On the role of 5-hydroxytryptamine in the peripheral action of fenfluramine: studies with the isolated rat soleus muscle.
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Animals↗
Biomedical subjects
C Nathan
Publications and source records attributed to C Nathan.
Tumor necrosis factor and CD11/CD18 (beta 2) integrins act synergistically to lower cAMP in human neutrophils.
The ability of neutrophils (PMN) to undergo a prolonged respiratory burst in response to cytokines such as tumor necrosis factor-alpha (TNF) depends on expression of CD11/CD18 (beta 2) integrins and interaction with matrix protein-coated surfaces (Nathan, C., S. Srimal, C. Farber, E. Sanchez, L. Kabbash, A. Asch, J. Gailit, and S. D. Wright. 1989. J. Cell Biol. 109:1341-1349). We tested the hypothesis that changes in cAMP mediate the joint action of cytokines and integrins. When plated on FBS- or fibrinogen-coated surfaces, PMN responded to TNF with a sustained fall in intracellular cAMP. This did not occur without TNF; in suspended PMN; in PMN treated with anti-CD18 mAb; or in PMN genetically deficient in beta 2 integrins. A preceding fall in cAMP appeared essential for TNF to induce a respiratory burst, because drugs that elevate cAMP blocked the burst if added any time before, but not after, its onset. Adenosine analogues and cytochalasins also block the TNF-induced respiratory burst if added before, but not after, its onset. Both also blocked the TNF-induced fall in cAMP. The effect of cytochalasins led us to examine the relationship between cAMP and actin reorganization. The same conditions that led to a sustained fall in cAMP led at the same time to cell spreading and the assembly of actin filaments. As with the respiratory burst, cAMP-elevating agents inhibited TNF-induced cell spreading and actin filament assembly if added before, but not after, spreading began. Thus, occupation of TNF receptors and engagement of CD18 integrins interact synergistically in PMN to promote a fall in cAMP. The fall in cAMP is closely related to cell spreading and actin reorganization. These changes are necessary for TNF to induce a prolonged respiratory burst. We conclude that integrins can act jointly with cytokines to affect cell shape and function through alterations in the level of a second messenger, cAMP.
1-Methyl-3-isobutylxanthine↗
Pilot trial of selective decontamination for prevention of bacterial infection in an intensive care unit.
Selective decontamination of the oropharynx and gastrointestinal tract with nonabsorbable antimicrobials and sucralfate, a stress ulcer prophylactic that maintains the normal gastric acid bacterial barrier, were compared for prevention of pneumonia in a cardiac surgery intensive care unit. Over 8 months, 51 patients received selective decontamination and 56 received sucralfate. The selective decontamination regimen included polymyxin, gentamicin, and nystatin given as an oral paste and as a solution; patients also received standard antacid or histamine2 blocker stress ulcer prophylaxis. Patients in the selective decontamination group had significantly less colonization of the oropharynx and stomach by gram-negative bacilli (12% vs. 55%, P less than .001), significantly fewer infections due to gram-negative bacilli (6% vs. 20%, P = .02), and fewer infections overall (12% vs. 27%, P = .04). There was one episode of pneumonia in the selective decontamination group and five in the sucralfate group. Mortality and length of stay did not differ between the groups, but those receiving selective decontamination had less than one-third as many days of systemic antibiotic therapy with no increase in colonization or infection with resistant gram-negative bacilli. Thus, selective decontamination appeared to reduce both extrapulmonary and pulmonary infections.
Anti-Bacterial Agents↗
Transfusion-associated acute Chagas disease acquired in the United States.
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Acute Disease↗
Failure of fenfluramine to affect basal and insulin-stimulated hexose transport in rat skeletal muscle.
Fenfluramine is an effective appetite suppressant that mediates its action via serotoninergic neurons. We studied the effect of pure d- and l-fenfluramine on in vitro hexose transport in isolated rat soleus muscles and skeletal muscle cells in culture. We found no evidence to suggest that the fenfluramine enantiomers affect the basal transport activity. Furthermore, the drugs did not interfere with the ability of glucose to regulate its own transport. Muscle responsiveness to insulin was not altered by the enantiomers, nor did insulin unmask any effect of fenfluramine on muscle hexose transport. These conclusions are based on experiments performed with a wide concentration range of drug and insulin, from the therapeutic to suprapharmacological levels. We discuss our results in view of published data on the effects of fenfluramine on peripheral glucose metabolism.
Animals↗
Comparison of transforming growth factor-beta and a macrophage- deactivating polypeptide from tumor cells. Differences in antigenicity and mechanism of action.
A factor in medium conditioned by mouse tumor cells was shown previously to suppress the capacity of mouse peritoneal macrophages to undergo a respiratory burst and to kill protozoal pathogens (macrophage deactivation factor, MDF). Recently, pure transforming growth factor-beta (TGF-beta) proved to be a potent macrophage deactivator as well. Two lines of evidence suggest that MDF is not identical with TGF-beta. First, rabbit anti-TGF-beta IgG neutralized the respiratory burst-suppressing activity of TGF-beta without affecting the bioactivity of MDF, even when the latter was treated with acid to activate potentially latent TGF-beta. Second, in contrast to MDF, which decreases the affinity of the NADPH oxidase for NADPH, permeabilized macrophages that had been deactivated with TGF-beta displayed the same Km and Vmax of the oxidase as activated macrophages. As with MDF, TGF-beta had no effect on two other potential control points over the secretion of respiratory burst products, namely, hydrogen peroxide catabolism or glucose uptake. Finally, neither MDF nor TGF-beta affected the extent or affinity of binding of phorbol diesters to macrophages, the activity or cofactor requirements for protein kinase C, or the ability of protein kinase C to translocate quantitatively from cytosol to membrane fractions in response to phorbol diesters. Thus, 1) MDF is not identical with TGF-beta, and 2) in contrast to the activation or deactivation of macrophages by numerous other agents, TGF-beta regulates macrophage respiratory burst capacity at a level other than the apparent affinity of the oxidase for its substrate.
Animals↗
Cytokine-induced respiratory burst of human neutrophils: dependence on extracellular matrix proteins and CD11/CD18 integrins.
Human polymorphonuclear leukocytes (PMN) released large quantities of hydrogen peroxide in response to tumor necrosis factor, but only when the cells were adherent to surfaces coated with extracellular matrix proteins. The PMN did not respond when exposed to cytokines and matrix proteins in suspension, or when exposed to cytokines while adherent to surfaces coated with stearic acid. PMN from children with genetic deficiency of the CD11/CD18 integrins underwent a normal respiratory burst upon adherence to uncoated polystyrene, but not in response to tumor necrosis factor when tested on polystyrene that was coated with serum, fibronectin, vitronectin, fibrinogen, thrombospondin, or laminin. Anti-CD18 antibodies, alone of sixteen antibodies tested, induced a similar defect in PMN from normal donors, when the PMN were tested on surfaces coated with serum, fibrinogen, thrombospondin, or laminin; no defect was induced by the anti-CD18 monoclonal antibody IB4 in normal PMN tested on surfaces coated with fibronectin or vitronectin. Thus, for cytokines to induce a respiratory burst in PMN, the cells must be able to use CD11/CD18 integrins and must interact with matrix proteins in the solid phase. CD11/CD18, which is already known to serve as a receptor for fibrinogen, may also be a receptor for thrombospondin and laminin. Finally, receptor(s) exist on PMN for fibronectin and vitronectin which are not blocked by the anti-CD18 antibody IB4 but which are nonetheless CD11/CD18 dependent.
Antibodies↗
The epidemiology of Pseudomonas aeruginosa in oncology patients in a general hospital.
Pseudomonas aeruginosa colonization and infection was studied over a 6-mo period in a 36-bed mixed general medical-oncology unit. We used selective media for serial surveillance cultures on 283 patients, the environment, and personnel. Twelve percent of patients were colonized on admission and 10% acquired P. aeruginosa. Using serotyping and multilocus enzyme electrophoresis, we identified 63 genetically distinctive strains; four prevalent strains accounted for 21% of isolates. Only 5 of 33 nosocomial acquisitions were due to horizontal transmission. Nine acquisitions were linked to environmental sources (e.g., sink surfaces), which often harbored antibiotic-resistant strains but posed a risk only to oncology patients. Although significant Pseudomonas infections occurred in only 11% of colonized patients, 63% of colonized severely neutropenic patients--predominantly those who had acquired the prevalent, often environmentally linked strains--developed infections. Thus, P. aeruginosa was a significant pathogen in oncology patients; typing by multilocus enzyme electrophoresis allowed the detection of important environmental sources.
Female↗
Introduction to Congress and the International Centre of Medicine and Law.
Developments in the practice of medicine and the practice of law have led to an interrelationship between the two. The distinctions between law, ethics and morality are highlighted as characteristic of the people to whom they apply and are further subject to influences consequent on colonisation, political dogma and economics. This is the context in which the International Centre of Medicine and Law has been established in Southern Africa. The Centre's environment is such that it is influenced by both the Old World and the Third World. The value system of the indigenous African people who in Southern Africa make up 90% of the population while respecting human rights, is one of group orientation.
Africa, Southern↗
Patients' rights in a Third World southern African country, with special reference to Bophuthatswana: is there any potential for privatisation?
Patients' rights to medical care, to inviolability without informed consent, and to medical screening tests, for example, are determined by the legal system to which they are subject. The interests of the individual must be weighed against the interests of the society to which he or she belongs, as this must be the criterion used to establish the extent of their rights, if any. The rights of an AIDS patient in a First World country and those of an AIDS patient in a Third World country are bound to differ in extent. The emphasis in the simultaneous duties of the state towards an individual AIDS patient and to society as a whole will differ from state to state. The First and Third World sectors are differentiated with reference to privatisation, and legal forms are touched upon.
Africa, Southern↗
Ethical and legal aspects to death: the burial.
As a form of ritualized behaviour, the burial promotes and maintains the emotional well-being of the individual and the social cohesion of the group. Sources of burial law in Southern Africa are summarized and the present legal situation with regard to burial is given in some detail. Fulton sums up the essence of our subject historically and comparatively as follows: 'Burial of the dead is an ancient practice among men. From paleolithic times to the present, man has responded to the death of his fellow man with solemnity and ceremony. The event of death has evoked not only a religious awe in men, but its threat to the survival of communal life has also engendered fear, just as its disruption of family life has aroused sorrow.'
Attitude to Death↗
Isolation of a complementary DNA clone encoding a precursor to human eosinophil major basic protein.
A 14-kD protein was purified from human PMNs and its NH2-terminal sequence was determined. Comparison of a portion of the NH2-terminal sequence of this protein to the recently reported NH2-terminal sequence of eosinophil major basic protein (MBP) showed them to be identical. To aid further characterization of the structural and functional properties of this molecule, we isolated from an HL-60 cDNA library a single class of cDNA clones whose sequence matched exactly the NH2-terminal amino acid sequence of the 14-kD polypeptide. Northern analysis of HL-60 cells suggests that MBP is constitutively expressed in HL-60 cells and is highly transcribed from a single copy gene. The sequence of the full-length cDNA clones predicts that MBP is synthesized as a 23-kD precursor form (pro-MBP) which is subsequently cleaved to release the mature 14-kD MBP. The putative pro-MBP has a predicted pI of 6.0, but both the charged and the hydrophobic residues are asymmetrically distributed, creating a bipolar molecule. The NH2-terminal half has a predicted pI of 3.7 and is hydrophilic, while the COOH-terminal half (corresponding to mature MBP) has a predicted pI of 11.1 and is hydrophobic.
Base Sequence↗
Deactivation of macrophages by transforming growth factor-beta.
Macrophage activation--enhanced capacity to kill, in a cell that otherwise mostly scavenges--is essential for host survival from infection and contributes to containment of tumours. Both microbes and tumour cells, therefore, may be under pressure to inhibit or reverse the activation of macrophages. This reasoning led to the demonstration of macrophage deactivating factors from both microbes and tumour cells. In some circumstances the host itself probably requires the ability to deactivate macrophages. Macrophages are essential to the healing of wounds and repair of tissues damaged by inflammation. Yet the cytotoxic products of the activated macrophages can damage endothelium, fibroblasts, smooth muscle and parenchymal cells (reviewed in ref. 6). Thus, after an inflammatory site has been sterilized, the impact of macrophage activation on the host might shift from benefit to detriment. These concepts led us to search for macrophage deactivating effects among polypeptide growth factors that regulate angiogenesis, fibrogenesis and other aspects of tissue repair. Among 11 such factors, two proteins that are 71% similar proved to be potent macrophage deactivators: these are transforming growth factor-beta 1 (TGF-beta 1) and TGF-beta 2.
Animals↗
Analysis of the nonfunctional respiratory burst in murine Kupffer cells.
Murine Kupffer cells (KCs), which constitute one of the largest populations of tissue macrophages, differ from most other cells of the myelomonocytic lineage in lacking the capacity for a respiratory burst. A collagenase perfusion technique followed by adherence to plastic at low temperature yielded pure cultures of KCs uniformly expressing receptors for Fc and C3bi, and containing virtually no morphologically detectable intracytoplasmic debris. Such KCs took up and oxidized glucose via the hexose monophosphate shunt about the same as peritoneal macrophages (PCs). Respiratory burst stimuli failed to enhance the hexose monophosphate shunt in KCs, probably because no H2O2 was produced. Detergent-permeabilized KCs generated no O2- in the presence of 1 mM NADPH, in striking contrast to all PC populations studied. Yet, KCs contained at least one component of the O2(-)-producing oxidase, cytochrome b559, in the same quantities as PCs and neutrophils. Cytochrome b559 was demonstrated by a novel double-reduction spectral technique that eliminated interference from hemoglobin and mitochondrial cytochromes. Consistent with the presence of the oxidase, KCs acquired normal respiratory burst capacity after prolonged incubation in vitro. The defect in triggering the respiratory burst in KCs was selective for the reduction of O2 by NADPH, in that reduction of O2 by endogenous arachidonate was readily demonstrate in response to zymosan. The percent of arachidonate released, the percent oxygenated, and the suppression of prostacyclin and leukotriene C production, as well as the pattern of LFA-1 expression, all resembled the pattern reported with PCs several days after exposure to bacteria. Indeed, exposure of PCs to low numbers of zymosan particles led gradually to complete suppression of respiratory burst capacity and refractoriness to its enhancement by rIFN-gamma, as evident in KCs both before and after their explanation. Thus, the modulation of oxidative metabolism that characterizes KCs probably arises from frequent endocytic encounters. This phenomenon may permit macrophages to act as scavengers without oxidative damage to bystander cells.
Animals↗
Ovarian stimulation for in vitro fertilization and GIFT combining administration of gonadotropins and blockade of the pituitary with D-Trp6-LH-RH.
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Administration, Cutaneous↗
Identification of arginine as a precursor of endothelium-derived relaxing factor.
Nitric oxide (NO) is a major endothelium-derived relaxing factor (EDRF) released in response to vasodilating amines, peptides, proteins, ionophores, and nucleotides. EDRF is an important regulator of smooth muscle tone and platelet aggregation and adhesion. Histamine and acetylcholine relax the intact norepinephrine-constricted guinea pig pulmonary artery by an EDRF-dependent mechanism in a medium free of amino acids. N omega-Monomethylarginine (N-MeArg; 0.25 mM) inhibited this relaxation by 64-73%. Inhibition by N-MeArg developed rapidly and was immediately and completely reversed by excess L-arginine but not by D-arginine or by citrulline. N-MeArg did not diminish relaxation induced by nitroprusside, an NO-generating agent, indicating that N-MeArg acts on endothelium rather than on smooth muscle. These observations strongly suggest that, in the intact guinea pig pulmonary artery, EDRF originates from enzymatic action on the guanido nitrogen(s) of an endogenous pool of arginine. This is strikingly similar to the origin of reactive nitrogen intermediates in activated macrophages.
Acetylcholine↗
Ovarian stimulation for in-vitro fertilization combining administration of gonadotrophins and blockade of the pituitary with D-Trp6-LHRH microcapsules: pilot studies with two protocols.
In women undergoing in-vitro fertilization and embryo transfer (IVF-ET), a total of 408 IVF cycles were stimulated using human menopausal gonadotrophin (HMG) or pure follicle stimulating hormone (FSH) plus HMG in combination with a single injection of D-Trp6-LHRH microcapsules in order to enhance the ovarian response to gonadotrophins and to avoid spontaneous LH surges. Sixty-seven pregnancies were achieved. Two protocols were employed. In protocol 1 ('blocking protocol', n = 268), the pituitary was first inhibited with a full dose (3.75 mg) of D-Trp6-LHRH in microcapsules and ovarian stimulation was started after the hypogonadotrophic hypogonadal state was ascertained (E2 less than 50 pg/ml). In protocol 2 ('flare-up protocol', n = 140), the treatment with D-Trp6-LHRH microcapsules (half-dose = 1.80 mg) and the ovarian stimulation with gonadotrophins were started at the same time. Higher doses of gonadotrophins were needed (39.5 +/- 11.2 ampoules FSH and/or HMG) in protocol 1, in which the pituitary was blocked prior to and during the stimulation, than in protocol 2 (20 +/- 9 ampoules) where the exogenous gonadotrophin stimulation appeared to be augmented by the initial agonistic effect of the injection of D-Trp6-LHRH microcapsules. In patients with purely tubal infertility, under 38 years old and no male factor, the results obtained with protocols 1 and 2 were similar in terms of pregnancy rate per cycle or per embryo transfer: 22.6 versus 20.5% and 28.3 versus 27.4%, respectively. However, considering the cost benefit, 'flare-up' protocols appeared to be a better choice and could be recommended.
Adult↗