Cellular and molecular mechanisms of radiation inhibition of restenosis. Part I: role of the macrophage and platelet-derived growth factor

BACKGROUND: Desflurane, enflurane and isoflurane can be degraded to carbon monoxide (CO) by carbon dioxide absorbents, whereas sevoflurane and halothane form negligible amounts of CO. Carbon monoxide formation is greater with drier absorbent, and with barium hydroxide, than with soda lime. The mechanism, role of absorbent composition and water, and anesthetic structures determining CO formation are unknown. This investigation examined sequential steps in anesthetic degradation to CO. METHODS: Carbon monoxide formation from anesthetics and desiccated barium hydroxide lime or soda lime was determined at equimole and equiMAC concentrations. Carbon monoxide formation from deuterium-substituted anesthetics was also quantified. Proton abstraction from anesthetics by strong base was determined by deuterium isotope exchange. A reactive chemical intermediate was trapped and identified by gas chromatography-mass spectrometry. The source of the oxygen in CO was identified by 18O incorporation. RESULTS: Desflurane,enflurane,andisoflurane(difluoromethylethyl ethers), but not sevoflurane (monofluoromethyl ether), methoxyflurane (methy-ethyl ether), or halothane (alkane) were degraded to CO. The amount of CO formed was desflurane > or = enflurane > isoflurane at equiMAC and enflurane > desflurane > isoflurane at equimole concentrations. Proton abstraction from the difluoromethoxy carbon was greater with potassium than with sodium hydroxide, but unmeasurable with barium hydroxide. Carbon monoxide formation was correlated (r = 0.95-1.00) with difluoromethoxy (enflurane > desflurane > isoflurane > or = methoxyflurane = sevoflurane = 0) but not ethyl carbon proton abstraction. Deuterium substitution on enflurane and desflurane diminished CO formation. Chemical trapping showed formation of a difluorocarbene intermediate from enflurane and desflurane. Incorporation of H2(18)O in barium hydroxide lime resulted in C18O formation from unlabeled enflurane and desflurane. CONCLUSIONS: A difluoromethoxy group is a structural requirement for haloether degradation to CO. Results are consistent with initial base-catalyzed difluoromethoxy proton abstraction (potassium > sodium hydroxide, thus greater CO formation with barium hydroxide lime vs. soda lime) forming a carbanion (reprotonated by water to regenerate the anesthetic, hence requirements for relatively dry absorbent), carbanion decomposition to a difluorocarbene, and subsequent difluorocarbene reaction to form CO.     

Parent?×?child socialization: Implications for the development of depressive symptoms.

A Parent?×?Child model of socialization was applied to the development of depressive symptoms. It was expected that when parents used intrusive support frequently, children engaging in negative self-evaluative processes would be more vulnerable to depressive symptoms than children engaging in positive self-evaluative processes. Children in the 5th through 7th grades took part in a 2-wave longitudinal study over 6 months. Parents' use of intrusive support was assessed using reports from children (N?=?806) and mothers (N?=?74). Children's self-evaluative processes and depressive symptoms were assessed using reports from children. The results suggest that both parents and children contribute to the development of depressive symptoms. When parental intrusive support was high, children engaging in negative self-evaluative processes experienced more depressive symptoms over time than did children engaging in positive self-evaluative processes. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Human immunodeficiency virus type 1 in the semen of men receiving highly active antiretroviral therapy

BACKGROUND: Highly active antiretroviral therapy can effectively decrease the levels of human immunodeficiency virus type 1 (HIV-1) virions in peripheral plasma and seminal fluid of infected men. Whether the genital tract of HIV-1-infected men who are receiving highly active antiretroviral therapy and who have no detectable virus in the peripheral plasma harbors replication-competent virus is not known. METHODS: We collected peripheral-blood and semen samples from seven men with HIV-1 infections who were receiving highly active antiretroviral therapy and who had no detectable viral RNA (fewer than 50 copies per milliliter) in plasma and analyzed the samples for cell-associated proviral DNA using a quantitative polymerase-chain-reaction assay. Replication-competent viruses were evaluated by cell-coculture assays. Proviral DNA and replication-competent virus obtained from peripheral-blood and seminal cells were also analyzed by sequencing relevant viral genes. RESULTS: Despite the long-term suppression of HIV-1 RNA in the plasma of the seven men, proviral DNA was detected in seminal cells in four. Replication-competent viruses were recovered from peripheral-blood cells in three men and from the seminal cells in two of these three men. The viruses recovered from the seminal cells had no genotypic mutations suggestive of resistance to antiretroviral drugs and were macrophage-tropic, a feature that is characteristic of HIV-1 strains that are capable of being sexually transmitted. CONCLUSIONS: In HIV-1-infected men who are receiving highly active antiretroviral therapy and who have no detectable levels of viral RNA in plasma the virus may be present in seminal cells and therefore may be capable of being transmitted sexually.     

Effect of cation exchange on dimethyl methylphosphonate permeation kinetics in a pentablock hydrocarbon ionomer and a perfluorocarbon ionomer

The present work is concerned with the effect of cation exchange, with calcium, aluminum and cupric cations, on the permeation kinetics of dimethyl methylphosphonate (DMMP) in a pentablock ionomer (Nexar™) and a perfluoroionomer (Nafion™). The diffusion constant was determined by matching a Fickian solution to early time data, with a zero-time shift, initially attributed to the effect of immobilization. The diffusion time-lag relation was applied in an expanded form to include contributions of immobilization and relaxation. The primary effect of cation exchange was a marked reduction in diffusion constant and introduction of significant relaxation. The effects were explored in a two step procedure in which the sample was first exposed to DMMP vapor at activity 0.6 and then at activity 0.8. In cation modified Nexar at the lower activity the delay in onset of permeation was due solely to immobilization. The delay was absent at the higher activity, indicating that extent of immobilization was unchanged with increased concentration, but approach to steady state was still relaxation controlled. In cation modified Nafion delay in onset of permeation was dominated by relaxation, but kinetics at the higher activity was essentially Fickian. The strong relaxation effects appear to be a consequence of cation modification, which results in a network of ionic crosslinks formed by multivalent cation–sulfonate interactions. The combined analytical and experimental procedure developed in this study provided a systematic set of values for the effect of cation exchange and ionomer characteristics on parameters controlling DMMP permeation kinetics.     

Predicting changes in children's self-perceptions of academic competence: A naturalistic examination of evaluative discourse among classmates.

Classroom discourse was examined as a predictor of changes in children's beliefs about their academic capabilities. Kindergarten, first-grade, and second-grade students (N=106) participated in 2 waves of data collection, approximately 1 year apart. During the 1st year of the study, children's verbal interactions with their classmates were observed and recorded. Children rated their self-perceptions of academic competence during the 1st and 2nd years. Analyses revealed that changes over time in children's competence perceptions could be predicted from the types of statements that children made and had directed toward them by classmates. Examining sequences of child and classmate statements proved helpful in explaining the observed changes in children's perceptions of competence. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Glucocorticoid-mediated inhibition of interleukin-2 receptor alpha and -beta subunit expression by human T cells

We have shown previously that vanadium ions (vanadate and vanadyl) inhibit autophosphorylation of histidine but not that of serine in ATP citrate lyase (ACL). Here we report the results concerning the effect of monovanadate (+ oligomers), decavanadate as well as vanadyl on the activity of ACL of the rat liver. Susceptibility of ACL to inhibition by vanadate was rather low. Vanadate at concentration 10(-4) mol/l inhibited ACL by only 10% and at 10(-3) mol/l concentration monovanadate inhibited ACL by 37%. Decavanadate had comparable potency to inhibit ACL. So was vanadyl which produced 20%, 32% and 66% inhibition at 10(-4) mol/l, 10(-3) mol/l and 10(-2) mol/l concentrations, respectively. From the kinetic data it appears that inhibition by mono- and deca-vanadate of ACL with respect to both ATP and citrate was of competitive nature. Vanadyl inhibited ACL noncompetitively with respect to these substrates. However, all three species of vanadium ions inhibited ACL noncompetitively with respect to CoA. Endogenous (auto)phosphorylation of the ACL histidine as well as its response to vanadate depended on the presence of he substrate (citrate + CoA). The kinetic characteristics of vanadium ions action of ACL was compared with that previously demonstrated for vanadium inhibition of succinyl-CoA synthetase. Plausibility of our hypothesis that inhibition of histidyl phosphorylation at the catalytic site may be a common mechanism by which vanadium ions suppress the activity of the histidyl containing enzymes catalyzing the phosphoryl transfer is discussed.     

Conserved elements containing NF-E2 and tandem GATA binding sites are required for erythroid-specific chromatin structure reorganization within the human beta-globin locus control region

Proper expression of the genes of the human beta-globin gene locus requires the associated locus control region (LCR). Structurally, the LCR is defined by the presence of four domains of erythroid-specific chromatin structure. These domains, which have been characterized as DNase I hypersensitive sites (HSs), comprise the active elements of the LCR. The major focus of this research is to define the cis -acting elements which are required for the formation of these domains of unique chromatin structure. Our previous investigations on the formation of LCR HS4 demonstrated that NF-E2 and tandem, inverted GATA binding sites are required for the formation of the native HS. Similarly arranged NF-E2 and tandem GATA sites are present within the core regions of the other human LCR HSs and are evolutionarily conserved. Using site-directed mutagenesis of human HSs 2 and 3 we have tested the hypothesis that these NF-E2 and GATA sites are common requirements for the formation of all LCR HSs. We find that mutation of these elements, and particularly the GATA elements, results in a decrease or complete loss of DNase I hypersensitivity. These data imply the presence of common structural elements within the core of each LCR HS which are required for erythroid-specific chromatin structure reorganization.     

Inhibition of cholesterol esterification in macrophages and vascular smooth muscle foam cells: Evaluation of E5324, an Acyl-CoA cholesterol acyltransferase inhibitor

Cholesteryl esters (CE) comprise the principal lipid class that accumulates within macrophages and smooth muscle cells of the atherosclerotic lesion. Acyl-CoA cholesterol acyl-transferase (ACAT) is the major enzyme responsible for esterification of intracellular cholesterol. We evaluated the ability of E5324 (n-butyl-N″-[-2-[3-(5-ethyl-4-phenyl-1H-imidazol-1-yl)propoxyl]-6-methyl-phenyllurea), a novel, orally absorbable ACAT inhibitor, to inhibit esterification of fatty acids to cholesterol and CE accumulation in macrophages and in smooth muscle cells. E5324 significantly inhibited cholesterol esterification in rat aortic smooth muscle cells and in macrophages. In addition, E5324 reduced the cellular mass of CE, the significant measure of the efficacy of drugs designed to modulate cholesterol metabolism. E5324 treatment of macrophages exposed to acetylated low-density lipoprotein reduced CE mass by 97%, and treatment of lipid-loaded smooth muscle cells reduced CE mass by 29%. Although free cholesterol increased approximately twofold, this free cholesterol would presumably be accessible to the membrane for effluxin vivo (reverse cholesterol transport). These results demonstrate that E5324 can inhibit cholesterol esterification and CE mass in atherosclerotic foam cells, derived from either macrophages or arterial smooth muscle cells.     

Neuroimmune mechanisms in health and disease: 1. Health

A novel scientific discipline that examines the complex interdependence of the neural, endocrine and immune systems in health and disease has emerged in recent years. In health, the neuroimmunoregulatory network is fundamental to host defence and to the transfer of immunity to offspring; the network also plays important roles in intestinal physiology and in tissue regeneration, healing and reproduction. The proliferation of lymphocytes in primary lymphoid organs (bone marrow, bursa of Fabricius [in birds] and thymus) and in secondary lymphoid organs (spleen, lymph nodes and mucosal lymphoid tissue) depends on prolactin and growth hormone. These hormones allow immune cells to respond to antigen and to soluble mediators, called cytokines. Immune-derived cytokines are capable of inducing fever and of altering neuro-transmitter activity in the brain and hormone secretion by the pituitary gland. The activation of the hypothalamus-pituitary-adrenal axis by cytokines leads to immunosuppression. Lymphoid organs are innervated, and tissue mast cells respond to neurologic stimuli. In general, acetylcholine and substance P exert immunostimulatory and proinflammatory effects, whereas epinephrine and somatostatin are immunosuppressive and anti-inflammatory. In this article, the authors predict that novel approaches to immunomodulation will be possible by altering the level or efficacy of immunoregulatory hormones and neurotransmitters.