Showing papers by "Vanderbilt University published in 1971"

Factors affecting mortality of gram-negative rod bacteremia.

Abstract: A retrospective analysis of 218 patients with gram-negative rod bacteremia was made in order to evaluate factors affecting survival of these patients. In patients with comparable underlying disease, no significant increase in mortality was found to be associated with race, sex, hospital service, level of leukocyte count, hospital-acquired infection, or the portal of entry of infection. Factors associated with an increased mortality from gram-negative rod bacteremia were shock, azotemia, Pseu- domonas bacteremia, and low or normal temperature during bacteremia. Appropriate antibiotic therapy significantly increased survival of all patients except those with the most severe underlying disease. A combination of antibiotics including colistimethate sodium, kanamycin sulfate, and penicillin, or its congeners, provided effective antimicrobial therapy against a higher percent of bacterial strains causing bacteremia than other drug regimens used during the period of this study.

The role of cyclic amp in the interaction of glucagon and insulin in the control of liver metabolism

Abstract: It is now well established that insulin exerts direct effects on mammalian liver to inhibit the production of glucose and urea and to promote the uptake of potassium ions. It has been proposed that these effects of insulin may be partly due to a decrease in liver cyclic AMP.l The proposal is based on the following observations: ( 1) insulin produces a small but significant decrease in the level of cyclic AMP in the perfused rat liver; (2) depletion of insulin in vivo by treatment with insulin antiserum or alloxan results in a twofold increase in liver cyclic AMP; (3) exogenous cyclic AMP and hormones such as glucagon and epinephrine which raise the level of cyclic AMP produce effects on the liver which are opposite to those caused by insulin; (4) insulin antagonizes the actions of epinephrine, glucagon, or cyclic AMP in the perfused liver; and ( 5 ) insulin reduces the accumulation of liver cyclic AMP in the presence of glucagon. In this article we will present more recent observations on the interaction of glucagon, epinephrine, and insulin in the control of hepatic metabolism. The investigations have employed the isolated rat liver perfused by a modification of the technique of Mortimore.* The perfusion medium consisted of Krebs-Henseleit bicarbonate buffer containing 3 % bovine albumin and 20% bovine erythrocytes. Livers were from fed rats weighing 100-150 g and the perfusion flow rate was about 7 ml per minute. The perfusions were carried out in two ways. In most cases, livers were perfused for one hour with recirculating medium and hormones were infused into the portal vein at a constant rate. In these experiments, the hormone concentrations were calculated by dividing the quantity of hormone infused during the hour by the final volume of perfusate. Since this does not allow for degradation of hormone, the values are doubtlessly overestimated. In the second type of experiment livers were perfused initially for 20 minutes with recirculating media containing no additions in order to establish steady metabolic rates and levels of cyclic AMP. The perfusion system was then changed to one with nonrecirculating medium by diverting the perfusate leaving the liver into a beaker. After a six-minute control period, infusions of hormone were commenced and livers and effluent media were sampled at designated intervals. In these experi-

Cyclic adenosine monophosphate in brain areas: microwave irradiation as a means of tissue fixation.

Abstract: Amounts of cyclic adenosine monophosphate in discrete regions of the brain were estimated after exposure of rats to microwave irradiation. Amounts were highest in the cerebellum and brainstem, intermediate in the hypothalamus and midbrain, and lowest in the hippocampus and cortex. Decapitation increased the concentration of cyclic adenosine monophosphate in all brain areas, although the increase in the cerebellum was three to four times greater than that in other areas. Microwave irradiation may provide a means of rapidly fixing brain tissue in situ while permitting easy dissection of the brain. In this way artifacts produced by decapitation can be eliminated, and concentrations of heat-stable compounds in the brain can be estimated under conditions which more closely approximate those in vivo.

The role of adenosine 3':5'-cyclic monophosphate in the regulation of insulin release by isolated rat islets of Langerhans.

Abstract: 1. Concentrations of cyclic AMP (adenosine 3′:5′-cyclic monophosphate) and rates of insulin release were measured in islets of Langerhans isolated from rat pancreas and incubated for various times in the presence of glucose, 3-isobutyl-1-methylxanthine, caffeine, theophylline, adrenaline and diazoxide. 2. Caffeine and theophylline produced small but significant increases in both cyclic AMP and release of insulin when they were incubated in the presence of 10mm-glucose. 3. 3-Isobutyl-1-methylxanthine produced a marked increase in the intracellular concentration of cyclic AMP in the presence of 5mm- and 10mm-glucose. However, insulin release was stimulated only in the presence of 10mm-glucose. 4. In response to rising concentrations of extracellular glucose (5–20mm) there was no detectable increase in the intracellular concentration of cyclic AMP even though there was a marked increase in the rate of insulin release. 5. In response to 10mm-glucose insulin release occurred in two phases and 3-isobutyl-1-methylxanthine potentiated the effect of glucose on both phases. The intracellular concentration of cyclic AMP remained constant with glucose and rose within 10min to its maximum value with 3-isobutyl-1-methylxanthine. 6. Adrenaline and diazoxide inhibited insulin release and lowered the intracellular concentration of cyclic AMP when islets were incubated with glucose or 3-isobutyl-1-methylxanthine. 7. It is suggested that glucose does not stimulate insulin release by increasing the concentration of cyclic AMP in islet cells. However, the concentration of cyclic AMP in islet cells may modulate the effect of glucose on the release process.

Tissue differences in antigenic properties of non-histone protein-DNA complexes

Abstract: THAT DNA and histones are not tissue specific1,2 implies that other components of chromatin may be responsible for the tissue specific control of eukaryotic gene expression. We now report studies of the antigenic properties of non-histone protein-DNA complexes isolated in an undissociated state from native chromatin and compare these with the properties of native chromatin. Because DNA is a very weak immunogen3, the antigenic determinants in these preparations should be principally caused by the protein components.

A man-machine approach toward solving the traveling salesman problem

Abstract: The traveling salesman problem, (form a circuit through N points with no subloops in such a way as to minimize the length of the circuit), is a close kin to many board wiring problems. It has been attacked by many mathematical methods with only meager results. Only for special forms of the problem or for problems with relatively few points can it be solved exactly even using very large amounts of computer time. Heuristic procedures have been proposed and tested with only slightly better results. This paper will describe a computer-aided heuristic technique which uses only a modest amount of computer time in real time to solve large (100-200) point problems. This technique takes advantage of both the computer's and the human's problem solving abilities. The computer is not asked to solve the problem in a brute force way as is the case in many of today's heuristics but it is asked to organize the data for the human in a fashion that allows the human to solve the problem easily.The techniques employed in this paper require that the computer and the human cooperate to find the solution to the problem in reasonable amounts of both of their times. The computer initially uses a series of heuristics that produce groups of points and some partial connections of these points. The human is asked to connect the points within the groups and then connect the groups in a manner that produces a circuit and appears to the human to maximize the ratio of enclosed area to perimeter. The computer takes this solution and uses another set of heuristics to make improvements. The solution is displayed to the human and if he is satisfied the procedure stops; if not the former procedure is repeated until the human is satisfied that cost for finding a better solution exceeds his estimate of the best possible improvement that could be obtained by further work. The heuristic procedures seek to group points around information obtained from solving a series of mathematical programming problems (assignment problems) and some observed correlations between these problems and the traveling salesman problem.The results are very good. The man-machine interaction solution for all problems in the literature is within one per cent of the solution for a fraction of the computer time. The experience to date indicates that the technique can be taught to inexperienced persons and their results, after training, are similar to those of the authors'.

Dissociation of the Disappearance of Bioactive and Radioimmunoreactive ACTH from Plasma in Man

Abstract: The disappearance of ACTH from human blood in vivo and in vitro has been measured simultaneously by bioassay and by radioimmunoassays using 2 antisera, one directed against the N-terminal steroidogenic portion of the ACTH molecule, the other directed against the C-terminal portion. Bioactive ACTH disappeared from the circulation faster than immunoreactive ACTH in normal subjects given either single injections or 6-hr infusions of ACTH. A similar dissociation between bioactivity and immunoreactivity was seen in vitro when ACTH was incubated in blood, plasma or plasmin solution. Disappearance of added ACTH was faster from whole blood and from frozenthawed plasma than from fresh plasma. The enzyme inhibitor Trasylol slowed the disappearance of both bioactive and immunoreactive ACTH. C-terminal ACTH immunoreactivity disappeared more slowly than N-terminal ACTH immunoreactivity. High-speed centrifugation prior to freezing or heat inactivation after freezing, addition of sodium edetate, or incubation a...

The formation and metabolism of cyclic GMP.

Abstract: Cyclic guanosine 3',5'-monophosphate (cyclic GMP) is the only cyclic nucleotide other than cyclic adenosine 3',5'-monophosphate (cyclic AMP) known to occur naturally. Despite the wealth of information about the role of cyclic AMP in mammals and in lower phyla, little or nothing is known about the function of cyclic GMP, although it has been over seven years since its identification in nature.' Levels of cyclic GMP in urine,2-R p l a ~ m a , ~ ~ and tissues *-12 have been studied under a number of conditions, and it is clear that levels of cyclic GMP and cyclic AMP can be changed either independently of each other or in opposite directions. Cyclic GMP levels in human urine and plasma were increased by the administration of calcium,6 high doses of parathyroid or alpha adrenergic agent^,^ and its levels in perfused hearts were elevated by acetyl choline.I0 Except for parathyroid hormone, these agents either did not elevate or lowered cyclic AMP levels. Cyclic GMP is generally about two orders of magnitude less potent than cyclic AMP in stimulating the activity of protein kinases in cell-free systems.13-16 This and the fact that its tissue levels are generally about 10% of those of cyclic AMP R--12 make it very unlikely that cyclic GMP is a physiologic substitute for cyclic AMP. A protein kinase with a relative specificity for cyclic GMP has been identified,'; but its natural substrate and function are unknown. Exogenous cyclic GMP can effectively reproduce a number of effects of cyclic AMP in the perfused liver,lR-*O but this seems to be due to its ability to accumulatt within the liver in much higher amounts than cyclic AMP and thus is of doubtful physiological importance.20 High concentrations of exogenous cyclic GMP can lead to an elevation of intracellular cyclic AMP in some tissues, presumably by inhibiting phopshodiesterase.21 The physiologic relevance of this effect of cyclic GMP also is questionable since the existence of such concentrations under natural circumstances is highly improbable. These and other aspects of cyclic GMP have been reviewed elsewhere.Z223

Extracellular cyclic nucleotides.

Abstract: The actions of a wide variety of hormones are mediated by alterations in the intracellular levels of cyclic AMP in the target tissues responding to the hormones.?\" The second messenger function of cyclic AMP is discussed in detail elsewhere in this volume. The biological role of cyclic GMP, the other naturally occurring cyclic nucleotide, has not yet been determined. In recent years, considerable interest has developed in studying the levels of cyclic AMP and cyclic GMP in extracellular fluids. The increasing interest in this field has been largely for the following reasons: 1. Occurrence. Cyclic AMP was first identified extracellularly in human urine in 1962.20 Cyclic GMP was found in urine a year later, representing the initial discovery of this compound in nature.4 As discussed later, the presence of one or both nucleotides has now been observed in a large number of extracellular fluids (biologic fluids and secretions, incubation and perfusion media, culture broths, et cetera) . 2. Relation to intracellular levels. Changes in extracellular levels of the cyclic nucleotides have been shown to reflect alterations in intracellular levels of the compounds in response to a variety of endocrinologic and other manipulations (see below), and this finding has been found useful in in vitro as well as in in vivo studies. 3 . Regulation of intracellular concentration. The translocation of cyclic AMP into the extracellular space might serve as a means of terminating its metabolic activity. It is probable that the extrusion of cyclic AMP by several strains of E. coli functions in this regard; 5 5 . 64 evidence on this point in other systems is lacking. 4. Extracellular function. Cyclic AMP appears to serve as an extracellular messenger or chemotactic agent in one or more species of cellular slime mold, mediating cell aggregation and perhaps aiding in food seeking.6, 48. 4*--1O However in no other system studied has a physiological role for extracellular cyclic nucleotides been identified, and the very large quantities of extracellular cyclic AMP required to produce physiological responses in intact mammalian tissues would make such a role appear unlikely in higher organisms.

Evidence of safety of long-term, high, oral doses of DDT for man.

Abstract: Twenty-four volunteers ingested technical or p,p′-DDT at rates up to 35 mg per man per day for 21.5 months. They were then observed for an additional 25.5 months, and 16 were followed up for five years. Storage of DDT and DDE and excretion of DDA were proportional to dosage. The fat of those receiving technical insecticide at the highest rate contained 105 to 619 ppm of DDT when feeding stopped. The average dosage of p,p′-DDT administered in this study was 555 times the average intake of all DDT-related compounds by 19-year-old men in the general population and 1,250 times their intake of p,p′-DDT. Since no definite clinical or laboratory evidence of injury by DDT was found in this study, these factors indicate a high degree of safety of DDT for the general population.