Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Myristoyl-CoA:protein N-myristoyltransferase (NMT; EC 2.3.1.97) catalyzes the cotranslational linkage of myristate to the N-terminal glycine residues of several cellular, viral, and oncoproteins. We have recently synthesized a series of sulfur- and oxygen-substituted analogs of myristic acid that are similar in length to the 14:0 fatty acid yet have hydrophobicities equivalent to dodecanoate or decanoate. Previous in vitro enzyme assays and metabolic labeling studies indicate that some of these analogs are excellent substrates for NMT and are incorporated into subsets of cellular N-myristoyl proteins. Their sequence-specific incorporation probably arises from cooperative interactions between the acyl CoA and peptide binding sites of NMT. The human immunodeficiency virus 1 (HIV-1) and Moloney murine leukemia virus (MoMLV) depend on myristoylation of gag polyprotein precursors for assembly. We have tested four analogs--12-methoxydodecanoic acid, 10-propoxydecanoic acid, 5-octyloxypentanoic acid, and 11-ethylthioundecanoic acid--for their ability to block replication of these retroviruses. All reduce HIV-1 replication when incubated with CD4+ H9 cells for 10 days at 10-100 microM. 12-Methoxydodecanoic acid is most effective, producing a concentration-dependent decrease in (i) reverse transcriptase activity (to levels that were 5-10% of control at 20-40 microM), (ii) p24 levels, and (iii) syncytia formation. This degree of inhibition of HIV-1 replication is equivalent to that seen with 5 microM 3'-azido-3'-deoxythymidine and is accomplished without apparent toxicity, as measured by cell viability, protein, and nucleic acid synthesis. 5-Octyloxypentanoic acid inhibits MoMLV assembly in a dose-dependent fashion without accompanying cellular toxicity, while 12-methoxydodecanoic acid has no effect. These data suggest that the use of cellular NMT activity to deliver analogs of myristate with altered physical-chemical properties to proteins that undergo this cotranslational modification may represent an effective anti-viral therapeutic strategy as well as a way to investigate the role of covalently bound fatty acid in viral assembly.
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PMID:Replication of human immunodeficiency virus 1 and Moloney murine leukemia virus is inhibited by different heteroatom-containing analogs of myristic acid. 281 17

To find out whether Pneumocystis carinii pneumonia (PCP) can be detected while still in an early phase by the degree of exercise-induced oxygen desaturation, arterial oxygen saturation was measured by continuous pulse oximetry in patients positive for antibody to the human immunodeficiency virus and clinically suspected of having PCP, in patients with other chest diseases, and in controls. Among patients with proven PCP 94% of those with low arterial oxygen pressures (PaO2) showed desaturation on exercise oximetry, as did 80% of those with a normal oxygen pressure at rest, whereas only 10% of patients with other chest disorders and HIV disease showed significant desaturation.
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PMID:Severe exercise hypoxaemia with normal or near normal X-rays: a feature of Pneumocystis carinii infection. 290 79

Opiate addiction and stress have been associated with altered immune responses. In this study, we evaluated the influence of morphine and the stress responsive opioid peptide beta-endorphin (beta-END) on O-2 and H2O2 production by cultured human peripheral blood mononuclear cells. Exposure of these cells during 48 hr of culture to morphine and beta-END at pharmacologically (10(-8) M) and physiologically (10(-12) M) relevant concentrations, respectively, markedly suppressed peripheral blood mononuclear cell O-2 and H2O2 release in response to the respiratory burst stimuli opsonized zymosan and phorbol myristate acetate. Both opioids also induced a minimal, but statistically significant, increase in resting O-2 and H2O2 generation. The modulatory effects of morphine and beta-END on peripheral blood mononuclear cell oxygen metabolism appeared to involve a classical opioid receptor, because opioid activity was blocked by naloxone and was not observed with N-acetylated-beta-END. Using purified lymphocyte and monocyte preparations, we determined that although opioids directly increase monocyte-resting oxygen metabolism, lymphocytes are the primary target cell in opioid-mediated suppression of monocyte respiratory burst activity. The release of a suppressive product from opioid-triggered lymphocytes was inhibited by cyclosporine. Based on the results of this study, we propose that opioid-mediated suppression of mononuclear phagocyte respiratory burst activity is another factor to be considered in the immunodeficiency of opiate addiction and stress.
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PMID:Opioid-mediated suppression of cultured peripheral blood mononuclear cell respiratory burst activity. 303 15

Mounting evidence suggests that opiate addiction and stress are associated with impaired cell-mediated immunity. We tested the hypothesis that morphine and the endogenous opioid beta-endorphin (beta-END), a pituitary peptide released in increased concentrations during stress, can suppress the production of the key macrophage-activating lymphokine interferon-gamma (IFN-gamma) by cultured human peripheral blood mononuclear cells (PBMNC). Using a radioimmunoassay to measure IFN-gamma, we found that exposure of PBMNC to biologically relevant concentrations of both opioids significantly inhibited IFN-gamma generation by cells stimulated with concanavalin A and varicella zoster virus. Studies of the mechanism of suppression revealed (a) a classical opioid receptor is involved (suppression was antagonized by naloxone and was specific for the NH2 terminus of beta-END), (b) monocytes are the primary target cell for opioids (monocyte-depleted lymphocyte preparations showed little suppression), and (c) reactive oxygen intermediates (ROI) and prostaglandin E2 are important mediators (scavengers of ROI and indomethacin eliminated the suppression). Based on these findings we suggest that opioid-triggered release of inhibitory monocyte metabolites may play a role in the immunodeficiency associated with narcotic addiction and stress.
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PMID:Opioid-mediated suppression of interferon-gamma production by cultured peripheral blood mononuclear cells. 304 Aug 7

The elderly are at risk for an increased incidence and severity of certain infections. The contribution of age-related immunologic impairment to the pathogenesis of these infections has been difficult to determine because of a number of confounding variables associated with aging. Nevertheless, studies in vitro and in animals support the hypothesis that immunodeficiency accompanies the aging process. Multiple factors may be responsible for altered cell-mediated immunity in the elderly, including thymic involution, reduced levels of thymic hormones, and an increase in the number of immature T lymphocytes. While studies of T cell subpopulations have yielded conflicting results, it appears that T cell proliferative responses are diminished. Aging is also associated with abnormalities of humoral immunity. Although the number and functional activities of neutrophils from healthy elderly persons are relatively intact, diminished bactericidal activity and altered oxygen metabolism have been reported in extremely old individuals. While the relative importance and clinical impact of these immunologic abnormalities remain unclear, future studies may provide new strategies for the prevention and treatment of infections in this rapidly growing segment of the population.
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PMID:Immunodeficiency of the elderly. 332 63

The therapy of rhinocerebral mucormycosis includes aggressive surgical debridement, administration of high-dose amphotericin B, and control of underlying predisposing conditions, especially diabetes and immunosuppression or immunodeficiency. Hyperbaric oxygen suppresses fungal growth in vitro and has theoretical value in treating mucormycosis because it reduces the tissue hypoxia and acidosis that accompany vascular invasion by the fungus. In a retrospective review of patients at Duke University Medical Center with rhinocerebral mucormycosis, six patients were treated with hyperbaric oxygen and seven cases (involving six patients) were treated without hyperbaric oxygen. All patients received surgical debridement and amphotericin B. Two of six patients receiving hyperbaric oxygen therapy died, and four of seven patients not receiving hyperbaric oxygen therapy died. Adverse effects from hyperbaric oxygen were minimal. Because mucormycosis occurs infrequently, this retrospective review involved a small number of patients. Despite this limitation, adjunctive hyperbaric oxygen appears to be a promising clinical modality for the treatment of rhinocerebral mucormycosis and warrants further investigation.
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PMID:Adjunctive hyperbaric oxygen for treatment of rhinocerebral mucormycosis. 339 82

A series of 2',3'-unsaturated and 3'-substituted 2',3'-dideoxynucleoside analogues of purines and pyrimidines have been synthesized and evaluated for their inhibitory activity against human immunodeficiency virus (HIV). The 2',3'-unsaturated analogues of 2',3'-dideoxycytidine (ddeCyd) and 2',3'-dideoxythymidine (ddeThd), 3'-azido-2',3'-dideoxythymidine (AzddThd), 3'-fluoro-2',3'-dideoxythymidine, 2',3'-dideoxycytidine (ddCyd), and 2',3'-dideoxyadenosine (ddAdo) emerged as the most potent inhibitors of HIV-induced cytopathogenicity in the human T lymphocyte cell lines ATH8 and MT4. In ATH8 cells ddCyd, ddeCyd, and ddAdo had the highest therapeutic index whereas in MT4 cells AzddThd, ddThd, ddCyd, and ddAdo were the most selective. Derivatives from ddThd in which the substituent group was linked to the 3'-carbon atom via a thio, sulfonyl, or oxygen bridge were far less inhibitory to HIV than was AzddThd.
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PMID:3'-substituted 2',3'-dideoxynucleoside analogues as potential anti-HIV (HTLV-III/LAV) agents. 349 72

Atopic dermatitis (AD) is characterized by many signs of immunodeficiency. Our interest was to investigate if there are also alterations of the chemiluminescence (CL) response of polymorphonuclear leukocytes (PMN) as a measure of the release of toxic oxygen radicals. Isolated PMN of 13 patients with AD with mild to moderate disease activity were stimulated with a chemotactic peptide (f-met-phe), zymosan-activated serum (ZAS), zymosan particles and phorbolmyristate acetate. In the AD group, we found a significantly decreased response after stimulation with ZAS in comparison to the controls. With the other stimuli tested no significant difference was detected. The decreased response of PMN to stimulation with ZAS from patients with AD associated with a normal reactivity to the other stimuli could be due to specific desensitization of the PMN by C5a in vivo.
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PMID:Chemiluminescence response of polymorphonuclear leukocytes in atopic dermatitis. 357 May 2

Chronic granulomatous disease (CGD), an immunodeficiency syndrome characterized by extreme susceptibility to bacterial infections, is due to a defect of the respiratory burst in human phagocytes. NADPH oxidase, the enzyme that catalyzes the reduction of oxygen and the release of oxidative radicals, was studied in polymorphonuclear leucocytes (PMNs) in a family affected by an x-linked inheritance form at high penetrance of the disease. The contents of cytochrome b, suggested as the terminal component of the oxidase electron transport chain, and FAD, the hypothetical proximal component of the chain, were determined in patients and in carriers. Cytochrome b showed the typical behaviour of x-linked CGD: total absence in patients, intermediate values in carriers. FAD content evaluated on plasma membranes was less decreased than cytochrome b. Carriers also showed a decrease of this flavoprotein. Cytochrome b and FAD contents were compared to NBT test and superoxide production: a clear correlation was observed for the cytochrome b, but FAD plasma membrane evaluation could also be an interesting tool for the metabolic characterization of the disease in patients and in carriers.
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PMID:Cytochrome b and FAD content in polymorphonuclear leucocytes in a family with X-linked chronic granulomatous disease. 378 83

Phagocyte function can be assayed by many laboratory tests including a cytomorphological method that uses Candida cells as target. The aim of this study was to correlate this technique with the production of toxic oxygen metabolites, measured by chemiluminescence (CL). The biological function of polymorphonuclear (PMN) cells and monocytes from the blood of 24 normal subjects and 25 patients with immunodeficiency diseases were studied. CL was measured using opsonized zymosan as the stimulating agent and, for the evaluation of Candida killing activity, C. pseudotropicalis and C. albicans were used as targets. A linear correlation between CL and lytic activity was observed with both PMN and monocytes from normal subjects and patients (r = 0.563 to 0.955; P less than 0.05 to less than 0.001). Our results indicate that the production of toxic oxygen metabolites, as measured by CL is closely related to the killing of Candida by PMN and monocytes.
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PMID:Comparison of Candida killing activity measured by chemiluminescence and cytomorphological methods in human phagocytes. 381 44


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