1971 Program: American Society for Clinical Investigation, Inc. 63rd Annual Meeting

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Quantitative immunology of immune hemolytic anemia: I. The fixation of C1 by autoimmune antibody and heterologous anti-IgG antibody

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The fixation of the first component of complement (C[unk]1) by rabbit and goat anti-IgG antibodies reacting with auto- or isoimmune antibodies attached to red cells has been investigated. Two molecules of the rabbit IgG anti-IgG were required to fix a single molecule of C[unk]1, whereas only one molecule of goat IgM anti-IgG was required. The relationship between the number of auto- or isoimmune antibody molecules attached to the red cells and the amount of C[unk]1 fixed by anti-IgG was determined by the concentration of anti-IgG. A concentration of anti-IgG was found such that the number of molecules of C[unk]1 fixed was directly proportional to the concentration of auto- or isoimmune antibody. By this method a sensitive, reproducible minimum estimate of the amount of cell-bound and serum antibody could be made.

Authors

Wendell F. Rosse

Quantitative immunology of immune hemolytic anemia: II. The relationship of cell-bound antibody to hemolysis and the effect of treatment

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The concentration of cell-bound and serum antibody was determined in a series of patients with warm antibody immune hemolytic anemia by determining the amount of C[unk]1 fixed to the cells by anti-IgG. This was compared to the rate of hemolysis as determined by hemoglobin concentration and reticulocyte count, or the endogenous production of carbon monoxide. The rate of hemolysis was, in general, proportional to the concentration of cell-bound antibody. In splenectomized patients, the rate of hemolysis was very much less than in unsplenectomized patients for a given concentration of cell-bound antibody. When prednisone was given, three effects were noted: (a) at high doses of drug, the concentration of cell-bound antibody decreased rapidly and the concentration of serum antibody increased, suggesting that the affinity of antibody for antigen had been altered; (b) in patients achieving remission, the concentration of serum antibody fell to low levels but rose again if the dose of prednisone was insufficient; (c) in one patient, prednisone appeared to inhibit sequestration of highly sensitized cells.

Authors

Wendell F. Rosse

The interaction of human macrophages and lymphocytes in the phytohemagglutinin-stimulated production of interferon

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In studies of 13 normal adults to determine the blood cell types responsible for interferon production induced by phytohemagglutinin, the following observations were made. (a) In cultures containing 96-100% pure macrophages derived from blood monocytes, no interferon was detected in either the presence or the absence of phytohemagglutinin for up to 92 hr. (b) In cultures of 99.5-100% pure lymphocytes, low levels of interferon were detected in the presence, but not in the absence, of phytohemagglutinin. (c) An average fivefold increase in interferon titers occurred when pure lymphocytes were combined with the macrophages in culture with phytohemagglutinin. The peak response of interferon occurred at 68 hr after the initiation of the combined cultures. For maximum response, phytohemagglutinin was required for the duration of the culture, and both cell types in association were necessary. Medium from phytohemagglutinin-stimulated macrophages or lymphocytes could not substitute for the corresponding intact cell. However, frozen-thawed macrophages in combination with lymphocytes and phytohemagglutinin produced an intermediate interferon response. An increase in either cell type produced an increased response in the range studied: lymphocytes, 0.45-1.8 × 106 per ml; and macrophages, 0.5-2.1 × 105 per ml. Syngeneic fibroblasts, HeLa cells, or mouse macrophages could not substitute for the human macrophages in the combined cultures with phytohemagglutinin. (d) Although all cultures producing interferon showed some degree of transformation (thymidine-3H incorporation into deoxyribonucleic acid), no direct correlation between the degree of phytohemagglutinin-induced lymphocyte transformation and the interferon titers was observed.

Authors

Lois B. Epstein, Martin J. Cline, Thomas C. Merigan

On the lipoprotein abnormality in type III hyperlipoproteinemia

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Two lipoprotein species were isolated by starch block electrophoresis from the very low density lipoproteins (VLDL) (Sf 20-400) of patients with type III hyperlipoproteinemia. One of these, α2-VLDL, had a content of lipid and protein and physical characteristics similar to VLDL from normal subjects or patients with other forms of hyperglyceridemia. The other species, β-VLDL, contained more cholesterol and less triglyceride in relation to the protein, than normal VLDL. Only the apoprotein of low density lipoprotein was immunochemically detectable in the β-VLDL; the proteins in the α2-VLDL reacted with antisera specific for low density lipoprotein and high density lipoprotein. The electrophoretic mobility of β-VLDL was similar to that of low density lipoprotein and significantly less than that of α2-VLDL. Isolated β-VLDL had a lesser mean flotation rate than α2-VLDL, but both α2- and β-VLDL were found throughout the Sf 20-400 flotation range.

Authors

Steven Quarfordt, Robert I. Levy, Donald S. Fredrickson

Quantification of human platelet inositides and the influence of ionic environment on their incorporation of orthophosphate-³²P

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Platelets are a rich source for the study of inositol lipids in man. The substitution of an EDTA-KCl solution for the water component of the Bligh and Dyer procedure permitted quantitative extraction of polyphosphoinositides. The latter, with monophosphoinositide, were found to comprise, on a molar basis, 6.7% of total platelet phospholipids. Study of the incorporation of orthophosphate-32P into platelet phospholipids was further simplified by separating eight 32P-labeled lipids, including the inositides, with a single chromatographic development on formaldehyde-treated paper. Particular attention was paid to the influence of ionic environment on the pattern and degree of labeling.

Authors

Phin Cohen, M. Johan Broekman, Arie Verkley, Johannes W. W. Lisman, Arie Derksen

Responses of coronary vessels to adrenergic stimuli

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Coronary responses to adrenergic stimuli were determined in the intact beating heart before and after administration of practolol, 4-(2-hydroxy-3-isopropylaminoproproxy) acetanilide, which in low doses blocks myocardial but not vascular beta receptors. The left circumflex coronary artery of dogs was perfused with arterial blood at constant flow, and coronary perfusion pressure was measured.

Authors

Donald R. McRaven, Allyn L. Mark, Francois M. Abboud, Howard E. Mayer

Postnatal development of renal function: micropuncture and clearance studies in the dog

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Postnatal renal development was studied in dogs between 2 and 77 days. Single, superficial nephrons were evaluated by micropuncture, concurrently with measurements of total renal function and morphometric analyses in the same animals.

Authors

Michael Horster, Heinz Valtin

Intracortical distribution of number and volume of glomeruli during postnatal maturation in the dog

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Morphometric analysis was carried out on kidneys of neonatal dogs in which function of the entire kidney and of single nephrons had been evaluated. Measurements were begun after neogenesis of nephrons had been completed, i.e., at the end of the 3rd postnatal wk. They were continued to 74 days by which time glomerular function, expressed per unit of renal weight, had reached the mature level. For statistical analysis, the cortical histogram at each age was divided into eight zones of equal depth between the capsule and corticomedullary junction.

Authors

Michael Horster, Barry J. Kemler, Heinz Valtin

Evidence for an effect of insulin on the peripheral utilization of ketone bodies in dogs

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The rates of transport and oxidation of acetoacetate have been measured in seven anesthetized, pancreatectomized, ketotic dogs using a constant infusion of acetoacetate-3-14C. Control experiments were performed in 14 normal dogs. In addition to the acetoacetate-14C, the latter were infused at a constant rate with varying amounts of unlabeled acetoacetate so as to obtain a range of ketone transport (26-65 μmoles/min·kg) comparable with that observed in the diabetic dogs (21-41 μmoles/min·kg). The specific activities of acetoacetate and β-hydroxybutyrate in blood became equal during the infusion of labeled acetoacetate, indicating that the net transport of acetoacetate represents that of total ketones. In each group, the concentration of ketones was an exponential function of the rate of transport, but for any value below 30 μmoles/min·kg, ketone concentration in the diabetic dogs was about 3 times that in normal dogs, indicating an impairment of mechanisms for utilizing ketones in insulin deficient animals. Maximal capacity to utilize ketones in diabetic dogs was slightly more than half that of normal ones. A similar fraction (32-63%) of the infused 14C appeared in respiratory CO2 in the two groups and was independent of the rate of transport. In seven of the normal dogs, administration of insulin and glucose increased removal of the infused ketones and increased the fraction of 14C appearing in respiratory CO2. These results demonstrate that utilization of ketones in extrahepatic tissues is influenced by insulin; impaired utilization contributes to diabetic ketosis and is probably essential to the production of severe ketoacidosis.

Authors

E. O. Balasse, R. J. Havel

Muscle and splanchnic glutamine and glutamate metabolism in postabsorptive and starved man

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Arterio-venous differences across forearm muscle in man in both prolonged starvation and in the postabsorptive state, show an uptake of glutamate and a relatively greater production of glutamine. Splanchnic arteriovenous differences in the postabsorptive state show a net uptake of glutamine and lesser rate of glutamate production. These data suggest that muscle is a major site of glutamine synthesis in man, and that the splanchnic bed is a site of its removal. The relative roles of liver and other tissues in the splanchnic circuit were not directly assessed, only the net balance. These data in man are in conflict with most previous studies in other species attributing the major proportion of glutamine production to the liver and, pari passu, to the splanchnic bed.

Authors

E. B. Marliss, T. T. Aoki, T. Pozefsky, A. S. Most, G. F. Cahill Jr.

The rapid induction by phytohemagglutinin of increased α-aminoisobutyric acid uptake by lymphocytes

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The effect of phytohemagglutinin (PHA) on the ability of human lymphocytes to transport the nonutilizable amino acid, α-aminoisobutyric acid (AIB) has been studied. PHA binds rapidly to plasma membrane receptor sites with half maximal binding requiring approximately 7.5 min. During the first 30 min after PHA addition to lymphocytes no change was detected in AIB transport, but then a linear increase in the initial rate of AIB transport occurred over the next 9 hr. Subsequently, the rate of AIB transport stabilized at a level 6-7 times greater than that found in control lymphocytes. The change in membrane function developed even when de novo protein synthesis was inhibited by 85-90% with puromycin or cycloheximide. However, the PHA effect did not occur when the lymphocytes were maintained at 4°C.

Authors

John Mendelsohn, Sister Ann Skinner, Stuart Kornfeld

Pulmonary Artery Pressure and Alveolar Gas Exchange in Man during Acclimatization to 12,470 ft

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Pulmonary hemodynamics and gas exchange were studied in four physicians during 72 hr acclimatization to 12,470 ft. Pulmonary catheters were left in three subjects for 72 hr. Resting mean pulmonary arterial pressure (P̄ĀP̄) rose progressively during the first 24 hr from 10.3 ±1.0 to 21.1 ±4.0 torr and remained at this level. During this same 24 hr period cardiac output increased from 7.1 ±1.4 to 8.4 ±2.0 liters/min and total pulmonary resistance rose from 122 ±16 to 209 ±40 dynes·sec/cm-5. Excercise at 60 w after 24 hr of hypoxia increased P̄ĀP̄ to 28.8 ±5.1 torr and decreased total pulmonary resistance to 155 ±25. Shunt fractions were 11 ±3.8% after 24 hr at altitude and fell to 7 ±0% after 72 hr. Alveolar to arterial O2 difference (P(A-a)O2) breathing oxygen fell from 116 ±10.8 to 92 ±33.3 torr during the same period of acclimatization, whereas dead space to tidal volume ratio (VD/VT) rose from 33 ±4.0% to 40 ±5.3% and P(A-a)O2 breathing ambient air rose from 8 ±2.6 to 11 ±3.0 torr. Inspiratory static lung compliance decreased significantly from a control of 176 ±8 to 141 ±8 ml/cm H2O after 72 hr of hypoxia.

Authors

Richard S. Kronenberg, Peter Safar, Joseph Lee, Fred Wright, William Noble, Eric Wahrenbrock, Robert Hickey, Edwin Nemoto, John W. Severinghaus

C1r, subunit of the first complement component: purification, properties, and assay based on its linking role

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A method to obtain C1r, a subunit of the first complement component, in a highly purified state has been described for the first time. The stepwise method starts with a neutral euglobulin precipitation, after diethylaminoethyl- and carboxymethyl-cellulose chromatography and a final preparative polyacrylamide electrophoresis step. Such C1r preparations are devoid of C1q and C1s activities and show only one protein band on analytic polyacrylamide electrophoresis. Rabbits injected with this preparation produced antisera showing only one precipitation band. The stability of C1r activity was determined under different conditions, and C1r was found to be labile at 37°C, pH 7-8 and low ionic strength.

Authors

Maria M. E. De Bracco, R. M. Stroud

Circulating insulin: the proinsulin-like properties of “big” insulin in patients without islet cell tumors

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When plasma is filtered on Sephadex G-50, insulin immunoreactivity is recovered in two peaks. “Big” insulin, the higher molecular weight component, and “little” insulin, the lower molecular weight component, have elution volumes that correspond to those of proinsulin-125I and insulin-125I respectively. When plasma was extracted with acid ethanol and filtered in 1.0 M acetic acid, the patterns and proportions of “big” and “little” insulin were indistinguishable from those obtained by filtration of whole plasma in neutral buffer. When “big” insulin was isolated from plasma and mixed with a tracer of porcine proinsulin-125I, trypsin converted the “big” insulin immunoreactivity to the gel filtration pattern of “little” insulin in the same way that it converted the proinsulin radioactivity. More than 90% of both “big” insulin and proinsulin were converted at optimal trypsin concentrations. Our present guinea pig anti-insulin serum failed to distinguish “big” from “little” but a porcine proinsulin anti-serum, under appropriate conditions of assay, reacted strongly with “big” insulin but not at all with “little.” When tested on isolated fat cells, “little” insulin had the same bioactivity as porcine insulin, whereas “big” insulin had the same low activity as porcine proinsulin. These studies suggest that “big” insulin represents either single-chain proinsulin and/or a proinsulin intermediate that has similar low bioactivity.

Authors

Barry M. Sherman, Phillip Gorden, Jesse Roth, Pierre Freychet

Human norepinephrine metabolism: Its evaluation by administration of tritiated norepinephrine

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It has become increasingly apparent that evaluation of human norepinephrine metabolism simply by assay of catecholamines in urine is inadequate for differentiation of many physiological or pathological states. In an attempt to examine norepinepherine metabolism in the human subject, tritium-labeled d,l-norepinephrine was administered to 11 normal adults and the definitive turnover rates and relative specific activities of norepinephrine and its major catabolites, vanillylmandelic acid, 3-methoxy-4-hydroxyphenylethyleneglycol, and normetanephrine, as well as the cumulative 24 hr isotope excretion were determined. The major endogenous norepinephrine catabolites were also quantitatively assayed. In order to verify the reliability of the isotope label, parallel studies were carried out in two patients to whom norepinephrine-14C was administered. Metabolic studies were repeated after the administration of reserpine to gain further insight into the distribution of the label.

Authors

Stanley E. Gitlow, Milton Mendlowitz, Laura M. Bertani, Sherwin Wilk, Elizabeth K. Wilk

Immunological protection against digoxin toxicity

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The lethal dose of digoxin was determined by administering 10 ml of a digoxin-saline solution to 26 nonimmunized rabbits through an ear vein over a 10 min period. Rabbits receiving less than 0.45 mg/kg digoxin showed no toxic effect, whereas all 15 rabbits that received 0.5 mg/kg developed an early arrhythmia and died within 1 hr. Moreover, eight rabbits which had been immunized with antigens unrelated to digoxin or injected with Freund's adjuvant mixture all died after receiving 0.6 mg/kg digoxin. Thus, it was concluded that 0.6 mg/kg digoxin was uniformly lethal in rabbits that had not been immunized or had received antigens unrelated to digoxin.

Authors

Donald H. Schmidt, Vincent P. Butler Jr.

Cholesterol synthesis in the intestine of man: regional differences and control mechanisms

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Cholesterol in the circulating serum pool is derived either from absorption of dietary cholesterol or from endogenous synthesis principally in the liver and gastrointestinal tract. While the control of intestinal cholesterogenesis has been elucidated in several lower animal species, no data currently are available in the case of man. In the present study using tissue specimens obtained by suction biopsy in 29 normal subjects, we have shown the rate of cholesterogenesis is low in the stomach (25 ±6 mμmoles/g per 2 hr) and rectum (40 ±8 mμmoles/g per 2 hr); in the small bowel the rate progressively decreases in the proximal duodenum (90 ±16 mμmoles/g per 2 hr); distal duodenum (80 ±11 mμmoles/g per 2 hr); and distal jejunum (35 ±5 mμmoles/g per 2 hr); but abruptly increases in the distal ileum (280 ±33 mμmoles/g per 2 hr). Indirect evidence is provided that the intestinal crypt epithelium is the main site of this sterol synthesis. Fasting for 48 hr suppressed the rate of cholesterogenesis in the distal duodenum from a control value of 80 ±11 mμmoles/g per 2 hr to 40 ±8 mμmoles/g per 2 hr while cholesterol feeding for 7 days did not alter the rate of cholesterol synthesis (75 ±12 mμmoles/g per 2 hr). This resistance to cholesterol feeding also was present in the distal ileum where control and cholesterol-fed subjects had comparable rates of cholesterogenesis (280 and 261 mμmoles/g per 2 hr, respectively). Interruption of the enterohepatic circulation, in contrast, resulted in greatly enhanced sterol synthesis with a mean rate of 259 ±29 mμmoles/g per 2 hr being found in the duodenum of four patients with biliary obstruction as compared with the rate of 80 ±11 mμmoles/g per 2 hr in control subjects. These studies indicate that the mechanisms of control of cholesterol synthesis by the human intestine are similar to those described for the intestine of lower animals; this also appears to be true for the human liver. Thus, the marked differences in over-all cholesterol metabolism between various lower mammalian species and man cannot be explained by fundamental differences in control mechanisms; rather, these differences must reflect variations in some other parameter of cholesterol metabolism.

Authors

John M. Dietschy, William G. Gamel

Acute undifferentiated human diarrhea in the tropics: I. Alterations in intestinal microflora

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The microflora of the small and large intestine was determined in 17 adults with acute undifferentiated diarrhea in Calcutta, India. On the basis of bacteriologic findings, the patients could be divided into two groups: those with a predominant flora of Escherichia coli (eight patients) and those with a mixed coliform flora (nine patients). In the former group, E. coli were distributed throughout the small and large bowel. Broth filtrates of these isolates contained an enterotoxin which caused fluid accumulation in the rabbit intestinal loop model. Toxigenic E. coli were cleared rapidly from the small bowel during the acute period; some patients only had the “hot” strains in their fecal effluent. During convalescence, the serotypes of E. coli changed and the new strains did not elaborate enterotoxin. Only one of the eight patients had a serotype previously associated with diarrhea. Acute undifferentiated diarrhea in the remaining cases was apparently caused by untypable E. coli or by typable strains not generally considered pathogenic.

Authors

S. L. Gorbach, J. G. Banwell, B. D. Chatterjee, B. Jacobs, R. B. Sack

Acute undifferentiated human diarrhea in the tropics: II. Alterations in intestinal fluid and electrolyte movements

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The nature and magnitude of fluid and electrolyte loss into the small intestine were defined by the marker perfusion technique in patients with acute undifferentiated diarrhea (AUD) in the tropics. The patients were divided into two groups according to their small bowel bacteriologic findings, namely those with a predominant Escherichia coli flora and those with a mixed flora. 11 normal subjects served as controls. Net jejunal fluid secretion occurred into the lumen in four of seven patients with E. coli flora and three of seven with a mixed flora. The magnitude of secretion in the jejunum was greater in the E. coli flora patients than in those with a mixed flora. Four E. coli patients and one mixed flora patient had net fluid secretion in the ileum, although the magnitude of secretion in this area was less than in the jejunum. Intestinal fluid had higher bicarbonate concentration in the ileum than in the jejunum but was isotonic in both regions. It resembled in composition fluid from the same region of intestine in normal individuals. Recovery of normal fluid and electrolyte absorptive function was usually complete in both jejunum and ileum by 6-8 days after onset of the disease. Increase in unidirectional flux rates for H3O and 24Na occurred in acute E. coli flora diarrhea and returned to normal levels in recovery: increase in Jβ (plasma to lumen flux) primarily accounted for the increase in fluid loss. Intestinal biopsy revealed no alterations in villous architecture.

Authors

J. G. Banwell, S. L. Gorbach, N. F. Pierce, R. Mitra, A. Mondal

Renal handling of low molecular weight proteins: I. l-Chain metabolism in experimental renal disease

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Immunoglobulin L-chain metabolism was studied in normal mice, mice with sodium maleate-induced renal tubular disease but normal glomerular filtration rate (GFR), and mice with both tubular disease and decreased GFR. The proteinuric rate of L-chain was increased twofold in mice with tubular disease alone though there was no alteration in the over-all rate at which L-chain disappeared from the circulation in these animals. This was in sharp contrast to findings in mice with tubular disease and a decreased glomerular filtration rate in which L-chain disappearance rates were markedly reduced. These findings demonstrate that in the normal state, L-chain and presumably other proteins of similar size pass through the glomerulus and are avidly taken up and catabolized by the convoluted tubular cells. In tubular proteinuric states this linked uptake-catabolic function fails, resulting in elevated urinary excretion but normal serum levels and turnover rates of these proteins. In uremic states with decreased glomerular filtration, less small protein is delivered into the tubular lumen and the processes of excretion and catabolism are reduced. This results in prolongation of the survival of small proteins and explains the elevated serum concentrations of these proteins observed in uremia.

Authors

R. Peter Mogielnick, Thomas A. Waldmann, Warren Strober

Ventilatory mechanics and expiratory flow limitation during exercise in patients with obstructive lung disease

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The interrelationships among transpulmonary pressure, flow, and volume during exhausting exercise were studied in 12 males with chronic obstructive lung disease. Expiratory pressure during exercise was compared with flow-limiting pressure (Pmax) measured at rest. In 11 patients, expiratory pressure during exercise exceeded Pmax, indicating that ventilation became mechanically inefficient. Pmax values of the patients were lower than those of normal subjects. Evidence of expiratory flow augmentation during exercise was noted in two subjects. Since 10 subjects achieved maximal expiratory flow predicted from flow-volume curves when heart rate was not maximal, we conclude that exercise capacity in most subjects was clearly limited by the deranged ventilatory apparatus. Elevations in mean intrathoracic pressure during exercise also may interfere with venous return and impose an additional limitation.

Authors

William A. Potter, Snorri Olafsson, Robert E. Hyatt

Cyclic 3′,5′-adenosine monophosphate in the human leukocyte: synthesis, degradation, and effects on neutrophil candidacidal activity

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Prostaglandins E1 and E2 (PGE1 and PGE2) stimulate adenyl cyclase activity in broken cell preparations of normal human leukocytes, whereas prostaglandin F1a produces no effect. PGE1 and PGE2 also cause increased accumulation of cyclic 3′,5′-adenosine monophosphate-3H (3H-labeled AMP) in intact leukocytes which have been preincubated with adenine-3H in vitro. Theophylline inhibits leukocyte phosphodiesterase activity and potentiates the stimulatory effect of the prostaglandins on intracellular accumulation of cyclic 3′,5′-AMP-3H.

Authors

Henry R. Bourne, Robert I. Lehrer, Martin J. Cline, Kenneth L. Melmon

Skin capillary blood flow in scleroderma

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Skin blood flow was measured by the clearance of radioactive xenon (133Xe) injected intracutaneously in eight patients with scleroderma and nine control subjects under conditions of controlled temperature and humidity. Scleroderma patients, on being cooled 1 hr at 18°C, had a rate constant of 133Xe clearance from the dorsal finger skin which was 0.04 ±0.07 min-1 (mean ±SD), compared with 0.23 ±0.15 min-1 in normal subjects (P < 0.005). The corresponding mean cutaneous blood flows were 2.9 ml/100 g per min in the scleroderma patients and 16.4 ml/100 g per min in normal subjects. After reflex warming by waterbath, clearance was similar in the two groups (0.33 ±0.1 vs. 0.40 ±0.09); these data suggest that diminished clearance in scleroderma patients on cooling resulted, at least in part, from functional or reversible interruption of the circulation. The skin temperatures of scleroderma patients after reflex warming remained lower than those of normal subjects, despite similar increases in sublingual temperatures. The dissociation of 133Xe clearance and skin temperature in scleroderma patients (i.e. subnormal skin temperatures with normal 133Xe clearance after reflex warming) suggests either abnormal thermal properties of scleroderma skin or selective vasoconstriction of the vessels which regulate heat exchange. The demonstrated interruption of the capillary circulation on cooling of the skin in patients with scleroderma may be important in the pathogenesis of this disorder. After oral pretreatment with guanethidine, five patients with scleroderma had increased 133Xe clearance and calculated blood flow on cooling, rising to normal in three of these patients. The potential of this technique for the quantitative sequential evaluation of skin blood flow in subjects with scleroderma and for the evaluation of empirical therapy is suggested.

Authors

E. Carwile LeRoy, John A. Downey, Paul J. Cannon

The effect of administration of human growth hormone on the plasma growth hormone, cortisol, glucose, and free fatty acid response to insulin: evidence for growth hormone autoregulation in man

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The effect of administration of human growth hormone (HGH) (3 mg every 6 hr for 6 days) on the endogenous GH response to insulin-induced hypoglycemia at 8, 12, 24, and 48 hr posttreatment was studied in 11 healthy male adults. Free fatty acid, cortisol, and glucose responses pre- and posttreatment with HGH were evaluated concurrently. Control subjects received saline injections to evaluate relationship of GH responses to the periodicity of insulin tolerance tests. The data were compared for each subject pre- and posttreatment with HGH as well as by comparison of the results of the saline-treated group with those of the HGH-treated group.

Authors

Robert L. Abrams, Melvin M. Grumbach, Selna L. Kaplan

Hypogammaglobulinemia associated with accelerated catabolism of IgG secondary to its interaction with an IgG-reactive monoclonal IgM

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Hypogammaglobulinemia due to a new pathophysiological mechanism was studied in a patient with Sjögren's syndrome, a monoclonal IgM and a mixed (IgM-IgG) cryoglobulinemia. The IgM (IgMdk) component of the cryogel possessed light chains of λ-type with highly restricted electrophoretic mobility analagous to those of a Waldenström's macroglobulin. IgMdk reacted specifically with native IgG, with IgG subclasses 1, 2, and 4, and with the Fc piece of IgG to form a cryogel. Serum concentrations of IgG 1, 2, and 4 were 10% of normal, whereas the IgG3 level was slightly increased and the IgM level was markedly increased. Viscosity and analytical ultracentrifugation studies with the purified mixed cryogel (IgM-LgG) indicated soluble complex formation over a temperature range (36-38°C) attainable in vivo. Immunoglobulin turnover studies revealed a markedly elevated rate of IgM synthesis with a normal survival of IgM, IgA, and IgE. IgG3, which failed to form complexes with IgMdk at body temperature, had a normal synthetic rate and survival. In contrast, the other IgG subclasses showed reduced synthesis and shortened survival. These studies are the first indicating a short survival of some IgG subclasses with a normal survival of another. The hypogammaglobulinemia appears to be due in part to a new mechanism of accelerated protein catabolism: The rapid elimination of IgG due to its interaction with an IgG-reactive monoclonal IgM.

Authors

Thomas A. Waldmann, John S. Johnson, Norman Talal