation of the arrested ventricle, and tension-velocity relations were analyzed over a range of ventricular endiastolic volumes. At any level of ventricular volume, the hypothyroid state was associated with a displacement of the tension-velocity relation of the left ventricle downwards and to the left, and the time to peak tension was prolonged (154 msec, normal 139 msec). In the hyperthyroid state, the tension-velocity relation of the left ventricle was displaced upwards and to the right, and the time to peak tension was reduced (80 msec). The changes in the tension-velocity relations indicate that the inotropic state of the left ventricle in the intact dog varies directly with the animal's thyroid state. This influence on myocardial contractility necessarily constitutes an important and integral part of the response of the intact circulation to altered thyroid state.

Authors

Roger R. Taylor, James W. Covell, John Ross Jr.

Biosynthetic And structural studies of a heavy chain disease protein

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A new heavy chain disease protein (γHCD-JM) has been characterized by antigenic and structural criteria. The protein belongs to the IgG3-subclass and is closely related to Fc-fragment of G3-immunoglobulins. The predominant N-terminal amino acid of this protein is glutamic acid in the uncyclized form, and that of another γHCD is glycine.

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Daniel Ein, Donald N. Buell, John L. Fahey

ACKNOWLEDGEMENT

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