Mechanics of Sphincter Action. STUDIES ON THE LOWER ESOPHAGEAL SPHINCTER

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Abstract

The purpose of this study was to evaluate the mechanical factors involved in the genesis of lower esophageal sphincter pressure. We determined the relationship between intraluminal pressure and inside diameter, estimated the ratio between the wall thickness to inside radius, and calculated the tension in the wall of the lower esophageal sphincter as a function of the inside diameter. Various degrees of circumferential stretch were applied by introducing probes of different diameters in the rat lower esophageal sphincter in vivo. The intraluminal pressure produced by the lower esophageal sphincter around each probe was measured and pressure-diameter curves were constructed during (a) resting state, (b) contraction produced by electrical stimulation, and (c) relaxation produced by esophageal distension. The intraluminal pressure at an inside diameter of 0.5 mm was similar to that at inside diameter of 3.2 mm. This was true for the sphincter at rest as well as upon electrical stimulation. The pressure diameter curve, however, was sigmoid in shape; at first it showed a decline and then an increase followed by decline in pressure again with increasing diameters. The ratio of wall thickness to inside radius or the magnification factor varied with inside diameters as expected and this ratio increased steeply at small inside diameters. The tension diameter curves of the sphincter muscle showed that optimal tension development occurred not near sphincter closure but at a much wider diameter of 3.2 mm and that this muscle developed tension even at small luminal diameters. This behavior of the sphincter muscle ensures effective intraluminal pressure over a wide range of luminal diameters.

Authors

Piero Biancani, Raj K. Goyal, Aris Phillips, Howard M. Spiro

Neutralizing and Non-neutralizing Antibodies to Bovine Thyroid-Stimulating Hormone and its Subunits

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Abstract

To test the possibility that the long-acting thyroid stimulator (LATS) might represent an immune complex either of thyroid-stimulating hormone (TSH) with anti-TSH or of a subunit of TSH with an appropriate antibody, we immunized rabbits with bovine TSH (bTSH), bLH (luteinizing hormone), and their α and β subunits (bTSHα and bTSHβ). Binding, neutralizing, and nonneutralizing antibodies were demonstrated in the antisera obtained. First, antisera to TSH, TSHβ, and TSHα all bound [125I]TSH and [125I]TSHβ. Anti-bTSHβ antisera bound [125I]bTSHβ better than did anti-TSH sera, while the binding of [125I]bTSH was similar with both types of antiserum. Second, the thyroid-stimulating activity (McKenzie bioassay) of TSH could be neutralized by incubation with various dilutions of anti-TSH or anti-TSHβ. Finally, when incubation mixtures containing TSH and dilutions of anti-TSHβ antisera that only partially neutralized TSH were treated with an antiserum against rabbit immunoglobulins to precipitate immune complexes, the bioassay response of the TSH was abolished. This phenomenon was not observed when antiserum to the intact hormone was substituted in the incubation mixture. The removal of TSH biological activity from a mixture of TSH and anti-bTSHβ by addition of an anti-immunoglobulin indicated that biologically active immune complexes were formed between TSH and anti-TSHβ but not between TSH and anti-TSH. The time-course of the bioactivity and several other characteristics of these complexes differentiate them from LATS.

Authors

Gildon N. Beall, Inder J. Chopra, David H. Solomon, John G. Pierce, James S. Cornell

The Effects on Rabbits of Immunization with Bovine Thyroid-Stimulating Hormone and its Subunits

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Abstract

Rabbits were immunized with bovine thyroid-stimulating hormone (bTSH), bovine Inteinizing hormone (bLH), and their subunits. In two immunization experiments, thyroid-stimulating activity was found in the serum of 6 out of 12 rabbits immunized with bTSHβ subunits. The thyroid-stimulating activity in the anti-bTSHβ sera was greater at 2 h than at 8, was eluted with the globulin fraction from Sephadex G-100, was completely neutralized by both anti-bTSH and anti-rabbit gamma globulin, and was completely suppressed by administration of triiodothyronine (T3) to the immunized rabbit. These findings led to the conclusion that the thyroid-stimulating activity resided in soluble complexes of rabbit TSH bound to anti-bTSHβ. Two of nine rabbits immunized with bTSH developed thyroid-stimulating activity in their serum, but it was nonsuppressible by T3. None of the animals immunized with bTSHα, bLH, bLHβ, or bLHα developed serum thyroid-stimulating activity.

Authors

Gildon N. Beall, Inder J. Chopra, David H. Solomon, John G. Pierce, James S. Cornell

Pulmonary Gas Exchange in Nonnative Residents of High Altitude

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Abstract

This study represented an initial attempt, by means of cross-sectional investigation, to determine the effects of chronic exposure to high altitude on pulmonary gas exchange. Single-breath DLco and its components were determined at rest and during muscular work in two groups of healthy, non-smoking, sea level natives who had initiated 1-16 yr of residence at 3,100 m altitude either during physical maturation (at age 10±4 yr) or as adults (at age 26±4 yr). The relative degree of acclimatization achieved in these lowland residents was assessed through their comparison both with normal sea-level values and with two additional groups of short-term sojourners and natives to 3.100 m. DLco at rest and work was significantly elevated above normal and above sojourner values in both groups of resident lowlanders at 3,100 m. The high DLco in the native to 3,100 m was closely approximated in the younger resident lowlander at rest, but only during exercise in the adult resident lowlander. The high DLco at rest and during exercise in the resident lowlanders was not attributable to differences in Hb concentration or in alveolar lung volume: and was accompanied primarily by an increased estimated Dmco and to a lesser extent by an expanded Vc. The interpretation and implications of these findings were limited by the low quantitative capability of Vc and Dmco estimates and by the cross-sectional nature of the study. Nevertheless, the higher than normal DLco and Dmco in the non-native, long-term resident of 3,100 m was substantial, highly significant statistically, and consistent over a wide range of metabolic rates at rest and work. These data provide, then, a reasonable rationale upon which longitudinal experiments may be based to determine the true effects of chronic hypoxia on pulmonary gas exchange in man.

Authors

F. C. Cerny, J. A. Dempsey, W. G. Reddan

Studies on Mechanisms of Hypocalcemia of Magnesium Depletion

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Abstract

Studies were carried out to evaluate the mechanism of hypocalcemia in magnesium depletion. Day old chicks fed a magnesium deficient diet developed marked hypocalcemia, with a direct relation between serum calcium (y) and magnesium (x): y = 2.68 x + 4.24, r = 0.84 (both in mg/100 ml). Injections of parathyroid extract that increased serum calcium 2-3 mg/100 ml in normals had no effect in Mg-depleted birds. Very large dietary supplements of calcium or vitamin D3 increased mean serum calcium only from 5.3 to 7.7 and 7.8 mg/100 ml, respectively, while a normal magnesium diet for 3 days increased calcium from 5.3 to 9.9 mg/100 ml despite absence of dietary calcium. Intestinal calcium transport, studied in vitro, and the calcium concentration of the carcass was significantly increased in magnesium-depleted chicks, making it unlikely that reduced intestinal absorption of calcium caused the hypocalcemia. In magnesium-deficient chicks, the bone content of magnesium was decreased by 74%, the calcium content was unchanged, and the cortical thickness of bone was markedly increased. After 3 days of magnesium-repletion, cortical thickness was reduced with increased endosteal resorption. There was an increase in unmineralized osteoid tissue in the magnesium-depleted chicks. Parathyroid gland size and histology did not differ in magnesium-depleted and control birds. The results suggest that hypocalcemia develops due to altered equilibrium of calcium between extracellular fluid and bone, favoring increased net movement into the latter. Failure of parathyroid gland function could also exist, and unresponsiveness to parathyroid hormone (PTH) may also contribute to the hypocalcemia. However, failure of PTH action is probably due to the presence of excess osteoid tissue rather than a primary event leading to hypocalcemia.

Authors

Chilumula R. Reddy, Jack W. Coburn, David L. Hartenbower, Robert M. Friedler, Arnold S. Brickman, Shaul G. Massry, Jenifer Jowsey

Skeletal Muscle Resting Membrane Potential in Potassium Deficiency

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Abstract

The resting transmembrane potential of skeletal muscle (Em) is thought to be a function of the ratio of intracellular to extracellular potassium concentration ([Ki]/[Ko]). In potassium deficiency, the fall of [Ki] is proportionately less than the fall of [Ko], thus theoretically predicting a rise of Em. To examine this theory and to characterize Em in kaliopenic myopathy, muscle composition and Em were measured during moderate (n = 5) and severe (n = 11) K deficiency in the dog and compared with measurements in the severely K-deficient rat (n = 10). Mean measured Em rose during moderate K deficiency in four of five dogs (-85.4 to -94.6 mV) and during severe K deficiency in the rat (-89.1 to -94.9 mV). Both values closely approximated the increase in Em predicted by the Goldman equation. In contrast, during severe K deficiency in the dog, a significant decline (P < 0.001) of mean Em to -55 mV was observed.

Authors

Gordon L. Bilbrey, Luis Herbin, Norman W. Carter, James P. Knochel

Bone Magnesium Pools in Uremia

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Abstract

Bone magnesium pools were studied in vitro in bone specimens obtained from control subjects, from patients with chronic renal failure before and after renal transplantation, and in a patient with chronic hypomagnesemia. 30% of bone magnesium is in a surface limited pool present either within the hydration shell or else on the crystal surface. The larger fraction of bone magnesium was shown not to be associated with bone matrix but rather to be an integral part of the bone crystal. With incineration this pool was mobilized at the same temperature that sudden enlargement of bone crystal size occurred. It is suggested that heating causes surface calcium to displace magnesium from the apatite crystal. Both magnesium pools are increased in patients with chronic renal failure.

Authors

Allen C. Alfrey, Nancy L. Miller

Modulation of Plasma Aldosterone Concentration by Plasma Potassium in Anephric Man in the Absence of a Change in Potassium Balance

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In studies on seven anephric patients, glucose and insulin administration before hemodialysis produced a significant reduction in plasma potassium concentration (mean reduction = 1.3, 1.7, and 1.4 meq/liter at 60, 120, and 180 min, respectively) which was accompanied by a significant and sustained reduction in plasma aldosterone concentration. There was a significant correlation between plasma aldosterone and plasma potassium concentration (r = +0.74, P < 0.001) and between changes in the concentration of plasma aldosterone occurring in individual patients and the corresponding changes in plasma potassium concentration (r = +0.52, P < 0.01). There was no significant change in plasma sodium concentration, and plasma corticoid concentration, which was monitored as an index of ACTH elaboration, was reduced at 60 min but increased subsequently as symptoms attributable to hypoglycemia were observed.

Authors

C. Robert Cooke, John S. Horvath, Michael A. Moore, Turner Bledsoe, W. Gordon Walker

Glucose Turnover and Disposal in Maturity-Onset Diabetes

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The glucose turnover rate in maturity-onset diabetes in man has been variously reported as increased, normal, and decreased. The present experiments suggest that these discrepancies may have been due to methodology, and to nonrecognition of a circadian cycle in the glucose turnover rate that is present in health, and marked in diabetes.

Authors

H. F. Bowen, J. A. Moorhouse

Peripheral Blood Lymphocyte Cell Surface Markers during the Course of Systemic Lupus Erythematosus

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Abstract

Peripheral blood lymphocytes from 23 patients with active systemic lupus erythematosus (SLE) were serially studied. Changes in bone marrow-derived lymphocytes (B cells), as measured by surface Ig receptors and C3 receptors, and in thymus-derived cells (T cells) measured by rabbit T-cell-specific antiserum and E-binding techniques, were correlated with fluctuations in clinical disease activity and treatment. In normal controls B- and T-cell percentages remained relatively stable, although the situation in SLE was much more labile. A relative and absolute decrease in T lymphocytes and cells bearing a receptor for C3 was found in active lupus. Absolute numbers of cells bearing surface Ig were decreased to a lesser extent, whereas the proportion of these cells was increased. It is postulated that the increase in autoantibody formation and diminished delayed hypersensitivity seen in systemic lupus may be due to a loss of T-lymphocyte function.

Authors

Ronald P. Messner, Folke D. Lindström, Ralph C. Williams Jr.

Free α-Globin Pool in Human Bone Marrow

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A pool of free α-globin chains was found in the bone marrow samples from three controls, two patients with β-thalassemia trait, three with sickle β-thalassemia, three with hemoglobin (Hb) Lepore trait, one with αβ-thalassemia, four with homozygous β-thalassemia, and one doubly heterozygous for Hb Lepore and β-thalassemia. The average percentage of newly synthesized α-chains found in the free α-globin pool was 6.2% in the controls and 33.0% in the patients heterozygous for thalassemia or Hb Lepore. These controls and patients had balanced β- and α-globin synthesis in the bone marrow. In the homozygous patients and in the one patient doubly heterozygous for thalassemia and Hb Lepore, there was a marked deficit of β-chain synthesis in the bone marrow and also a large pool of newly synthesized free α-chains. The function of this pool of free α-chains is not known, but it may be involved in the regulation of globin chain synthesis in normal patients and in the compensatory synthesis of β-chains that occurs in the bone marrow of patients heterozygous for thalassemia or for Hb Lepore.

Authors

Frances M. Gill, Elias Schwartz

B Lymphocytes in Untreated Patients with Malignant Lymphoma and Hodgkin's Disease

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B and T lymphocytes in 37 untreated patients with malignant lymphoma and Hodgkin's disease were studied. B cells in the peripheral blood were investigated with respect to surface immunoglobulins and in a few patients with respect to intracytoplasmic immunoglobulins by means of immunofluorescence. T cell function was studied by direct phytohemagglutinin (PHA) microtest (from the same sample of whole blood), mixed lymphocyte culture (MLC), and by delayed hypersensitivity to various antigens. In the 13 patients with Hodgkin's disease the histologic subtype was nodular sclerosis in nine, lymphocyte predominant in two, mixed cellularity in two. Only one of these patients had disseminated disease (stage IV); he showed impaired cellular immunity, a very low percentage of B cells and low levels of serum immunoglobulins. Of the remaining patients with Hodgkin's disease, with one exception, normal percentages but rather low absolute numbers of B lymphocytes per mm3 of blood were found. One patient with a low percent and low absolute number of B lymphocytes showed very high serum IgG. Of 24 patients with non-Hodgkin's malignant lymphoma, seven (29%) showed monoclonal B cell proliferation in the peripheral blood (five μκ, two γκ). By morphologic criteria, 14 patients had involvement of bone marrow, five of these had involvement of peripheral blood. Four of the latter five patients showed marked increases in percentages and absolute numbers of B lymphocytes in the peripheral blood reflecting the monoclonal proliferation. In three additional patients monoclonal proliferation of lymphocytes was found by immunofluorescence although the blood smears appeared morphologically normal. Serum immunoglobulin abnormalities without monoclonal B cell proliferation in the peripheral blood were observed in six patients.

Authors

Kazimiera J. Gajl-Peczalska, John A. Hansen, Clara D. Bloomfield, Robert A. Good

Characterization of Ileal Vitamin B₁₂ Binding Using Homogeneous Human and Hog Intrinsic Factors

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Elucidation of the mechanism of intrinsic factor (IF)-mediated vitamin B12 (B12) binding to ileal binding sites has been hampered by the use of crude or only partially purified preparations of IF in previous studies. We have used homogeneous human IF and hog IF isolated by affinity chromatography to study [57Co]B12 binding to ileal mucosal homogenates. The following observations were made: (a) Human IF-B12 and hog IF-B12 were bound to human, monkey, hog, dog, rabbit, mouse, hamster, and guinea pig ileal, but not jejunal, homogenates in amounts significantly greater than free B12 or B12 bound to five other homogeneous B12-binding proteins; (b) only IF-mediated B12 binding was localized to ileal homogenates and was inhibited by EDTA; (c) values for the association constant (Ka) for the various ileal homogenates mentioned above and human IF-B12 and hog IF-B12 ranged from 0.3 × 109 M-1 to 13.0 × 109 M-1. Apparent differences in the Ka for human IF-B12 and hog IF-B12 existed in most species; (d) the number of ileal IF-B12 binding sites per gram (wet weight) of ileal mucosa ranged from 0.3 × 1012 to 4.9 × 1012. The same value was always obtained with human IF-B12 and hog IF-B12 for any given homogenate preparation; (c) 100-fold excesses of free B12 or human IF and hog IF devoid of B12 did not significantly inhibit human IF-B12 and hog IF-B12 binding to human and hog ileal homogenates.

Authors

David C. Hooper, David H. Alpers, Robert L. Burger, Carol S. Mehlman, Robert H. Allen

Thyrocalcitonin and the Jejunal Absorption of Calcium, Water, and Electrolytes in Normal Subjects

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Abstract

Jejunal absorption of calcium, water, and electrolytes was measured in 10 normal subjects by the triple-lumen perfusion method. During the control period, water and electrolyte movements were minimal when a bicarbonate-free test solution was infused. By contrast, bicarbonate-containing solutions were readily absorbed in the control period. Intravenous infusion of synthetic salmon calcitonin (SCT) (1 Medical Research Council U/kg wt/h) over 110-120 min resulted in a marked jejunal secretion of water, sodium, potassium, and chloride in 8 of the 10 subjects. This jejunal secretion occurred with both the bicarbonate-free and the bicarbonate-containing test solutions. Calcium absorption was not affected by SCT, and the serum calcium concentration did not fall during SCT infusion. These results suggest that diarrhea in patients with medullary carcinoma of the thyroid may be due to intestinal secretion secondary to high blood concentrations of thyrocalcitonin.

Authors

T. Kenney Gray, Frederick A. Bieberdorf, John S. Fordtran

Biosynthesis of Proparathyroid Hormone and Parathyroid Hormone by Human Parathyroid Glands

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Human parathyroid glands obtained at autopsy were incubated with [3H]leucine and [3H]lysine. After incubation, nonradioactive parathyroid tissue of either human or bovine origin was added. Radioactive parathyroid hormone and proparathyroid hormone were isolated from the gland and medium by organic solvent and salt fractionation, trichloroacetic acid precipitation, Sephadex G-100 gel filtration, and carboxymethyl cellulose column chromatography. The human hormonal peptides were identified in the ion-exchange column eluates by their relatively high levels of radioactivity, their elution positions, and their immunoreactivity to anti-PTH antiserum. The time-course of radioactive amino acid incorporation into these peptides and a brief incubation of the gland with radioactive amino acids, followed by various lengths of incubation with nonradioactive amino acids, indicated that a precursor-product relationship exists for the two peptides. An alternate method for isolation of the hormone and prohormone, which involves separation of peptides by urea-polyacrylamide gel electrophoresis, confirmed the identities of the human parathyroid hormone and proparathyroid hormone.

Authors

Luke L. H. Chu, Ronal R. MacGregor, Paul I. Liu, James W. Hamilton, David V. Cohn

Response of the Distal Tubule and Cortical Collecting Duct to Vasopressin in the Rat

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Abstract

Renal micropuncture observations in the rat suggest that the entire “distal tubule” (defined by the micropuncturist as that portion of the renal tubule extending between the macula densa and its first junction with another (renal tubule) may be responsive to vasopressin. However, this portion of the renal tubule contains two segments that are morphologically dissimilar. The “early” distal tubule is lined by epithelium characteristic of the distal convoluted tubule, while the “late” distal tubule is lined by epithelium characteristic of the cortical collecting duct. Thus, the present study was initiated to identify the most proximal site of action of vasopressin in the distal renal tubule. A water diuresis was established in rats with hereditary hypothalamic diabetes insipidus. In one-half of the animals the diuresis was interupted by an i.v. infusion of exogenous vasopressin. Morphological preservation of the kidneys was initiated after induction of vasopressin-induced antidiuresis or during maximum water diuresis. Cell swelling and dilatation of intercellular spaces, morphological findings indicative of vasopressin responsiveness, were observed in the cortical collecting duct including the late segment of the distal tubule, a segment that has also been described by morphologists as the initial collecting tubule. Morphological evidence of vasopressin-responsiveness was not observed in the early distal tubule (distal convoluted tubule). Additional morphological studies in Wistar, Long-Evans, and Sprague-Dawley rats demonstrated a marked difference in the random availability of distal convoluted tubules versus initial collecting tubules potentially available for micropuncture just beneath the renal capsule. The results suggest that hypotonic tubular fluid entering the early distal tubule (distal convoluted tubule) remains hypotonic to plasma until it enters the late distal tubule (initial collecting tubule) and that vasopressin-induced osmotic equilibration is a function of the latter segment alone. The findings emphasize the importance of morphological characterization of those segments of the renal tubule that are subjected to physiological investigation.

Authors

Philip B. Woodhall, C. Craig Tisher

Secretion of Calcitonin in Hypocalcemic States in Man

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Abstract

The control of calcitonin secretion in humans has been studied extensively only in patients with medullary thyroid carcinoma since the peripheral concentration of the hormone in normal subjects is too low for accurate measurement by existing assay procedures. However, we have recently found that the concentrations of calcitonin in the peripheral plasma of hypocalcemic subjects during provocative tests of hormone secretion were high enough to be measured by radioimmunoassay. Accordingly, the effect of calcium and pentagastrin infusions on plasma calcitonin was studied in nine patients with pseudohypoparathyroidism, seven patients with idiopathic hypoparathyroidism, and six patients with hypocalcemia not due to parathyroid disease. The infusion of calcium in these hypocalcemic subjects resulted in increases in plasma calcitonin to levels that could be readily detected by our radioimmunoassay. Pentagastrin infusion also caused an increase of plasma calcitonin in some subjects, but calcium was approximately 10 times more effective than gastrin in its stimulatory effect on hormone secretion. These results demonstrate that in humans as well as other mammals the secretion of calcitonin by parafollicular cells that are not involved by medullary thyroid carcinoma is directly related to plasma calcium and that gastrin can also stimulate hormone secretion. The results are consistent with the thesis that the secretion of calcitonin by normal human subjects does occur but at peripheral concentrations of the hormone below the detection limits of most existing immunoassays; hypocalcemia leads to increased stores of hormone that can be related by the appropriate stimuli.

Authors

Leonard J. Deftos, David Powell, Jacqueline G. Parthemore, John T. Potts Jr.

Mechanisms Regulating the Cardiac Output Response to Cyanide Infusion, a Model of Hypoxia

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When tissue metabolic changes like those of hypoxia were induced by intra-aortic infusion of cyanide in dogs, cardiac output began to increase after 3 to 5 min, reached a peak (220% of the control value) at 15 min, and returned to control in 40 min. This pattern of cardiac output rise was not altered by vagotomy with or without atropine pretreatment. However, this cardiac output response could be differentiated into three phases by pretreating the animals with agents that block specific activities of the sympatho-adrenal system. First, ganglionic blockade produced by mecamylamine or sympathetic nerve blockade by bretylium abolished the middle phase of the cardiac output seen in the untreated animal, but early and late phases still could be discerned. Second, beta-adrenergic receptor blockade produced by propranolol shortened the total duration of the cardiac output rise by abolishing the late phase. Third, when given together, propranolol and mecamylamine (or bretylium) prevented most of the cardiac output rise that follows the early phase.

Authors

Chang-seng Liang, William E. Huckabee

Effects of Splenectomy and Beta-Adrenoceptor Blockade on Cardiac Output Response to Acute Hypoxemia

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Abstract

Acute hypoxemia produced by the inhalation of 8% and 5% oxygen increased cardiac output in intact anesthetized dogs by 38% and 62%, respectively. Although practolol, a cardioselective beta-adrenergic blocking agent, reduced the increase in cardiac output in dogs subjected to severe hypoxemia (5% O2 breathing) from 62% to 43%, it only slightly reduced the cardiac output rise in dogs subjected to moderate hypoxemia (8% O2 breathing). Splenectomy, on the other hand, abolished the increase in cardiac output produced by moderate hypoxemia except for a small initial rise, but it reduced the increase in cardiac output during severe hypoxemia only to 37%. The entire increase, except for a small initial rise, disappeared only when splenectomized dogs were pretreated with practolol. Sham operation did not affect the cardiac output response to hypoxemia. It is concluded that an intact spleen is required for a significant portion of the increased cardiac output that occurs during both moderate and severe hypoxemia and that catecholamines do not participate in the regulation of cardiac output unless severe hypoxemia occurs.

Authors

Chang-seng Liang, William E. Huckabee

Ectopic Production of the Isolated Beta Subunit of Human Chorionic Gonadotropin

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Abstract

A material similar to the beta subunit of human chorionic gonadotropin (hCG-β) was detected in serum (300 ng/ml) and tumor extract from a 75-yr-old man with pancreatic adenosquamous carcinoma. This material was indistinguishable from hCG-β in three different types of radioimmunoassay that displayed widely varying reactions with glycoprotein trophic hormones and their subunits. In gel chromatography there appeared to be heterogeneity of the serum beta-like immunoactivity, including one component that coeluted with standard hCG-β tracer and another immunologically indistinguishable component that displayed a slightly lower elution volume. Neither complete human chorionic gonadotropin (hCG) nor its alpha subunit was detected in radioimmunoassays of serum, before or after fractionation, or in tumor extract. The absence of complete hCG was confirmed in a gonadotropin bioassay sensitive to 15 ng of hCG, which showed no bioactivity in serum or tumor extract containing 450 and 90 ng of hCG-β, respectively. This case probably represents the first demonstration of isolated polypeptide subunit production of ectopic origin and suggests that hCG-β, as well as other subunits, may prove useful as cancer markers.

Authors

Bruce D. Weintraub, Saul W. Rosen

Direct Effects of Salicylate on Renal Function in the Dog

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Sodium salicylate was administered to anesthetized dogs in doses sufficient to produce concentrations in plasma comparable to those common in human salicylate toxicity. Salicylate administration increased the rates of excretion of water, sodium, and chloride in the urine. Salicylate administration also increased the rate of excretion of potassium so that its clearance often exceeded that of creatinine. This enhancement of potassium excretion was dissociated from the alkalosis that accompanies salicyate toxicity. Administration of 5% CO2 in inspired gas did not attenuate the excretion of potassium; injection of salicylate into one renal artery caused a unilateral kaliuresis. Phosphate excretion increased progressively after administration of salicylate. On several occasions the clearance of phosphate equalled that of creatinine. Salicylate reduced renal tubular glucose reabsorption. When salicylate was injected into a renal artery, a glycosuria occurred ipsilaterally at filtered loads of glucose far below the reabsorptive capacity of the dog kidney. Salicylate administration also was associated with early elevation of glucose, phosphate, and potassium concentration in plasma. Salicylate administration reduced the content of adenosine triphosphate in the renal medulla. Salicylate was concentrated within the medulla between 1.5 and 3 times that of the cortex, a gradient equal to that for chloride.

Authors

A. Quintanilla, R. H. Kessler

Quantitative Relations of Fetal and Maternal Pitiutary - Adrenal Systems I. EFFECTS OF MATERNAL HYPOPHYSECTOMY

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Even though certain aspects of the fetal pituitary-adrenal system have been extensively studied, much remains to be learned of its basic development and function. In the present work, the effect of maternal hypophysectomy upon quantitative pituitary-adrenal relations in mother and fetus was investigated in pregnant beagle dogs. At 57 days gestation in each of seven normal animals and seven animals 3 wk posthypophysectomy, a cannula for collection of adrenal effluent was placed in a single fetus in utero under halothane anesthesia. A timed fetal adrenal sample was obtained; ACTH (10 mU) was injected into the fetus; 3 min thereafter a second fetal adrenal sample was collected and fetal and maternal peripheral arterial samples were drawn. All fetuses and their adrenal glands were weighed. Concentrations of cortisol and corticosterone were determined by a modification of the double-isotope dilution derivative method of Kliman and Peterson.

Authors

B. T. Jackson, H. F. J. Rauschecker, G. J. Piasecki

Life Span of Carbamylated Red Cells in Sickle Cell Anemia

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By using three isotopes of diisopropyl-phosphofluoridate ([3H]-, [14C]-, and [32P]DFP) simultaneously, the life span of red cells from 20 patients with sickle cell anemia (Hb SS) has been studied after varying degrees of carbamylation in vitro with cyanate (NCO) and carbamyl phosphate (CP). The results are expressed in terms of the red cell mean life span (MLS).

Authors

Paul F. Milner, Samuel Charache

Effect of Luminal Sodium Concentration on Bicarbonate Absorption in Rat Jejunum

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An exchange of Na+ for H+ has been proposed to explain why jejunal Na+ absorption is influenced by luminal concentrations of H+ and HCO3-. We studied the influence of luminal Na+ concentration on net HCO3- absorption by perfusing rat jejunum in vivo. When Na+ was omitted from the perfusion fluid, HCO3- absorption diminished by a fixed amount over a range of initial HCO3- concentrations of 15 to 80 mM. This change was not caused by alterations in transmural PD or direction of water movement. Because the rate of HCO3- absorption decreased as the luminal HCO3- concentration lessened, Na+-dependent HCO3- absorption accounted for an increasing percent of total absorption as the luminal concentration of HCO3- diminished.

Authors

Kenneth A. Hubel

Differentiation Capacity of Cultured B Lymphocytes from Immunodeficient Patients

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Abstract

Peripheral blood lymphocytes from 27 healthy individuals and from 18 patients with a diverse spectrum of defects in humoral immunity were examined for their capacity to undergo terminal differentiation in vitro. Pokeweed mitogen induced cells from normal persons to synthesize and secrete IgM. IgG, and IgA as detected by Immunofluorescence and incorporation of [14C]amino acids, Lymphocytes from three boys with X-linked agammaglobulinemia were stimulated to proliferate, but did not synthesize immunoglobulin. Lymphocyte cultures from three of four patients having agammaglobulinemia with B lymphocytes produced different immunoglobulin classes in ratios similar to the in vivo distribution of classes of B lymphocytes, Lymphocytes from a dysgammaglobulinemic boy deficient in serum IgG and IgA, but who had normal numbers of IgM-, IgG-, and IgA-bearing B lymphocytes, could not be stimulated by pokeweed mitogen to make IgG and IgA. Synthesis and secretion of IgA, as well as IgM and IgG, was detected in cell cultures from each of 10 patients with isolated IgA deficiency. The results suggest that deficiencies in immunoglobulin synthesis may reflect either (a) failure to develop B lymphocytes, (b) arrested development of B lymphocytes due to intrinsic metabolic abnormalities, or (c) disturbance of factors extrinsic to the B lymphocyte which are essential for normal induction of plasma cell maturation.

Authors

L. Y. F. Wu, A. R. Lawton, M. D. Cooper

Fuels, Hormones, and Liver Metabolism at Term and during the Early Postnatal Period in the Rat

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The metabolic response to the first fast experienced by all mammals has been studied in the newborn rat. Levels of fuels and hormones have been compared in the fetal and maternal circulations at term. Then, after cesarean section just before the normal time of birth, sequential changes in the same parameters were quantified during the first 16 h of the neonatal period. No caloric intake was permitted, and the newborns were maintained at 37°C. Activities of three key hepatic enzymes involved in glucose production were estimated.

Authors

J. R. Girard, G. S. Cuendet, E. B. Marliss, A. Kervran, M. Rieutort, R. Assan

Characteristics of Membrane-Bound and Free Hepatic Ribosomes from Insulin-Deficient Rats I. ACUTE EXPERIMENTAL DIABETES MELLITUS

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Abstract

Membrane-bound and free ribosomes were prepared by discontinuous density gradient centrifugation from livers of rats 2-3 days after receiving alloxan (75 mg/kg) or streptozotocin (100 mg/kg). Hepatocytes from these animals were also examined by electron microscopy and subjected to quantitative morphometric analysis. The results indicated that the two populations of hepatic ribosomes respond differently to acute insulin deficiency. There was an overall reduction (P < 0.001) in total number of bound ribosomes per volume cytoplasm: the remaining bound ribosomes underwent a shift to smaller-sized ribosomal messenger RNA (mRNA) aggregates (P < 0.02); and the proteinsynthetic activity of these bound ribosomes was less than normal (P < 0.02) when protein synthesis was directed by endogenous mRNA. However, there was no difference between bound ribosomes from livers of normal and diabetic rats when protein synthesis was directed by polyuridylic acid. In contrast, free ribosomes were unchanged in number and degree of ribosomal mRNA aggregation, but displayed a significantly increased rate of in vitro protein synthesis (P < 0.01) as compared to normal controls. This increased protein-synthetic activity occurred when amino acid incorporation was directed by endogenous mRNA or polyuridylic acid. These changes in structure and function of bound and free hepatic ribosomes were prevented by the concomitant administration of insulin. The decrease in protein-synthetic activity of bound hepatic ribosomes from acutely diabetic rats seems to be secondary to marked disruption and disaggregation of the rough endoplasmic reticulum (RER) with production of smaller ribosomal mRNA aggregates which incorporate less amino acids into protein. Increased protein synthetic activity of free ribosome appears to be related to the ability of these ribosomes to copy mRNA more efficiently.

Authors

Daniel T. Peterson, Frank P. Alford, Eve P. Reaven, Irene Ueyama, Gerald M. Reaven

The Role of Blood Osmolality and Volume in Regulating Vasopressin Secretion in the Rat

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Abstract

A sensitive and specific radioimmunoassay for plasma arginine vasopressin (AVP) has been used to study the effects of blood osmolality and volume in regulating AVP secretion in unanesthetized rats. Under basal conditions, plasma AVP and osmolality were relatively constant, averaging 2.3±0.9 (SD) pg/ml and 294±1.4 mosmol/kg, respectively. Fluid restriction, which increased osmolality and decreased volume, resulted in a progressive rise in plasma AVP to about 10 times basal levels after 96 h. A 2-3-fold increase in plasma AVP occurred as early as 12 h, when osmolality and volume had each changed by less than 2%. Intraperitoneal injections of hypertonic saline, which had no effect on blood volume, also produced a rise in plasma AVP that was linearly correlated with the rise in osmolality (r > 0.9) and quantitatively similar to that found during fluid restriction (plasma AVP increased 2-4-fold with each 1% increase in osmolality). Intraperitoneal injection of polyethylene glycol, which decreased blood volume without altering osmolality, also increased plasma AVP but this response followed an exponential pattern and did not become significant until volume had decreased by 8% or more. At these levels of hypovolemia, the osmoregulatory system continued to function but showed a lower threshold and increase sensitivity to osmotic stimulation. We conclude that AVP secretion is regulated principally by blood osmolality but that the responsiveness of this mechanism may be significantly altered by modest changes in blood volume.

Authors

Fredrick L. Dunn, Thomas J. Brennan, Averial E. Nelson, Gary L. Robertson

Periodic Hematopoiesis in Human Cyclic Neutropenia

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Abstract

Human cyclic neutropenia is characterized by severe depression of blood neutrophil levels approximately every 21 days. To investigate the mechanism of cyclic neutropenia four patients were studied with daily complete blood counts, serial bone marrow examinations, marrow reserve testing, serum muramidase determinations, DF22P granulocytokinetic studies, and, in one patient, in vivo [3H]TdR labeling. Periodogram analysis of the serial blood counts in the latter patient and visual inspection of multiple cycles in the others revealed periodic fluctuations in the levels of blood neutrophils, monocytes, lymphocytes, reticulocytes, and platelets. Rhythmic changes in the morphologic and radioisotopic studies as well as the marrow reserve tests and muramidase measurements were consonant with a mechanism of periodic failure of marrow production rather than peripheral destruction. Human cyclic neutropenia is analogous to cyclic neutropenia in the grey collie dog and may be viewed as the consequence of cyclic hematopoiesis.

Authors

D. Guerry IV, D. C. Dale, M. Omine, S. Perry, S. M. Wolff

Utilization of Acetate in the Human Forearm during Exercise after Ethanol Ingestion

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Abstract

The uptake of acetate in the human forearm was studied in five fasting (14 h) subjects during 10-min periods of ergometer work at 7 and 10 kilopond-meters per minute (kpm/min). A constant arterial acetate concentration was established by administration of a small quantity of alcohol (25 g) to the subjects after a control work period. Blood flow was measured by an indicator dilution technique. Acetate uptake varied linearly with the product of arterial acetate concentration and blood flow. Acetate metabolism was calculated to account for about 6.5% of the energy metabolism, assuming complete combustion to carbon dioxide and water. Oxygen uptake and blood flow did not change in the presence of acetate and ethanol.

Authors

F. Lundquist, L. Sestoft, S. E. Damgaard, J. P. Clausen, J. Trap-Jensen

Human Antiserum for Prevention of the Local Shwartzman Reaction and Death from Bacterial Lipopolysaccharides

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Abstract

Bacterial lipopolysaccharides from dead bacteria have been blamed for the continuing high mortality from gram-negative infections despite antibiotic treatment. Because animal antiserum against these lipopolysaccharides has been shown to protect against several of the effects of endotoxin, we undertook the development of antiserum in human subjects. 21 men were immunized with a single injection of Salmonclla typhimurium or Escherichia coli 0:111 heat-killed cells and immune serum was collected at 2 wk. Preimmune serum was obtained as a control in all animal experiments. 1 ml antiserum given intravenously protected mice against a lethal intravenous dose of homologous endotoxin (P < 0.005 for both antisera). E. coli antiserum reduced the incidence of positive local Shwartzman reactions with E. coli endotoxin from 100 to 38%; S. typhimurium antiserum reduced the incidence from 92 to 35%. (P < 0.0005 for both antisera). There was no protection against heterologous endotoxin in either animal model. These experiments demonstrate for the first time that human antiserum confers exceedingly potent passive immunity to the effects of endotoxin.

Authors

Elizabeth J. Ziegler, Herndon Douglas, Abraham I. Braude

Human Lymphocytes Bear Membrane Receptors for C3b and C3d

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Abstract

Human peripheral blood lymphocytes have membrane receptors for EAC43b (sheep erythrocytes sensitized with antibody and complement) and also for EAC43d, obtained by treating EAC43b with C3b inactivator. Human granulocytes bind only EAC43b, C3 fragments obtained by limited trypsin digestion of purified human C3 display both C3b and C3d sites, since they inhibit rosette formation of lymphocytes with EAC43b and EAC43d. These findings raise the possibility that C3b and C3d receptor sites may be selectively distributed among normal subpopulations of B lymphocytes as well as among leukemic leukocytes.

Authors

Aline Eden, Gary W. Miller, Victor Nussenzweig