The exchange of carbon dioxide in the pregnant rhesus monkey has been studied quantitatively using sodium bicarbonate-14C and applying the model of a system of seven compartments. The transfer rates among the various compartments, compartment sizes, and the rate of production of carbon dioxide by fetus and mother were determined with a computer programmed to fit the theoretical model to the data by adjusting the parameter values of the model until a “best fit” was obtained. It was confirmed that the exchange of carbon dioxide between fetal and maternal blood across the placenta is rapid, that between fetal blood and amniotic fluid is slow, and that there is no appreciable exchange between maternal blood and amniotic fluid. The mean net production of CO2 by fetus was 0.476 ±0.0402 mmoles/kg·min, and that by mother was 0.373 ±0.0279 mmoles/kg·min.
Kotaro Suzuki, Albert A. Plentl, Karlis Adamsons
The partition of 5,5-dimethyloxazolidine-2,4-dione (DMO) and of 11 amines between the vascular and extravascular spaces of the lung has been determined by the multiple indicator dilution technique. Four amines (nicotine, pentylamine, quinine, and benzylamine) were found to have pH-sensitive tissue to blood concentration ratios. Of these, tritiated nicotine appears to be the nost satisfactory indicator of tissue pH and values for the pH of the pulmonary extravascular space (pHe) have been calculated from the nicotine data. At an arterial pH (pHart) between 7.38 and 7.43 pHe averaged 6.69 ±0.07.
Richard M. Effros, Francis P. Chinard
Analyses of key glycolytic intermediates in freshly drawn red cells from six related individuals suggest that decreased hexokinase activity underlies the hemolytic process in the two members with overt hemolysis. Low red cell glucose 6-phosphate (G6P) was observed not only in the anemic patients but in the presumptive heterozygotes as well and served as a useful marker for the presence of the trait. Hexokinase activity was labile in distilled water hemolysates but was only slightly low when protected by glucose, mercaptoethanol, and ethylenediaminetetraacetate (EDTA). Normal red cell hexokinase was demonstrated to be dependent on glucose for maintenance of activity after heating to 45°C. The cells of the proposita are unable to utilize glucose efficiently at glucose concentrations lower than 0.2 mmole/liter whereas normal cells maintain linear glucose consumption to at least 0.05 mM glucose. These qualitative abnormalities could result from the presence of a mutant hexokinase with an abnormally reactive sulfhydryl group and altered substrate affinity in the red cells of this kindred.
Alan S. Keitt
Left ventricular end diastolic (LVEDP) and mean right atrial (RAP) pressures were recorded simultaneously in 30 patients with shock (14 acute myocardial infarction, 10 acute pulmonary embolism or severe bronchopulmonary disease, and 6 sepsis). Myocardial infarction was characterized by a predominant increase in LVEDP, pulmonary disease by a predominant increase in RAP, and sepsis by a normal relationship between LVEDP and RAP. In all three groups a significant positive correlation was noted between RAP and LVEDP, with the regression line in cor pulmonale deviated significantly toward the RAP axis and the regression line in myocardial infarction exhibiting a zero RAP intercept at an elevated LVEDP.
Jay N. Cohn, Felix E. Tristani, Ibrahim M. Khatri
Blockade of cardiac autonomic nervous activity by an intravenous injection of 0.2 mg/kg propranolol and 0.04 mg/kg atropine was used with cardiac catheterization to study intrinsic cardiac function in 47 patients with normal hearts and known graded myocardial disease. After blockade, significant hemodynamic abnormalities became apparent at rest in the majority of patients with known disease, many of whom had normal control findings. This occurred partly through a reduction in the normal range of cardiac function at rest, and partly through changes in the abnormalities associated with disease: after blockade, diseased hearts had normal stroke volumes, but beat more slowly, and had higher left ventricular filling pressures. The heart rate after blockade was fixed; this was defined as the intrinsic heart rate (IHR); it ranged from 57 to 126 beats/min in different patients. Both the IHR and left ventricular end-diastolic pressure after blockade were sensitively and quantitatively related to the severity of myocardial disease. When, after blockade, arterial pressure was raised by angiotensin, the IHR was unchanged; normal hearts maintained their stroke volume and increased stroke work; diseased hearts maintained stroke volume less well and stroke work was unchanged or fell. Abnormal ventricular responses corresponded well with abnormal ventricular function at rest.
Anthony D. Jose, Roger R. Taylor
Isolation of the liver from the circulation of rats eliminates almost completely their ability to convert [1,2]-3H vitamin D3 into its biologically active metabolite, 25-hydroxycholecalciferol, as well as certain other metabolites. It is concluded that the liver is the major if not the only physiologic site of hydroxylation of vitamin D3 (cholecalciferol) into 25-hydroxycholecalciferol.
G. Ponchon, A. L. Kennan, H. F. DeLuca
The effect of oral folic acid on jejunal glycolytic enzyme activity in five fasting obese patients and in three normal male volunteers on a constant 3000 cal diet was studied. The glycolytic enzymes, fructokinase, hexokinase, glucokinase, fructose-1-phosphate aldolase, and fructose diphosphate aldolase, and the disaccharidases, sucrase, maltase, and lactase were measured.
Norton S. Rosensweig, Robert H. Herman, Fred B. Stifel, Yaye F. Herman
Pituitary and gonadal function was studied in seven chromatin-negative men, ages 15-27 yr, with retarded sexual and somatic development, skeletal anomalies, and hyposmia. These hyposmic patients were compared with normal men, prepuberal boys and hypogonadal patients with hypopituitarism. The urinary follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels of hyposmic subjects were the same as those of normal boys and hypopituitary patients but significantly lower than those of normal men. Clomiphene citrate did not cause an increase in plasma FSH and LH levels in either hypogonadal group as it does in normal men. In contrast to hypopituitary patients, thyroid and adrenocortical function and release of growth hormone in the hyposmic subjects were normal. The plasma testosterone levels were equally low in prepuberal, hypopituitary, and hyposmic patients but were increased to a greater extent by human chorionic gonadotropin (HCG) treatment in prepuberal and hypopituitary subjects than in the hyposmic patients. Prolonged treatment with HCG has failed to return plasma testosterone levels to normal in two hyposmic patients. These observations suggest that there are defects of both pituitary and Leydig cell function in men with the syndrome of hypogonadism, skeletal anomalies, and hyposmia. They have impaired secretion of FSH and LH and a Leydig cell insensitivity to gonadotropin.
C. Wayne Bardin, Griff T. Ross, Arleen B. Rifkind, Charles M. Cargille, Mortimer B. Lipsett
A minor hemoglobin (Hb) component with the electrophoretic properties of the δ-chain variant Hb A2′ was encountered in two unrelated families of Russian-Jewish ancestry. This minor component, designated Hb NYU, was shown to result from the substitution of lysine for asparagine at δ12. We have confirmed studies of others that hemoglobin A2′ isolated from the hemoglobin of some African subjects, results from the replacement of the normal glycine at δ16 by arginine. Thus for interpretations of the incidence of δ-chain variants in different populations, electrophoretic data are not sufficient.
Helen M. Ranney, Alan S. Jacobs, Bracha Ramot, Thomas B. Bradley Jr.
The interconversion and extraction of testosterone and androstenedione across and within different tissues or areas have been studied by the constant infusion technique. The results were calculated using the 3H/14C ratios and radioactive concentrations of testosterone and androstenedione obtained from afferent and efferent blood and tissues at equilibrium. In each tissue studied, the interconversion between testosterone and androstenedione inside the tissue was significantly higher than the corresponding interconversion across the tissue. The pulmonary contribution to the total interconversion between testosterone and androstenedione was far more important than that of any of the other tissues studied. The hepatic metabolic clearance rates of testosterone and androstenedione were not different from their metabolic clearance rates in the mesenteric area. The extraction of each of these compounds, although not negligible, was lower in the kidney and the femoral bed compared with the extraction in the liver and the mesenteric area. Finally, with the possible exception of the liver, testosterone and androstenedione were more completely metabolized when they originated from the cells than from afferent blood.
The transport of plasma albumin and newly made albumin into ascitic fluid was studied in eight patients with cirrhosis and ascites. The thoracic duct was cannulated in two patients and lymph collected over a period of 2 hr. Simultaneously albumin-131I and carbonate-14C were injected intravenously. The albumin-131I measured the transfer of plasma albumin into ascites and into thoracic duct lymph. The carbonate-14C, by labeling newly formed albumin, permitted the estimation of the transfer of newly formed albumin into plasma, ascites, and lymph.
D. S. Zimmon, M. Oratz, R. Kessler, S. S. Schreiber, M. A. Rothschild
The transport of endogenous lipids in the lipoproteins of mesenteric lymph was studied in fasting rats with mesenteric lymph fistulas. The lymph was found to contain, in addition to chylomicrons (Sf >400), a significant amount of another, more dense, triglyceride-rich fraction, the very low density lipoproteins (VLDL), which showed a peak Sf of 102. The VLDL differed from chylomicrons not only in flotation, but also in per cent lipid composition and electrophoretic mobility in agarose gel. The VLDL fraction was found to contain 47% of the triglyceride and 54% of the cholesterol of fasting lymph and, in the fasting state, was the major lipoprotein species present.
Robert K. Ockner, Faith B. Hughes, Kurt J. Isselbacher
The transport of vitamin E (α-tocopherol) has been studied in the rat erythrocyte in vivo and in vitro. Uptake and efflux are independent of energy, but sensitive to temperature. Tocopherol is localized to the cell membrane. Rapid exchange takes place between erythrocytes and serum with an hourly fractional tocopherol efflux of 26%. The vitamin is transferred from the erythrocyte to the low density lipoproteins. These experiments indicate that tocopherol, like cholesterol, is a constituent of the erythrocyte membrane which is in dynamic equilibrium with the corresponding plasma compound.
R. Silber, R. Winter, H. J. Kayden
The effect of large doses of glucocorticoids on thyrotropin (TSH) secretion in normal and hypothyroid humans has been studied. Plasma TSH concentrations were measured before, during, and after treatment with dexamethasone given orally for 24-48 hr. In 17 patients with primary hypothyroidism, plasma TSH levels fell significantly during treatment to a mean of 54% of control (range 23-96%). Within 48 hr after the withdrawal of dexamethasone, TSH concentrations transiently increased above pretreatment values. The mean increase was to 156% of control (range 106-294). Similar changes, but of smaller magnitude, were observed in 15 normal subjects. Administration of single oral doses of dexamethasone and oral or intravenous doses of cortisol were followed by reduction of plasma TSH levels to 18-47% of control within 8-12 hr in eight hypothyroid patients. This fall also was followed by significant TSH rises above control values before they returned to the pretreatment levels. Mineralocorticoid administration was not followed by any changes in plasma TSH concentrations in three subjects.
John F. Wilber, Robert D. Utiger
An enzyme which degrades native collagen at neutral pH has been isolated from cultures of rheumatoid synovium in vitro, but little or no collagenolytic activity has been found in homogenates of fresh rheumatoid synovium. Similar to most other mammalian collagenases this synovial enzyme is readily inhibited by serum proteins. Proteins of synovial fluid are derived largely from serum and synovial fluid from noninflamed joints was found to inhibit synovial collagenase; the inhibitor was destroyed by trypsin, but not by hyaluronidase. Inhibitory activity was reduced in approximately one-half of the fluids from patients with rheumatoid arthritis. In a total of nine synovial fluids, collagenolytic activity was detectable. This activity was not present in constant amounts in synovial fluids aspirated at different times from the same patient and tended to vary inversely with the titer of inhibitory proteins. The collagenolytic activity in the synovial fluids from different patients was variably inhibited by serum proteins. Two distinct collagenases were detected in some rheumatoid synovial fluids and separated by gel filtration. One, labeled “B” enzyme, with an estimated molecular weight 20,000-25,000 resembled the collagenase obtained from synovial cultures. The other, labeled “A” enzyme degraded collagen fibrils as well as collagen in solution. Disc electrophoresis on acrylamide gels and electron microscopy of segment long spacing (SLS) aggregates of reaction products of the enzymes at 27°C demonstrated that both “A” and “B” enzymes cleaved collagen molecules at a point three-quarters from the amino terminal end of the molecule. Thus collagen degradation in rheumatoid arthritis could result from the operation of these two collagenases.
Edward D. Harris Jr., Donald R. DiBona, Stephen M. Krane
Washed human platelets were incubated with radioactive glycerol; the platelets were able to synthesize de novo the major phosphoglycerides including phosphatidic acid, phosphatidylinositol, phosphatidyl choline, phosphatidyl ethanolamine, and phosphatidyl serine. The specific activities of the phosphoglycerides obtained after glycerol incorporation indicate that phosphatidic acid, phosphatidylinositol, and phosphatidyl choline are metabolically active relative to phosphatidyl ethanolamine and that formation of phosphatidyl serine occurs to a much more limited extent. When platelets were incubated with bovine thrombin, 1 U/ml, the pattern of glycerol incorporation into phospholipid was changed. There was a 3-fold decrease in the total incorporation into lipid in 30 min with a relative 5-fold decreased incorporation into phosphatidyl choline and phosphatidyl ethanolamine and a 5-fold increased incorporation into phosphatidyl serine. The increased incorporation into phosphatidyl serine. The increased incorporation into phosphatidyl serine was maximal within the first 2 min but was transient, since within 20 minutes, the rate returned to that seen in platelets incubated with glycerol alone. Purified human thrombin also produced this same effect on phospholipid synthesis in platelets. Trypsin produced effects on phosphoglyceride formation similar to those seen with thrombin, and the trypsin-induced effect was inhibited by prior incubation of trypsin with soybean trypsin inhibitor, suggesting that proteolysis may be required for the observed effects on phospholipid synthesis.
Nancy Lewis, Philip W. Majerus
The body weight of rats was reduced by exercise or by restriction of food intake over a period of 18 wk. Body composition was studied to determine if exercise protects against the loss of lean tissue that can occur as a result of a negative caloric balance.
Lawrence B. Oscai, John O. Holloszy
The relationship between the dose of intravenously administered streptozotocin (a N-nitroso derivative of glucosamine) and the diabetogenic response has been explored by use of the following indices of diabetogenic action: serum glucose, urine volume, and glycosuria, ketonuria, serum immunoreactive insulin (IRI), and pancreatic IRI content. Diabetogenic activity could be demonstrated between the doses of 25 and 100 mg/kg, all indices used showing some degree of correlation with the dose administered. Ketonuria was only seen with the largest dose, 100 mg/kg. The most striking and precise correlation was that between the dose and the pancreatic IRI content 24 hr after administration of the drug, and it is suggested that this represents a convenient test system either for both related and unrelated beta cytotoxic compounds or for screening for modifying agents or antidiabetic substances of a novel type. Ability to produce graded depletion of pancreatic IRI storage capacity led to an analysis of the relationship between pancreatic IRI content and deranged carbohydrate metabolism. Abnormal glucose tolerance and insulin response were seen when pancreatic IRI was depleted by about one-third, while fasting hyperglycemia and gross glycosuria occurred when the depletion had reached two-thirds and three-quarters, respectively. The mild yet persistent anomaly produced by the lowest effective streptozotocin dose, 25 mg/kg, exhibits characteristics resembling the state of chemical diabetes in humans and might thus warrant further study as a possible model. Finally, the loss of the diabetogenic action of streptozotocin by pretreatment with nicotinamide was confirmed and was shown to be a function of the relative doses of nicotinamide and streptozotocin and of the interval between injections.
Alain Junod, André E. Lambert, Werner Stauffacher, Albert E. Renold
Patients with acute leukemia were given repeated cycles consisting of infusions of methotrexate followed by “rescue” with folinic acid. Peripheral blood leukemic cells were harvested from patients before cyclical treatment, and the rates of incorporation of thymidine and of deoxyuridine into deoxyribonucleic acid (DNA) were measuared in vitro. There was no relationship between the pretreatment incorporation of either deoxynucleoside into DNA and the clinical response to therapy. Methotrexate suppressed deoxyuridine incorporation into DNA by the leukemic blasts in vitro, but the patients whose cells were most sensitive to this effect did not necessarily go into remission when treated.
William M. Hryniuk, Joseph R. Bertino
Two hepatic cytoplasmic protein fractions, designated Y and Z, which bind sulfobromophthalein (BSP), bilirubin, and other organic anions, have been separated by G75 Sephadex gel filtration. The physiologic role of these protein fractions has been investigated. They are present in the 110,000 g supernatant fraction from the livers of all the species tested (rats, mice, guinea pigs, Rhesus monkeys, sheep, and man). Tissues which do not preferentially extract BSP or bilirubin from plasma do not contain these fractions, with the exception of small intestinal mucosa which contains Z. Anion binding by Y and Z fractions is not due to contamination with albumin. These fractions are responsible for the cytoplasmic localization of bilirubin in Gunn rats, and the fractions bind bilirubin, BSP, or indocyanine green (ICG), whether given in vivo or added in vitro to liver supernate from normal rats. Flavaspidic acid-N-methylglucaminate, bunamiodyl, and iodipamide, drugs known to interfere with the hepatic uptake mechanism, compete with bilirubin and BSP for binding to Z. These proteins appear to be important in the transfer of organic anions from plasma into the liver and provide a tool for the investigation of hepatic uptake mechanisms.
A. J. Levi, I. M. Arias
The formation of tissue iodoproteins during the peripheral metabolism of the thyroid hormones was examined by determining the concentration of nonethanol-extractable 125I (NE125I) in various tissues after the intravenous injection of 3,5,3′-triiodo-L-thyronine (T3-125I) and L-thyroxine-125I (T4-125I) in groups of rats with iodide-blocked thyroid glands. 3 days after T3-125I and 7 days after T4-125I injection the concentration of NE125I in the liver and kidney was 5-10 times greater than in plasma. Smaller but nonetheless significant concentrations of NE125I were demonstrated in skeletal and cardiac muscle. Hepatic subcellular fractionation studies revealed that the major portion of the liver NE125I was in the microsomal fraction. Lower concentrations of NE125I were present in the nuclear, mitochondrial, and soluble fractions. When similar studies were performed in groups of rats pretreated with phenobarbital, an increase in the metabolic clearance of T3-125I (30%) and T4-125I (100%) was observed along with a highly significant increase in the NE125I concentration of the liver and plasma. The increase in hepatic NE125I in these studies was primarily due to the microsomal component.
Martin I. Surks, Harold L. Schwartz, Jack H. Oppenheimer
This report describes studies of bilirubin kinetics in 13 healthy young adults. The plasma content of unconjugated bilirubin-14C was determined at frequent intervals for 24-30 hr after the intravenous injection of a tracer dose of unconjugated isotopic bilirubin. Fecal and urinary radioactivity were measured for 7 days. During this time cumulative recovery averaged 96% of the injected dose. The plasma curves were processed by digital computer. For the 30 hr experimental period, a sum of three exponentials, with average half-times of 18, 81, and 578 min, was required to describe the data. Using the plasma curve integral method, the hepatic bilirubin clearance (47 ±10 ml/min, mean ±SD), the bilirubin production rate (3.8 ±0.6 mg/kg per day), and the mean red blood cell life span (101 ±13 days) were calculated directly from the parameters of this function. To gain further insight into the metabolism of unconjugated bilirubin, the data were also used to determine the parameters of a multicompartmental model. In the model proposed, plasma unconjugated bilirubin exchanges with two additional pools one of which is thought to represent extrahepatic extravascular, and the other intrahepatic unconjugated bilirubin. Bilirubin is eliminated from the system via the proposed intrahepatic pool. From the data and the model, pool sizes and exchange rates between compartments were calculated, and the liver: plasma concentration gradient estimated. These studies provide a detailed analysis of the kinetics of unconjugated bilirubin in a healthy normal population and are intended to serve as a reference point for studies of abnormal states.
Paul D. Berk, Robert B. Howe, Joseph R. Bloomer, Nathaniel I. Berlin