Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Mucormycosis (phycomycosis) is an acute and often fatal infection, mostly seen in diabetics and immunocompromised patients, and seldom in healthy people. Therapy includes aggressive surgical debridement, amphotericin B and control of underlying predisposing condition (diabetes, immunosuppression or immunodeficiency). The rhino-sinuso-orbital presentation is typically observed in insulin-dependent diabetes mellitus with ketoacidosis. This metabolic condition may impair the polymorphonuclear function in a reversible way and this may favour infection by a mucoral. These spores germinate into hyphae, which invade local arteries and arterioles, causing thrombosis, vascular insufficiency and tissue hypoxia and acidosis, conditions which further enhance fungal growth. Hyperbaric oxygen has theoretical value in treating mucormycosis, since it reduces tissue hypoxia caused by the vascular insufficiency. We report an insulin-dependent diabetic patient with rhino-sinuso-orbital mucormycosis, who after being treated with amphotericin B and surgical debridement on two occasions, maintained clinical and tomographic evidence of active infection, and mucoral persistence in the lesion. An aggressive surgical debridement, using microsurgical techniques, was performed. Amphotericin B was increased up to a total dose of 3900 mg. (he had previously received 2900 mg) and hyperbaric oxygen was added as adjunctive treatment. The outcome was successful. There was no evidence of relapse after a 16-month follow-up. This observation would confirm the usefulness of hyperbaric oxygen as adjunctive therapy in mucormycosis.
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PMID:[Adjunctive treatment with hyperbaric oxygen in a patient with rhino-sinuso-orbital mucormycosis]. 192 93

Covalent linkage of myristate (tetradecanoate; 14:0) to the NH2-terminal glycine residue of the human immunodeficiency virus 1 (HIV-1) 55-kDa gag polyprotein precursor (Pr55gag) is necessary for its proteolytic processing and viral assembly. We have shown recently that several analogs of myristate in which a methylene group is replaced by a single oxygen or sulfur atom are substrates for Saccharomyces cerevisiae and mammalian myristoyl-CoA:protein N-myristoyltransferase (EC 2.3.1.97; NMT) despite their reduced hydrophobicity. Some inhibit HIV-1 replication in acutely infected CD4+H9 cells without accompanying cellular toxicity. To examine the mechanism of their antiviral effects, we performed labeling studies with two analogs, 12-methoxydodecanoate (13-oxamyristate; 13-OxaMyr) and 5-octyloxypentanoate (6-oxamyristate; 6-OxaMyr), the former being much more effective than the latter in blocking virus production. [3H]Myristate and [3H]13-OxaMyr were incorporated into Pr55gag with comparable efficiency when it was coexpressed with S. cerevisiae NMT in Escherichia coli. [3H]6-OxaMyr was not incorporated, even though its substrate properties in vitro were similar to those of 13-OxaMyr and myristate. [3H]13-OxaMyr, but not [3H]6-OxaMyr, was also efficiently incorporated into HIV-1 Pr55gag and nef (negative factor) in chronically infected H9 cells. Analog incorporation produced a redistribution of Pr55gag from membrane to cytosolic fractions and markedly decreased its proteolytic processing by viral protease. 13-OxaMyr and 3'-azido-3'-deoxythymidine (AZT) act synergistically to reduce virus production in acutely infected H9 cells. Unlike AZT, the analog is able to inhibit virus production (up to 70%) in chronically infected H9 cells. Moreover, the inhibitory effect lasts 6-8 days. These results suggest that (i) its mechanism of action is distinct from that of AZT and involves a late step in virus assembly; (ii) the analog may allow reduction in the dose of AZT required to affect viral replication; and (iii) combinations of analog and HIV-1 protease inhibitors may have synergistic effects on the processing of Pr55gag.
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PMID:Incorporation of 12-methoxydodecanoate into the human immunodeficiency virus 1 gag polyprotein precursor inhibits its proteolytic processing and virus production in a chronically infected human lymphoid cell line. 200 42

A 31-year-old woman, heroin addict since ten years, and infected by the human immunodeficiency virus (HIV) since one year, was admitted to the intensive care unit for respiratory failure (PaO2 = 40 mmHg and PaCO2 = 14.8 mmHg, despite breathing pure oxygen). She had been followed up for 6 months for increasing dyspnoea due to chronic cor pulmonale for which no satisfactory explanation had been put forward. Artificial ventilation with 8 cmH2O positive end-expiratory pressure and 100% oxygen was completely inefficient. She died within a few hours. Postmortem lung biopsy revealed talc particles within interalveolar walls and alveolar macrophages as well as the expected alterations in blood vessels. Pulmonary hypertension due to talc microemboli is a well-known cause of respiratory failure in heroin addicts. Such a diagnosis should not be overlooked in a patient infected with HIV. Respiratory failure may not be only due to opportunist infections, or tumours related to the HIV infection.
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PMID:[Respiratory failure in a HIV seropositive heroin addict female]. 200 73

We have explored the acyl-CoA substrate specificity of Saccharomyces cerevisiae myristoyl-CoA:protein N-myristoyltransferase (NMT) by synthesizing 81 fatty acid analogs and surveying their activity in a coupled in vitro assay containing Pseudomonas acyl-CoA synthetase and Escherichia coli-derived yeast NMT. Single oxygen or sulfur substitution for C-3 through C-13 is well tolerated by both enzymes. Detailed kinetic analyses suggest that the acyl-CoA and peptide-binding sites of NMT are relatively insensitive to placement of single group 6B heteroatoms. By contrast, di-oxygen-substituted analogs were very poor substrates, producing dramatic reductions in the affinity of NMTs peptide-binding site for a synthetic octapeptide substrate derived from the NH2-terminal sequence of a known N-myristoylprotein, the gag poly-protein precursor of human immunodeficiency virus 1 (HIV-1). This observation provides an example of binding site cooperativity in NMT. Replacement of one oxygen with sulfur at either the 6, 9, or 12 position of dioxatetradecanoic acids results in a general increase in peptide catalytic efficiency (Vmax/Km). An analysis of five fatty acids from octanoic to dodecanoic having terminal phenyl groups indicated that the best substrate was 10-phenyldecanoic acid even though Corey-Pauling-Koltun molecular models indicate that it has a length equivalent to that of tridecanoic acid. Six analogs having an equivalent length of 13 carbon atoms were subsequently prepared in which the phenyl group was systematically moved one methylene group closer to carboxyl. Movement of the phenyl just one carbon closer to carboxyl (producing 9-(p-methylphenyl) nonanoic acid) decreases peptide catalytic efficiency (Vmax/Km) severalfold compared to 10-phenyldecanoic acid. 10-(4-Tolyl)decanoic acid has the same relative positions of phenyl and carboxyl as 10-phenyldecanoic acid even though a methyl group is present on the phenyl ring. It produces peptide Km and Vmax values that are the same as 10-phenyldecanoic acid. Substitution of either oxygen or sulfur for a methylene group fails to override the effects noted when the phenyl group position is altered in the C-14 equivalent fatty acid series. Several fatty acids of differing chain lengths with cyclohexyl-, 2-furyl, and 2-thienyl groups at their omega termnius had activity profiles that paralleled those of the comparable phenyl-substituted compounds. Myristic acid analogs with triple bonds (beginning at positions 2 through 13), cis-double bonds (positions 3 through 13) and trans-double bond isomers (E5, E6, and E7) were also tested.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The substrate specificity of Saccharomyces cerevisiae myristoyl-CoA:protein N-myristoyltransferase. Analysis of myristic acid analogs containing oxygen, sulfur, double bonds, triple bonds, and/or an aromatic residue. 202 98

The protease of the human immunodeficiency virus is essential for replication of the virus, and the enzyme is therefore an attractive target for antiviral action. We have found that the viral protease is inhibited by approximately stoichiometric concentrations of copper or mercury ions. Inactivation by Cu2+ was rapid and not reversed by subsequent exposure to EDTA or dithiothreitol. Direct inhibition by Cu2+ required the presence of cysteine residue(s) in the protease. Thus, a synthetic protease lacking cysteine residues was not inhibited by exposure to copper. However, addition of dithiothreitol as an exogenous thiol rendered even the synthetic protease susceptible to inactivation by copper. Oxygen was not required for inactivation of either the wild-type or the synthetic protease. These results provide the basis for the design of novel types of protease inhibitors.
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PMID:Copper inhibits the protease from human immunodeficiency virus 1 by both cysteine-dependent and cysteine-independent mechanisms. 206 37

A series of 9-(phosphonoalkyl)purines, which are analogues of 9-[2-(phosphonomethoxy)ethyl]purines (guanine, PMEG, 1; adenine, PMEA, 2), were synthesized. The analogues were tested for activity against herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), human cytomegalovirus (HCMV), Rauscher murine leukemia virus (R-MuLV), and human immunodeficiency virus type 1 (HIV-1). With variations in the length of the alkyl chain, the optimal activity was achieved with two carbons between the purine base and the phosphonomethoxy functionality. Despite the structural similarity and the close pKa2 value of 8 to that of PMEG, no phosphorylation of 8 was observed by the bovine brain guanylate kinase. Since all isosteric analogues of PMEG (7-9) were not inhibitory against HSV-1 and HSV-2, the presence of the 3'-oxygen atom in the PME purines proved critical for anti-HSV activity. Introduction of the 1'-methyl group on the PMEG side chain significantly reduced its anti-HSV activity. Analogue 11, which is a mimic of the phosphate by incorporation of the alpha,alpha-difluoro carbon, was ineffective against HSV-1 and HSV-2. These results suggest that the structural requirements of PME purines for anti-HSV activity appear to be very strict.
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PMID:Acyclic purine phosphonate analogues as antiviral agents. Synthesis and structure-activity relationships. 215 12

Myristoyl-CoA:protein N-myristoyltransferase (NMT) catalyzes the covalent attachment of myristic acid to the NH2-terminal Gly residues of a number of viral and cellular proteins. The remarkable specificity of this enzyme for myristoyl CoA observed in vivo appears to arise in large part from a cooperativity between NMT's acylCoA and peptide binding sites: the length of the acylCoA bound to NMT influences the interactions of peptide substrates with NMT. We have previously synthesized analogs of myristic acid with single oxygen or sulfur for methylene substitutions. These heteroatom substitutions produce significant reductions in acyl chain hydrophobicity without accompanying alterations in chain length or stereochemical restrictions. In vitro studies have shown that the CoA thioesters of these analogs are substrates for S. cerevisiae NMT and that the efficiency of their transfer to octapeptide substrates is peptide sequence-dependent. In vivo studies with cultured mammalian cells have confirmed that these fatty acid analogs are selectively incorporated into a subset of cellular N-myristoylproteins, that only a subset of analog-substituted proteins undergo redistribution from membrane to cytosolic fractions, and that these analogs can inhibit the replication of human immunodeficiency virus I and Moloney murine leukemia viruses--two retroviruses that depend upon N-myristoylation of their gag polyprotein precursors for assembly. We have now extended our analysis of NMT-acylCoA interactions by synthesizing additional analogs of myristic acid and testing them in a coupled in vitro assay system. Myristic acid analogs with two oxygen or two sulfur substitutions have hydrophobicities comparable to that of hexanoic acid and decanoic acid, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Novel fatty acyl substrates for myristoyl-CoA:protein N-myristoyl-transferase. 219 61

To confirm the presence of exercise dysfunction in patients seropositive for the human immunodeficiency virus (HIV), 32 such patients without AIDS were evaluated with cardiopulmonary exercise testing, pulmonary function testing, bronchoalveolar lavage, chest roentgenography, and gallium scanning. No evidence of pulmonary opportunistic infection was found. When compared to an otherwise similar group of HIV-seronegative controls, the patients exercised to a significantly lower workload (195 +/- 30 versus 227 +/- 31 W, p less than 0.001). The ventilatory anaerobic threshold (VAT) values were also significantly lower for the patients (49.2 +/- 13.0 versus 61.9 +/- 9.1% of maximum predicted VO2, p less than 0.001). Nine of the patients had VAT values less than the 95% confidence interval for the controls. This subgroup exercised to a significantly lower maximum VO2 (69.9 +/- 11.2 versus 95.9 +/- 17.5% of maximum predicted VO2, p less than 0.001) and workload (165 +/- 21 versus 227 +/- 31 W) when compared to the control group. These patients demonstrated a mild tachypnea throughout exercise relative to the controls and had a significant increase in the slope of the heart rate to VO2 relationship. These findings are most consistent with a limitation of oxygen delivery to exercising muscles, which may represent occult cardiac disease in this group.
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PMID:Exercise dysfunction in patients seropositive for the human immunodeficiency virus. 231 95

Bronchoalveolar lavage was used in 170 immunocompromised patients for detection of causative agents. Pneumocystis carinii was isolated 18 times from HIV-positive patients and 14 times from patients suffering from immunodeficiencies due to various other diseases. Patients with AIDS were in better clinical condition, had fewer infiltrates on chest x-ray, a higher oxygen partial pressure and lower LDH-plasma concentration than HIV-negative patients. In spite of the earlier stage of the disease patients with AIDS experience prodromal symptoms for a longer time and the number of isolated pneumocystis was larger. Mortality in AIDS patients was significantly lower than in patients with other causes of immunodeficiency.
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PMID:[Pneumocystis carinii pneumonia in HIV-positive and HIV-negative patients]. 233 26

Five children with positive serology for human immunodeficiency virus (HIV) infection by enzyme-linked immunosorbent assay and Western blot were followed for chronic pulmonary disease. Lung biopsies were performed in all patients, and confirmed the diagnosis of pulmonary lymphoid hyperplasia. All children demonstrated progressive hypoxia and increasing alveolar capillary oxygen gradients over at least 1 year of follow-up. All children were on periodic intravenous gamma globulin treatment for a B-cell defect prior to the initiation of corticosteroid therapy. Prednisone was initially given at a dose of 2 mg/kg daily and was subsequently tapered to an alternate day regimen. All children showed improvement in oxygenation. No deterioration in immune function was noted, and there was no increase in bacterial infection. This study indicates that corticosteroids can successfully reverse the severe hypoxia that may result from pulmonary lymphoid hyperplasia in pediatric AIDS patients.
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PMID:Corticosteroid treatment for pulmonary lymphoid hyperplasia in children with the acquired immune deficiency syndrome. 244 50


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