1973 PROGRAM AMERICAN SOCIETY FOR CLINICAL INVESTIGATION, INC. 65TH ANNUAL MEETING

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Pharmacodynamic Studies of Beta Adrenergic Antagonism Induced in Man by Propranolol and Practolol

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The pharmacodynamic activities of two beta adrenergic antagonists, propranolol and practolol, were compared in eight hypertensive patients. The activity of each antagonist was established in relation to its blood concentration at maximal and submaximal adrenergic blockade defined by inhibition of exercise tachycardia. Maximal inhibition of exercise tachycardia was comparable with both drugs and averaged 74±7% of the control value during drug treatment. This inhibition was achieved with a blood concentration of 2.5±0.4 μg/ml practolol and 0.10±0.08 μg/ml propranolol. The antagonist activities of these drugs against adrenergic stimulation with isoproterenol infusion indicated a much greater relative potency of propranolol against this stimulus, and in vivo estimates of PA2 values differed by more than 600-fold. Relative antagonist activity of practolol during isoproterenol stimulation was equivalent both at cardiac (inotropic and chronotropic) and at vascular adrenergic receptors, whereas greater antagonist activity of propranolol was observed at vascular receptors than at cardiac receptors. Thus, the activity of practolol was not limited to cardiac receptors as previously suggested. Practolol did not reduce cardiac output at any dose level and the effect on resting blood pressure was small. Both practolol and propranolol had much greater hypotensive activity during exercise. These studies have defined the differing pharmacodynamic activities on the cardiovascular system of two effective beta adrenergic receptor antagonists and have established the blood levels of these antagonists necessary to achieve effective adrenergic blockade.

Authors

Gunter Bodem, H. L. Brammell, John V. Weil, Charles A. Chidsey

Effects of Glutamine Deamination on Glutamine Deamidation in Rat Kidney Slices

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Glutamate is known to inhibit the activity of isolated glutaminase I; however, its actual physiologic importance in regulating renal ammoniagenesis has not been established. To determine the regulatory role of glutamate on the metabolism of glutamine by rat kidney slices, we followed the effects on glutamine (2 mM) deamidation of increased removal of glutamate via augmented deamination. Three agents (malonate, 2,4-dinitrophenol, and methylene blue) were known to and shown here to hasten exogenous glutamate deamination. In slices from 10 control rats, 21.5±1.7 (SEM) μmol/g of ammonia were formed from amide nitrogen and 9.3±0.5 (SEM) μmol/g from the amino nitrogen of glutamine in vitro. Over 90% of the glutamine deamidated formed glutamate at one point in its catabolism. After addition of malonate (10 mM), 2,4-dinitrophenol (0.1 mM), or methylene blue (0.5 mM), the production of ammonia from the amino group rose to 29.3±6.0 (SEM) μmol/g, 20.0±1.8 (SEM) μmol/g, and 15.5±4.2 (SEM) μmol/g, respectively; ammonia production from the amide nitrogen rose also, 45.1±7.3 (SEM) μmol/g, 39.7±2.6 (SEM) μmol/g, and 41.9±3.7 (SEM) μmol/g. In the case of the former two, a minimum of 99% and 75% of the glutamine catabolized formed glutamate. Despite increased glutamine catabolism, there was no build up of glutamate in the media. A correlation between the formation of ammonia from the amino and amide nitrogen was apparent. Since none of the three agents selected affected phosphate activated glutaminase I activity directly or appeared to affect glutamine transport, we interpret the increase in deamidation as an expression of deinhibition of glutaminase I activity secondary to lowered glutamate concentrations at the deamidating sites through more rapid removal of glutamate via hastened deamination. Interestingly, slices removed from acidotic rats produced more ammonia from both the amino 29.1±3.8 (SEM) and amide nitrogens 45.9±4.3 (SEM) of glutamine, without a buildup of glutamate in the medium. At least 90% of the glutamine deamidated formed glutamate. A common mechanism is proposed to explain these results and the previous ones.

Authors

Harry G. Preuss, Olympia Vivatsi-Manos, Leonard L. Vertuno

Alteration of Bile Canalicular Enzymes in Cholestasis. A POSSIBLE CAUSE OF BILE SECRETORY FAILURE

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Bile secretory failure (cholestasis) may result from several possible mechanisms involved in bile secretion. We have examined the possibility that abnormalities in enzyme content, composition, and turnover of liver plasma membrane constituents are altered in cholestasis.

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Francis R. Simon, Irwin M. Arias

Partial Target Organ Resistance to Thyroid Hormone

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An 8-year old boy with a small goiter, normal basal metabolic rate (BMR), and elevated serum thyroid hormone levels (thyroxine [T4] 19.5 μg per 100 ml, free T4 4 ng per 100 ml, triiodothyronine [T3] 505 ng per 100 ml) was studied. He had measurable serum thyroid-stimulating hormone (TSH) levels (average 5.5 μU per ml), and the thyroxine-binding proteins, hearing, and epiphyseal structures were normal. There was no parental consanguinity nor were there thyroid abnormalities either in the parents or six siblings.

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Hans Henning Bode, Marco Danon, Bruce D. Weintraub, Farahe Maloof, John D. Crawford

Functional Evaluation of Prolactin Secretion in Patients with Hypothalamic-Pituitary Disorders

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Prolactin secretion was assessed in 23 patients with hypothalamic-pituitary disorders using L-Dopa suppression, chlorpromazine (CPZ), and thyrotropin-releasing hormone (TRH) stimulation tests. Based on the responses to these tests, three groups of patients were identified: those with panhypopituitarism (group I) and those with partial hypopituitarism either with (group II) or without (group III) evidence of hypothalamic involvement.

Authors

G. Tolis, M. Goldstein, H. G. Friesen

DNA:Anti-DNA Complexes: Their Detection in Systemic Lupus Erythematosus Sera

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Antibody to DNA was measured before and after treatment of systemic lupus erythematosus (SLE) sera with bovine pancreatic deoxyribonuclease (DNase I). In 11 of 15 cases of SLE with active renal disease there was a significant increase in DNA-binding after DNase digestion, while no such increase was noted in inactive SLE, normal controls or in patients with nonlupus renal disease. The significant rise in DNA-binding after digestion indicated that DNA had bound in vivo to the anti-DNA in these sera. A striking correlation between the occurrence of these complexes and disease activity was shown. In eight cases of SLE nephritis where serial blood samples were obtained, the greatest increase in DNA-binding after DNase digestion occurred at the time of the severest renal disease. In addition, serum from a case of SLE with acute cerebritis but without evidence of renal disease also had a significant rise in binding during the acute phase. This assay provides proof of the existence of circulating DNA:anti-DNA complexes in some cases of SLE and can also be used to measure an apparently critical parameter of disease activity.

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Ronald J. Harbeck, Emil J. Bardana, Peter F. Kohler, Ronald I. Carr

Renal Sodium- and Potassium-Activated Adenosine Triphosphatase and Sodium Reabsorption in the Hypothyroid Rat

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The relationship between net tubular reabsorption of sodium and renal microsomal sodium- and potassium-activated adenosine triphosphatase (Na-K-ATPase) was evaluated in hypothyroid and hyperthyroid rats and in age-matched euthyroid controls. Tubular sodium reabsorption per gram of kidney was lower in thyroidectomized rats than in controls (186±14 vs. 246±12 μeq/min; P < 0.005) and was accompanied by a quantitatively similar reduction in Na-K-ATPase specific activity (49.4±2.4 vs. 65.8±2.3 μmol inorganic phosphate (Pt)/mg protein per h; P < 0.001). This decrement was present in both cortex and outer medulla, and was limited to Na-K-ATPase since other representative enzymes not involved in sodium transport (magnesium-dependent adenosine triphosphatase [Mg-ATPase], glucose-6-phosphatase, 5′-nucleotidase) remained unchanged or increased in the hypothyroid animals. Conversely, Na-K-ATPase rose when sodium reabsorption increased in euthyroid rats treated with triiodothyronine.

Authors

Adrian I. Katz, Marshall D. Lindheimer

Determination of Iodothyronine Absorption and Conversion of L-Thyroxine (T₄) to L-Triiodothyronine (T₃) using Turnover Rate Techniques

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The absorption of L-thyroxine (T4) and L-triiodothyronine (T3) and the fractional rate of conversion of T4 to T3 were determined from the turnover rates of T4 and T3 in seven patients without endogenous thyroid function during separate treatment periods with these iodothyronines. Serum T3 concentration was measured by a radioimmunoassay procedure in which the iodothyronines are separated from the plasma proteins before incubation with anti-T3 antibody. Metabolic clearance rates were calculated by an integral (noncompartmental) approach since the use of single compartment kinetics led to a 40% overestimation of the metabolic clearance rate of T3. Based on the amount of hormone ingested and the observed hormonal turnover rates, the absorption of T4 and T3 (iodothyronine turnover/iodothyronine ingested) in man could be estimated. Absorption of T3 was complete in three subjects but decreased to 43% in a fourth who was suffering from mild congestive heart failure. Mean T4 absorption was 48.0±2.6% (SEM) for seven subjects. The mean fractional rate of T4 to T3 conversion determined during T4 replacement therapy (T3 turnover/T4 turnover) was 42.6% (range 30.7-50.8%). Thus, approximately one-half of the T4 which was deiodinated was converted to T3 suggesting that monodeiodination is an obligatory step in the peripheral metabolism of T4. Calculations based on these results together with other available data suggest that under normal physiologic circumstances the major portion of the T3 pool is derived from monodeiodination of T4.

Authors

Martin I. Surks, Alan R. Schadlow, Jerrold M. Stock, Jack H. Oppenheimer

Erythrocyte Catabolism by Macrophages In Vitro THE EFFECT OF HYDROCORTISONE ON ERYTHROPHAGOCYTOSIS AND ON THE INDUCTION OF HEME OXYGENASE

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Phagocytosis of erythrocytes was studied in vitro in an incubation system consisting of rat peritoneal macrophages and antibody-coated 59Fe-labeled erythrocytes. The system was characterized in terms of the rate and magnitude of erythrophagocytosis, determined by the interiorization of the 59Fe label. On incubation of 150 × 106 macrophages with 75 × 106 antibodycoated erythrocytes, erythrophagocytosis began within a few minutes and was essentially completed after 2 h when 50% of the offered red cells had been ingested by the macrophages. Heme oxygenase (HO) activity, which is very low in native macrophages, increased 4- to 10- fold in response to the ingested erythrocytes; this enzyme stimulation occurred with a delay of 3 h in relation to erythrophagocytosis. Actinomycin D or puromycin prevented the increase of HO activity without affecting erythrophagocytosis, which suggests that the enzyme stimulation was due to substrate-mediated enzyme induction.

Authors

Diethard Gemsa, C. H. Woo, H. Hugh Fudenberg, Rudi Schmid

Increased Plasminogen Activator (Urokinase) in Tissue Culture After Fibrin Deposition

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Lysis of fibrin in tissue culture has been shown to be due to plasminogen activator identified immunologically as urokinase. The present study examines fibrinolytic events in culture, particularly mechanisms leading to increased urokinase levels and accelerated fibrinolysis.

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Maria B. Bernik

Comparative Effects of Angiotensin and ACTH on Cyclic AMP and Steroidogenesis in Isolated Bovine Adrenal Cells

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The comparative effects of angiotensin II and adrenocorticotropic hormone (ACTH) on cyclic AMP and steroidogenesis were investigated employing isolated bovine adrenal cells from the zona fasciculata. Like ACTH, angiotensin produced a prompt increase in cyclic AMP which preceded the increase in corticosteroid production. Although this increase in cyclic AMP was small when compared to that induced by ACTH, it correlated with the amount of steroidogenesis. This observation is consistent with the view that cyclic AMP is the intracellular mediator of the steroidogenic action of angiotensin.

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Andre Peytremann, Wendell E. Nicholson, Ronald D. Brown, Grant W. Liddle, Joel G. Hardman

Effect of Intraluminal Flow on Proximal Tubular Reabsorption

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Micropuncture techniques in the rat were used to reinvestigate the possibility that intraluminal flow rate per se may influence net volume reabsorption by the proximal tubule. An experimental design was devised which lowered intraluminal flow without affecting filtration rate of the nephron under study or without directly affecting other renal hemodynamics. In 11 rats flow of tubular fluid between early and late proximal tubular sites was reduced by partially collecting tubular fluid at the early puncture site. In 42 nephrons the rate of flow of tubular fluid was reduced an average of 45% without changing nephron filtration rate and there was an associated reduction in reabsorption between the two sites which averaged 29%. This indicated 63% balance between delivery of tubular fluid and the rate of reabsorption between two sites along proximal tubules. The results of these studies indicate that a reduction in delivery of normal filtrate along the proximal tubule is associated with a concordant reduction in the absolute rate of reabsorption. Since this relationship occurred in the absence of changes in renal hemodynamics or even a change in filtration rate of the nephron under study it is concluded that changes in intraluminal load per se play an important role in the phenomenon of glomerulotubular balance.

Authors

Ettore Bartoli, John D. Conger, Laurence E. Earley

Partial Purification of Plasma Thromboplastin Antecedent (Factor XI) and its Activation by Trypsin

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A persistent puzzle in our understanding of hemostasis has been the absence of hemorrhagic symptoms in the majority of patients with Hageman trait, the hereditary deficiency of Hageman factor (factor XII). One proposed hypothesis is that alternative mechanisms exist in blood through which plasma thromboplastin antecedent (PTA, factor XI) can become active in the absence of Hageman factor. In order to test this hypothesis, the effect of several proteolytic enzymes, among them thrombin, plasma kallikrein, and trypsin, was tested upon unactivated PTA. PTA was prepared from normal human plasma by Ca3(PO4)2 adsorption, ammonium sulfate fractionation, and successive chromatography on QAE-Sephadex (twice). Sephadex-G150, and SP-Sephadex. The partially purified PTA was almost all in its native form, with a specific activity of 45-70 U/mg protein; the yield was about 10%. It contained no measurable amounts of other known clotting factors, plasmin, plasminogen, nor IgG. Incubation of PTA with trypsin generated potent clot-promoting activity that corrected the abnormally long clotting time of plasma deficient in Hageman factor or PTA but not in Christmas factor. This clot-promoting agent behaved like activated PTA on gel filtration (apparent molecular weight: 185,000) and was specifically inhibited by an antiserum directed against activated PTA. These data suggested that PTA can be converted into its active form by trypsin. PTA was not activated by thrombin, chymotrypsin, papain, ficin, plasmin, plasma kallikrein, tissue thromboplastin, or C̄. Trypsin converted PTA to its active form enzymatically. Whether trypsin serves to activate PTA in vivo is not yet clear.

Authors

Hidehiko Saito, Oscar D. Ratnoff, James S. Marshall, Jack Pensky

Tubuloglomerular Feedback NONLINEAR RELATION BETWEEN GLOMERULAR HYDROSTATIC PRESSURE AND LOOP OF HENLE PERFUSION RATE

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The present experiments were performed to quantify the effect of changes in distal tubular sodium delivery on glomerular flow dynamics both below and above the normal physiologic range. Glomerular capillary pressure as derived from the tubular stop flow pressure was assessed while the loop of Henle of the same nephron was perfused with varying flow rates. During Ringer perfusion no change of glomerular capillary pressure was observed when flow was increased from 0 to 13 nl/min. Further increasing flow to 27 nl/min was associated with a reduction of glomerular hydrostatic pressure by an average of 7.0±4.4 cm H2O (±SD). During perfusion at a rate of 43 nl/min glomerular pressure was decreased by a mean of 10.5±4.0 cm H2O. Changing the flow rate in small steps revealed that a significant reduction of capillary pressure was found when increasing the flow rate from 13 to 21 nl/min and that the maximum response was reached at 32 nl/min. No effect of perfusion rate changes on glomerular capillary pressure was observed when 300 mM mannitol was used as perfusion fluid. These results imply that a nonlinear relationship exists between end-proximal flow rate and glomerular capillary pressure. It is suggested that during deviations of distal sodium delivery into a positive direction filtration rate is intrarenally regulated probably by prevalence of afferent arteriolar constriction. During reductions of distal sodium load intrarenal regulation is either abolished or it involves proportionate resistance changes of both afferent and efferent arterioles.

Authors

Jürgen Schnermann, A. Erik G. Persson, Bengt Ågerup

The Glucose Receptor A DEFECTIVE MECHANISM IN DIABETES MELLITUS DISTINCT FROM THE BETA ADRENERGIC RECEPTOR

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Acute serum insulin responses in 10 normal subjects after rapid intravenous injection of glucose (5 g) or isoproterenol (2 μg) were of similar magnitude and timing (glucose: 431±349%; mean Δ3-5′ insulin (IRI)±SD, per cent basal and isoproterenol: 359±216%; mean Δ2-4′ IRI±SD, per cent basal). To elucidate the relationship of glucose-induced insulin secretion to pancreatic beta adrenergic receptors and the implications of this relationship with regards to abnormal insulin secretion in diabetes mellitus, two questions were studied. (a) To determine whether glucose-induced insulin secretion is dependent upon beta adrenergic activity, the effect of beta adrenergic blockade with intravenous propranolol (0.08 mg/min) upon acute insulin responses to isoproterenol and glucose were compared in normal subjects. (b) To determine whether acute insulin responses to beta adrenergic stimulation were intact in diabetes mellitus, the effect of isoproterenol upon serum insulin levels was studied in diabetic subjects. Beta adrenergic blockade in the normal subjects obliterated acute insulin responses to isoproterenol (before: 361±270%, during: - 31±15%; n = 6, P < 0.001) but did not significantly affect responses to glucose (before; 311±270%; during: 284±206%; n = 5). The mean acute insulin response after isoproterenol in the diabetic group was significantly elevated over basal levels (152±74%; n = 10, P < 0.001) but the response after glucose was not (- 11±11%). These data suggest that insulin responses to glucose in normal subjects are mediated by specific pancreatic glucose receptors which are independent from beta adrenergic receptors and that abnormal glucose-induced insulin secretion in diabetics is due to defects within glucose receptors and not beta adrenergic receptors as has been previously hypothesized.

Authors

R. Paul Robertson, Daniel Porte Jr.

Acute Reversal of Experimental Diabetic Ketoacidosis in the Rat with (+)-Decanoylcarnitine

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The effect of (+)-decanoylcarnitine, a potent inhibitor of long-chain acylcarnitine transferase, was tested for its ability to inhibit hepatic ketogenesis both in the isolated perfused liver and in vivo in severely ketotic alloxan diabetic rats. In vitro the inhibitor caused an almost complete block in ketone body production. In vivo (+)-decanoylcarnitine caused a rapid reversal of ketosis under conditions where large doses of insulin had little effect. A combination of the two agents produced an even more striking fall in plasma ketone levels.

Authors

J. Denis McGarry, Daniel W. Foster

Transverse Spread and Longitudinal Dissociation in the Distal A-V Conducting System

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Isolated preparations of portions of the canine intraventricular conducting system were studied by microelectrode techniques in order to determine the nature of transverse spread and longitudinal dissociation of impulses in bundle branches and false tendons. Driving stimuli were delivered to an eccentric location on normal conducting tissue, and the arrival times of the propagating impulses were mapped along the length and width of the bundle branch, or along the false tendon ipsilateral and contralateral to the site of stimulation. The difference between the arrival times on the two sides was found to decrease progressively as a function of distance from the site of stimulation, the data suggesting that transverse spread of impulses involves propagation through transverse crossover points between the longitudinally oriented conducting elements. Impulses originating eccentrically became uniformly conducted across the transverse axis of bundle branches 8-15 mm from the level of the stimulating electrode, and of false tendons 2-4 mm from the stimulus site. True longitudinal dissociation, producing conduction maps different from those representing normal transverse propagation, was seen occasionally in tissue having longitudinally oriented strips of abnormal tissue. However, early premature stimulation commonly resulted in longitudinal temporal dissociation of the premature responses, possibly due to functional block in the transverse crossover fibers.

Authors

Robert J. Myerburg, Kristina Nilsson, Benjamin Befeler, Agustin Castellanos Jr., Henry Gelband

Hypocomplementemia of Membranoproliferative Nephritis DEPENDENCE OF THE NEPHRITIC FACTOR REACTION ON PROPERDIN FACTOR B

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Membranoproliferative nephritis in children is frequently associated with a hypocomplementemia produced at least in part by C3 breakdown mediated by a circulating anticomplementary factor known as C3 nephritic factor (C3NeF). C3 breakdown by this factor in vitro requires the presence of a pseudoglobulin cofactor and magnesium. The present study provides evidence that properdin factor B (C3 proactivator) is activated in the nephritic factor reaction and is the direct mediator of C3 breakdown by C3NeF. Depletion of factor B from mixtures of normal human serum (NHS) and plasma from a patient with membranoproliferative nephritis (MPP), either by heating or by immune equivalence absorption, blocks C3 breakdown by C3NeF. Addition of purified factor B to these mixtures restores the anticomplementary effect. When purified factor B is added to mixtures of MPP and purified C3, breakdown also occurs. Associated with the C3 breakdown is a change in the electrophoretic mobility of factor B from the beta to the gamma position, a shift which has been associated with cleavage activation of the molecule. Further, serum factor B levels are often low in patients with membranoproliferative nephritis and bear a rough inverse correlation with C3NeF levels. It thus appears that factor B is the previously described heat-labile C3NeF cofactor. Whether the C3NeF reaction proceeds via a pathway comparable to that activated by the cobra venom factor or via that activated by zymosan or inulin cannot be determined from the present data.

Authors

Edward J. Ruley, Judith Forristal, Neil C. Davis, Cynthia Andres, Clark D. West

Nitroglycerin and Heterogeneity of Myocardial Blood Flow REDUCED SUBENDOCARDIAL BLOOD FLOW AND VENTRICULAR CONTRACTILE FORCE

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The effects of both intracoronary and intravenous administration of nitroglycerin on transmural distribution of blood flow in the left ventricle after partial coronary artery occlusion was investigated using two independent methods. In 16 open chest, anesthetized dogs, tubing supplying the cannulated left coronary artery was partially occluded. Strain gauges sutured paralled to superficial and deep fibers of the myocardium separately recorded the contractile force of each layer. With occlusion set so that depression of the deep contractile force was imminent. 12 μg intracoronary nitroglycerin in seven dogs depressed only the deep contractile force without changing systemic hemodynamics. Intravenous administration of 180 μg nitroglycerin in nine dogs resulted in a decrease of deep contractile force and aortic pressure often associated with an increase in superficial contractile force. Distribution of myocardial blood flow during peak coronary flow after intracoronary administration of nitroglycerin or during a decrease in aortic pressure after intravenous nitroglycerin administration was determined by the tissue uptake of an intracoronary bolus of rubidium-80. This was compared with the uptake of potassium-42 injected before nitroglycerin. Intravenous or intracoronary administration of nitroglycerin caused a significant reduction in subendocardial blood flow with a decrease in the subendocardial/subepicardial ratio of isotope.

Authors

Robert Forman, Edward S. Kirk, James M. Downey, Edmund H. Sonnenblick

Diurnal Variation in the Responsiveness of Human Subjects to Human Growth Hormone

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The objective of this study was to compare the responsiveness of human subjects to the anabolic effects of human growth hormone (HGH) administered at 8 a.m. or at 11 p.m. Three doses of HGH were used: A, 0.0168 U/kg body weight (BW)3/4 per day; B, 0.0532 U/kg BW3/4 per day; C, 0.168 U/kg BW3/4 per day. The effect of each dose on daily balances of N, P, Na, and K and on BW was measured. The subjects were of two groups: (a) seven GH-deficient children, of whom three were deficient in ACTH; and (b) three patients with limb-girdle dystrophy. ACTH-deficient patients in group (a) received exogenous cortisol at 7 a.m. In all 10 subjects, the anabolic effects of dose C, and sometimes of B and A, administered at 11 p.m. were significantly (P < 0.05) greater than when administered at 8 a.m. In these experiments plasma cortisol concentration averaged 3 times greater at 8 a.m. than at 11 p.m.

Authors

Daniel Rudman, David Freides, Joseph H. Patterson, Donna L. Gibbas

B and T Lymphocytes in Primary Immunodeficiency Disease in Man

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B- and T-cell populations in 32 patients with different forms of primary immunodeficiency disease were studied. The B-cells in peripheral blood were investigated with respect to surface immunoglobulins by means of immunofluorescence. The T-cell function was studied utilizing quantitation of proliferative response to phytochemagglutinin (PHA)1 and delayed allergy to various antigens. In 10 patients lymph node lymphocytes were also evaluated 11 male children with infantile x-linked agammaglobulinemia were divided into two subgroups. One did not show immunoglobulin spots on peripheral blood lymphocytes at all, the other contained a very low percentage of IgM- and occasionally IgA bearing lymphocytes. Eight patients with common variable immunodeficiency had moderately decreased percentages of peripheral blood and lymph node lymphocytes with surface immunoglobulins, but these patients lacked immunoglobulin secreting cells. Four cases of isolated IgA deficiency had normal or high percentages, and two cases of ataxia-telangiectasia had high percentages of lymphocytes with IgA in so called receptor distribution in both peripheral blood and lymph nodes. In three patients with infantile combined immunodeficiency that had been corrected by marrow transplantation, the percentages of Ig-bearing lymphocytes increased to normal or high levels together with establishment of functional T-cell population and ultimate secretion of serum immunoglobulins. One case of Di George syndrome reconstituted by fetal thymus transplant showed gradual decrease of B lymphocytes in circulation parallel to restoration of T-cell population.

Authors

Kazimiera J. Gajl-Peczalska, Byung H. Park, W. Douglas Biggar, Robert A. Good

Studies of Human Adipose Tissue ADIPOSE CELL SIZE AND NUMBER IN NONOBESE AND OBESE PATIENTS

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The cellular character of the adipose tissue of 21 nonobese and 78 obese patients has been examined. Adipose cell size (lipid per cell) was determined in three different subcutaneous and deep fat depots in each patient and the total number of adipose cells in the body estimated by division of total body fat by various combinations of the adipose cell sizes at six different sites. Cell number has also been estimated on the basis of various assumed distribution of total fat between the subcutaneous and deep fat depots.

Authors

Lester B. Salans, Samuel W. Cushman, Rodger E. Weismann

Changes in Sucrase, Enterokinase, and Peptide Hydrolase after Intestinal Resection THE ASSOCIATION OF CELLULAR HYPERPLASIA AND ADAPTATION

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In a study of changes in digestive enzymes after massive intestinal resection and the mechanisms by which such changes occur, rats were sacrified 4 wk after removal of the proximal two-thirds of the small intestine. Alterations in the mucosal levels of sucrase, enterokinase, and dipeptide hydrolase (L-leucyl-L-alanine substrate) were examined in the light of associated changes in protein. DNA and wet mucosal weight, measured in standardized gut segments from various regions of intestine.

Authors

Denis M. McCarthy, Young S. Kim

Effects of a False Neurotransmitter, p-Hydroxynorephedrine, on the Function of Adrenergic Neurons in Hypertensive Patients

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Previous studies have shown that amphetamine and p-hydroxyamphetamine impair adrenergic transmission, and it has been suggested that this effect is mediated by an active metabolite, p-hydroxynorephedrine (PHN). Studies in experimental animals have shown that PHN can deplete and substitute for norepinephrine (NE) in the transmitter pool, thus meeting the criteria of a false neurotransmitter.

Authors

Robert E. Rangno, John S. Kaufmann, John H. Cavanaugh, Donald Island, J. Throck Watson, John Oates

Evidence for Stimulation of Renal Gluconeogenesis by Catecholamines

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Isoproterenol and norepinephrine (10-4 M) significantly increased cyclic AMP formation and glucose production by the isolated tubules of the renal cortex of the rat. These effects were abolished by propranolol. Theophylline diminished the effects of the catecholamines on gluconeogenesis despite a marked augmentation in cyclic AMP concentration. In the absence of calcium ion in the incubation medium, isoproterenol stimulates cyclic AMP production, but has no effect on gluconeogenesis. It is concluded that catecholamines enhance gluconeogenesis in renal cortical tubules by the stimulation of beta adrenergic receptors. This effect is probably mediated through adenyl cyclase-cyclic AMP system and requires an adequate level of ATP and the presence of calcium ion.

Authors

Kiyoshi Kurokawa, Shaul G. Massry

Formation of Prostaglandins during the Aggregation of Human Blood Platelets

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Prostaglandins E2 and F2α were formed in response to ADP, L-epinephrine, or collagen by human platelets suspended in plasma containing citrate anticoagulant and stirred at 37°C. The prostaglandins formed by platelets in response to collagen were rapidly released and the amounts formed were proportional to the amount of collagen added. The formation of the prostaglandins was associated with the single wave of aggregation induced by collagen or the second wave of aggregation induced by epinephrine. The above findings are discussed with reference to published studies on the biochemical changes occurring during platelet aggregation. It is suggested that the formation and release of prostaglandins is associated with the secretion of endogenous ADP and 5-hydroxytryptamine.

Authors

J. B. Smith, Carol Ingerman, J. J. Kocsis, M. J. Silver

Dietary-Induced Variation of Hypoxanthine-Guanine Phosphoribosyl Transferase Activity in Patients with the Lesch-Nyhan Syndrome

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We have studied three patients with the Lesch-Nyhan syndrome to assess the effect of dietary purines on erythrocyte hypoxanthine-guanine phosphoribosyltransferase (HGPRT) activity. During dietary purine restriction HGPRT activity rose in all three patients; resumption of normal dietary purine intake or the addition of adenine (10 mg/kg per day) to a purinefree diet resulted in a fall in HGPRT activity. These changes in enzyme activity appeared to be due to an activation or inactivation of the mutant enzyme without a change in the half-life or absolute amount of HGPRT enzyme protein.

Authors

William J. Arnold, William N. Kelley

Some characteristics of the rabbit vermiform appendix as a secreting organ

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Authors