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)

The product of the human immunodeficiency virus type 1 (HIV-1) vpr gene induces cell cycle arrest in the G2 phase of the cell cycle and is characterized by an accumulation of the hyperphosphorylated form of cdc2 kinase. This phenotype is similar to the effect of DNA-damaging agents, which can also cause cells to arrest at G2. We previously reported that Vpr mimicked some of the effects of a DNA alkylating agent known as nitrogen mustard (HN2). Here we extend these earlier observations by further comparing the activation state of cdc2 kinase, the kinetics of G2 arrest, and the ability to reverse the arrest with chemical compounds known as methylxanthines. Infection of cells synchronized in the G1 phase of the cell cycle with a pseudotyped HIV-1 resulted in arrest at G2 within 12 h postinfection, before the first mitosis. Similar to that induced by HN2, Vpr-induced arrest led to a decrease in cdc2 kinase activity. Vpr-mediated G2 arrest was alleviated by methylxanthines at concentrations similar to those needed to reverse the G2 arrest induced by HN2, and cells proceeded apparently normally through at least one complete cell cycle. These results are consistent with the hypothesis that Vpr induces G2 arrest through pathways that are similar to those utilized by DNA-damaging agents.
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PMID:Human immunodeficiency virus type 1 vpr gene induces phenotypic effects similar to those of the DNA alkylating agent, nitrogen mustard. 909 73

We conducted a cross-sectional survey to determine the relative course of patients with end-stage renal disease (ESRD) and human immunodeficiency virus (HIV) infection sustained on maintenance hemodialysis. All 34 patients with ESRD and HIV infection receiving hemodialysis in one hospital-based and three community-based outpatient hemodialysis facilities in Brooklyn, NY, were studied. We documented their known duration of HIV infection, duration of ESRD, and hemodialysis prescription, and noted the presence of clinical acquired immunodeficiency syndrome (AIDS). Total CD4 count, serum albumin concentration, and percent reduction of urea (predialysis blood urea nitrogen minus postdialysis blood urea nitrogen, divided by predialysis blood urea nitrogen x 100) were measured. The 34 study subjects (26 men and eight women) included 31 blacks (91%) and three Hispanics (9%) with a mean age of 42 +/- 7.5 years, 29 (85%) of whom had AIDS. Twenty subjects (59%) had a history of intravenous drug abuse. Only six subjects (18%) were receiving an antiretroviral drug (zidovudine = five, dideoxyinosine = one). In 23 subjects (68%), AIDS was diagnosed prior to ESRD and was presumed to be the cause of renal failure (HIV-associated nephropathy). The mean known duration of HIV infection was 50.5 +/- 34 months (median, 48 months); the mean duration of ESRD was 57 +/- 50 months, the mean total CD4 count was 140 +/- 150 cells/microL (median, 70 cells/microL), the mean hematocrit was 28% +/- 5%, and the mean serum albumin concentration was 3.5 +/- 0.37 g/dL. All subjects were receiving erythropoietin for anemia correction. The mean length of the prescribed thrice-weekly hemodialysis sessions was 3.5 +/- 0.4 hours. Our results suggest that the survival of many ESRD patients with HIV infection receiving hemodialysis has improved compared with the uniformly dismal survival rate reported in the 1980s. Decisions on whether to initiate renal replacement therapy in patients with AIDS and advanced renal failure should be individualized because the combination of ESRD and HIV infection does not necessarily signal near-term death.
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PMID:Uremia therapy in patients with end-stage renal disease and human immunodeficiency virus infection: has the outcome changed in the 1990s? 910 43

Reactive oxygen and nitrogen metabolites play a complex role in many diseases and in metabolic regulation. Because viruses replicate in living cells, such metabolites influence the growth of viruses in addition to serving as a host defense mechanism. Low levels of reactive oxygen species (ROS) play a role in mitogenic activation, and the early phase of lytic and nonlytic virus infection indeed resembles that of mitogenic cell activation. In addition to these subtle cell-activating effects shared by many viruses, influenza and paramyxoviruses activate a respiratory burst in phagocytic cells. These viruses are toxic when injected in animals. Cells lavaged from the lungs of mice infected with influenza virus are primed for enhanced superoxide generation. Moreover, xanthine oxidase is enhanced and the buffering capacity of small molecular antioxidants is decreased in the lungs, suggesting that infection leads to oxidative stress. The wide array of cytokines produced in the lungs during influenza could contribute to the systemic effects of influenza. Oxidative stress has also been shown in human immunodeficiency virus (HIV) infection in humans. Via activation of NF kappa B, ROS may activate viral replication, but oxidants are believed to contribute also to the loss of CD4 T cells by apoptosis. Antioxidants, together with agents interfering with the harmful effects of cytokines and lipid mediators, may have a role in the treatment of viral diseases. Such agents could not only alleviate disease symptoms but also decrease the long-term effects of chronic oxidative stress, which have been linked to the development of cancer in some viral infections.
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PMID:Oxidants and antioxidants in viral diseases: disease mechanisms and metabolic regulation. 916 74

Infection and fever evoke a cytokine-mediated host response resulting in negative nitrogen balance, muscle protein degradation, which includes the skeletal muscles as well as the heart muscle, and deteriorated muscle function. Physical training has an opposite effect. Moderate physical training also stimulates the immune system, whereas exhaustive and longlasting exercise is followed by a temporary immunodeficiency and an increased susceptibility to respiratory tract infections. Exercise in the acute phase of an infection may promote complications including myocarditis. Exercise in myocarditis is associated with increased organism-associated as well as immune mediated tissue damage. An increased sudden death (SUD) rate among young Swedish male orienteers existed in 1979-92, suggesting (a) common underlying cause(s). Myocarditis was one of the most conspicuous histopathological features. Chlamydia pneumoniae, or a similar organism cross reacting in diagnostic tests, is hypothesized to be a factor causing this increased death rate. High frequency of intense exercise sessions, which was a common practice among the deceased, may have been immunosuppressive, promoting the development of severe myocardial disease.
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PMID:Interaction between infection and exercise with special reference to myocarditis and the increased frequency of sudden deaths among young Swedish orienteers 1979-92. 925 81

Crystal structures of complexes of a D30N mutant of feline immunodeficiency virus protease (FIV PR) complexed with a statine-based inhibitor (LP-149), as well as with a substrate based on a modification of this inhibitor (LP-149S), have been solved and refined at resolutions of 2.0 and 1.85 A, respectively. Both the inhibitor and the substrate are bound in the active site of the mutant protease in a similar mode, which also resembles the mode of binding of LP-149 to the native protease. The carbonyl oxygen of the scissile bond in the substrate is not hydrated and is located within the distance of a hydrogen bond to an amido nitrogen atom from one of the two asparagines in the active site of the enzyme. The nitrogen atom of the scissile bond is 3.25 A from the conserved water molecule (Wat301). A model of a tetrahedral intermediate bound to the active site of the native enzyme was built by considering the interactions observed in all three crystal structures of FIV PR. Molecular dynamics simulations of this model bound to native wild-type FIV PR were carried out, to investigate the final stages of the catalytic mechanism of aspartic proteases.
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PMID:Crystal structures of the inactive D30N mutant of feline immunodeficiency virus protease complexed with a substrate and an inhibitor. 927

An approach to perform lymphocyte subset analysis on frozen-thawed whole blood (F/T WB) is described. WB from 24 human immunodeficiency virus type 1 (HIV-1) seropositive individuals and 21 controls was analyzed fresh and after frozen storage (with or without dimethyl sulfoxide) at -80 degrees C, in liquid nitrogen (LN2), and at -20 degrees C. Analysis of F/T WB utilized 3-color flow cytometry with CD45 and right angle light scatter gating. Absolute cell counts were obtained for 30 samples by using staining tubes containing internal bead standards [TruCount, Becton Dickinson Immunocytometry Systems (BDIS), San Jose, CA]. The mean difference between CD3+4+ percentages for F/T (-80 degrees C storage for up to 1 year) and fresh WB was less than -0.2% (95% limits +/-3%, P = 0.5) with 39 of 45 (87%) results falling within 2% of the fresh values (P = 0.74). Absolute CD3+4+ cell counts for F/T WB were generally lower than corresponding results for fresh aliquots (median difference was 33 cells/microl, P < 0.0001), but the results were highly correlated (r2 = 0.975, P < 0.0001). Results were more variable, although still highly correlated, for CD3+8+ cells, and with other freezing and storage conditions. It is concluded that lymphocyte subset analysis using F/T WB yields comparable results to fresh samples, which should prove useful for a number of practical applications.
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PMID:Lymphocyte subset analysis on frozen whole blood. 941 17

A common feature of human immunodeficiency virus (HIV) infection and aging is the loss of skeletal muscle mass. Although the causes of this loss of muscle are multifactorial, there may be some shared characteristics to this loss, and therefore common strategies for its prevention or reversal. For example, loss of muscle mass early in life and early in the progression of HIV infection may result from decreased levels of physical activity. The rapid loss of skeletal muscle mass at the end of life (sometimes referred to as failure to thrive syndrome) and in acquired immunodeficiency syndrome (AIDS) patients may also have common cause: cachexia. However, it also must be pointed out that loss of skeletal muscle mass with advancing age also may result from losses of motor units, decreased rate of skeletal muscle protein synthesis, and impaired regulation of appetite. These factors have not been demonstrated to be consequences of HIV infection. The use of exercise to treat the losses of muscle size, strength, and functional capacity holds great promise. Although the losses of muscle with HIV infection may be more rapid and dramatic than those seen with aging, resistance exercise training can attenuate or arrest this loss. In elderly people, resistance exercise has been demonstrated to result in increased nitrogen balance, muscle mass and strength, functional capacity, energy requirements, and when combined with a protein calorie supplement, increased energy intake. The use of resistance exercise in HIV-infected patients may also provide similar results. This review discusses many of the changes in body composition, physiological function, and metabolism associated with aging and HIV infection. The specific effects of exercise in the elderly and in patients infected with HIV on the treatment of muscle wasting, and its consequences are also discussed.
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PMID:Exercise and the treatment of wasting: aging and human immunodeficiency virus infection. 962 93

We previously showed that inoculation of rhesus macaques with molecularly cloned lymphocytetropic simian immunodeficiency virus (SIVmac239) results in SIV-associated nephropathy (SIVAN) and that the glomerulosclerotic lesions were associated with the selection of macrophagetropic (M-tropic) variants (V. H. Gattone et al., AIDS Res. Hum. Retroviruses 14:1163-1180, 1998). In the present study, seven rhesus macaques were inoculated with M-tropic SIVmacR71/17E, and the renal pathology was examined at necropsy. All SIVmacR71/17E-infected macaques developed AIDS, and most developed other systemic complications, including SIV-induced encephalitis and lentivirus interstitial pneumonia. There was no correlation between the length of infection (42 to 97 days), circulating CD4(+) T-cell counts, and renal disease. Of the seven macaques inoculated with SIVmacR71/17E, five developed significant mesangial hyperplasia and expansion of matrix and four were clearly azotemic (serum urea nitrogen concentration of 40 to 112 mg/dl). These same five macaques developed focal segmental to global glomerulosclerotic lesions. Increased numbers of glomerular CD68(+) cells (monocytes/macrophages) were found in glomeruli but not the tubulointerstitium of the macaques inoculated with SIVmacR71/17E. All macaques had glomerular deposits of immunoglobulin G (IgG), IgM, and tubuloreticular inclusions, and six of seven had IgA deposition. However, there was no correlation between the presence of circulating anti-SIVmac antibodies, immunoglobulin deposition, and glomerular disease. Tubulointerstitial infiltrates were mild, with little or no correlation to azotemia, while microcystic tubules were evident in those with glomerulosclerosis or azotemia. The four most severely affected macaques were positive for diffuse glomerular immunostaining for viral core p27 antigen, and there was intense staining in the glomeruli of the two macaques with the most severe glomerulosclerosis. Viral sequences were isolated from glomerular and tubulointerstitial fractions from macaques with severe glomerulosclerosis but only from the tubulointerstitial compartment of those that did not develop glomerulosclerosis. Interviral recombinant viruses generated with env sequences isolated from glomeruli confirmed the M-tropic nature of the virus found in the glomeruli. The correlation between the increased number of CD68(+) cells (monocytes/macrophages) in the glomeruli, the localization of p27 antigen in the glomeruli, and the glomerular pathology confirms and extends our previous observations of an association between glomerular infection and infiltration by M-tropic virus and SIVAN.
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PMID:Rhesus macaques infected with macrophage-tropic simian immunodeficiency virus (SIVmacR71/17E) exhibit extensive focal segmental and global glomerulosclerosis. 976 27

A number of N,N',N",N"'-tetrakis (omega-aminoalkyl) tetraazamacrocycles and related compounds were synthesized and evaluated for their inhibitory effects on human immunodeficiency virus type 1 (HIV-1) and duck hepatitis B virus (DHBV) replication. The activity of these compounds was found to be highly dependent upon structural features: (i) the length of the alkyl linker connecting the nitrogen atoms of the macrocyclic ring to the exocyclic nitrogen atoms of the terminal amino groups (five methylenes favoured antiviral activity); (ii) substitution of the terminal amino groups of the linker reduced antiviral activity; and (iii) the size of the tetraazamacrocyclic ring (14 or 15 atoms) did not markedly affect the antiviral activity. Some analogues were potent inhibitors of HIV-1 replication, with anti-HIV activity similar to that of biscyclam (JM 2763). In contrast, other analogues were found to be highly toxic in duck hepatocyte primary culture, the 2.2.15 cell line and to a lesser extent in MT-4 cells. Structural parameters, macrocyclic ring size and metal-chelating ability have been used to develop a structure-activity relationship model in order to aid the design of antiviral molecules derived from N,N',N",N"'-tetrakis (omega-aminoalkyl) tetraazamacrocycles.
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PMID:Design, synthesis and structure relationships of new N,N',N",N"'-tetrakis (omega-amino alkyl) tetraazamacrocycles. 987 79

Novel chain-extended nucleoside phosphoramidates of the anti-human immunodeficiency virus (HIV) drug d4T (stavudine) have been prepared as possible membrane-permeable prodrugs of the bio-active free 5'-monophosphates. Phosphorochloridate chemistry gave the target compounds in moderate to high yields, and all materials were fully characterized by spectroscopic and analytical methods. The compounds are related to the previously reported phenyl methoxyalaninyl derivative of d4T, which was shown to be a potent and selective inhibitor of HIV. In this study the amino acid nitrogen and ester moieties were separated by methylene spacers of between two and six carbon atoms. In vitro evaluation of these compounds indicated an almost complete lack of anti-HIV activity, the compounds being several orders of magnitude less potent than the corresponding alpha-amino acid derivatives. The reasons for the virtual lack of anti-HIV activity appear to involve poor enzyme-mediated hydrolysis.
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PMID:Synthesis and anti-HIV activity of some novel chain-extended phosphoramidate derivatives of d4T (stavudine): esterase hydrolysis as a rapid predictive test for antiviral potency. 987 82


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