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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Studies with a simian immunodeficiency virus (SIV)-infected fetal monkey model were conducted with a focus on fetal growth and viral pathogenesis. Twenty-six fetuses were inoculated in utero via ultrasound guidance with an uncloned pathogenic strain of SIV or vehicle during the second or third trimesters [gestational day (GD) 65, 110, or 130], sonographically monitored weekly (biometrics, blood flow), then necropsied at incremental time points postinfection. Peripheral blood hematologic (complete blood counts, clinical chemistries), immunologic (immunophenotyping), and endocrine studies [insulin-like growth factor (IGF), IGF-binding proteins (IGFBP)] were conducted. Severe intrauterine growth restriction (IUGR), oligohydramnios, and altered lymphocyte counts were noted for fetuses infected on GD 65. Less severe effects were detected for fetuses inoculated at the later time points, with severity dependent upon the length of SIV infection in utero. IGF studies indicated significant reductions in IGF-I and elevated immunoreactive levels of IGFBP-3 in infected fetuses during the third trimester. Parallel studies conducted with four fetuses infected on GD 65 with a nonpathogenic, molecularly cloned virus (SIVmac1A11) resulted in normal fetal growth, with no effects on hematopoiesis or IGF/IGFBP levels, and no evidence of clinical disease. Taken together, these studies show that (1) infection of fetuses during the early second trimester with an uncloned pathogenic strain of SIV results in severe IUGR and a disruption in the molar ratio of IGF:IGFBP-3, and (2) outcome of fetal SIV infection is determined by the timing of infection and the virulence of the viral inoculum.
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PMID:Effects of viral virulence on intrauterine growth in SIV-infected fetal rhesus macaques (Macaca mulatta). 755 76

Cancer remains the second most common cause of death in our society, and advanced disease is often refractory to surgical, chemotherapeutic, and radiologic interventions. One novel approach to cancer treatment involves targeting a cytotoxic agent to a cancer cell. Immunotoxins have been developed that contain a potent toxin (either Pseudomonas exotoxin, ricin toxin, or diphtheria toxin) coupled to a targeting moiety that directs the molecule to cells expressing a certain antigen. Chemically coupled immunotoxins have been developed over the past 12 years. These bind to and kill cells expressing many tumor-associated antigens. Initial clinical results were disappointing, but recent results have been more promising. Furthermore, newer immunotoxins have been developed that will soon be in clinical trials. Some of these are recombinant toxins that have been developed using techniques of genetic engineering. Transforming growth factor-alpha, acidic fibroblast growth factor, insulin-like growth factor-1, interleukin-2, interleukin-4, interleukin-6, the binding portions of monoclonal antibodies, and CD4 have been used to direct toxins to cancer cells or cells infected with the human immunodeficiency virus type 1. Efforts are under way to circumvent problems such as immunogenicity that may limit the clinical usefulness of immunotoxins.
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PMID:Immunotoxins and recombinant toxins in the treatment of solid carcinomas. 836 39

Metabolic and anthropometric changes induced by "pharmacological" versus "physiological" doses (5.0 vs. 2.5 mg, every other day) of recombinant human growth hormone (rhGH) were compared in 10 human immunodeficiency virus-positive patients with AIDS or AIDS-related complex. Five patients were randomly assigned to each treatment schedule in a 3-month prospective, double-blind clinical trial. Three of the 10 patients, none taking zidovudine and all with low initial CD4 counts, were withdrawn during the study due to acute opportunistic infections. During treatment, insulin-like growth factor-1 (IGF-1) levels increased significantly (p < 0.05) in the pharmacological hGH treatment group, whereas no significant change was observed in IGF-1 in the physiological dose rhGH group. In the pharmacological hGH treatment group, weight loss preceding the study was reversed (p < 0.05) in each of the four patients who completed the study. This weight gain was associated with increases (p < 0.05) in lean body mass and total body water, with concomitant decreases in fat mass (p < 0.05) and urinary nitrogen excretion. Muscle power and endurance, as assessed by standardized omnikinetic dynamometry, also improved. All four patients lost weight again (p < 0.05) 6 weeks after completion of the study and termination of rhGH treatment. Minor positive changes in body composition were also observed in the physiologic-dose hGH group. The pharmacological dose of hGH was associated with minor increments (p < 0.05) in fasting plasma glucose, insulin, and C-peptide concentrations, which were of negligible clinical significance.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Anthropometric, metabolic, and immunological effects of recombinant human growth hormone in AIDS and AIDS-related complex. 845 Mar 99

Thymus involvement and the development of thymic lesions in HIV-1 infection is hypothesized to suppress thymus function and limit T cell maturation and replenishment of the peripheral lymphoid pool. Therapeutic modulation to protect or enhance thymus function may therefore ameliorate peripheral lymphocytopenia and retard disease progression. Thymotrophic agents, such as insulin-like growth factor type I (IGF-I), may therefore represent adjunctive but important methods of treatment to protect or promote thymus function. The assessment of rhIGF-I in lentiviral infection and its impact on the thymus was performed using the feline immunodeficiency virus (FIV) model. Regeneration of the thymus in juvenile cats and amelioration of the thymic lesion after FIV infection was assessed by multiple measurements including thymic weight, stereologic analysis of the thymus cortex and medulla, histologic and immunohistologic analysis, quantitation of thymocyte and peripheral lymphocyte subsets, and quantitative competitive RT-PCR. Evidence of thymic cortical regeneration was observed in FIV-inoculated cats after 12 and 20 weeks of rhIGF-I treatment. Inflammation in the thymus was reduced during this period of treatment in this group of rhIGF-I/FIV-inoculated cats as evidenced by the reduced numbers of B cells detected. Viral replication rates in peripheral lymph nodes were not altered by rhIGF-I treatment and were decreased by 1 log in the thymus after 20 weeks of treatment. Peripheral blood CD4+ T cell counts also increased after 14 weeks of treatment. This suggests that rhIGF-I treatment can enhance thymus function and replenishment of the peripheral T cell pool.
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PMID:Investigation of recombinant human insulin-like growth factor type I in thymus regeneration in the acute stage of experimental FIV infection in juvenile cats. 1051 53

p73 has been shown to transcriptionally activate genes positively responsive to wild-type p53. In order to undertake a comparative study of functions of p53 and p73 we have cloned the cDNA of p73 from MCF-7 cells. Adenovirus onco-protein E1A inhibits the transactivation by p73; a deletion mutant of E1A incapable of interacting with p300 and CREB-binding protein (CBP) fails to disrupt the transactivation. Furthermore, CBP increases the transactivation mediated by p73 suggesting that CBP may function as a co-activator and E1A inhibits p73-mediated transactivation by sequestering p300 or CBP. We show that p73 can transcriptionally inhibit a number of cellular and viral promoters. However, wild-type p53, p73 alpha and p73 beta differ in their ability to inhibit transcriptional activity of different promoters. While wild-type p53 inhibits the promoters of the human cytomegalovirus (CMV) immediate-early gene, the long terminal repeat of human immunodeficiency virus type 1 (HIV LTR), human cyclin A (cyc A) gene, and insulin-like growth factor receptor I (IGF-I-R), p73 alpha only inhibits the HIV LTR and cyc A promoters significantly; and p73 beta inhibits the CMV, HIV LTR and cyc A promoters. A mutant of p73 alpha having amino acid substitutions at positions 268 and 300 on the presumptive DNA-binding domain fails to transactivate the p21 promoter but represses the CMV and the HIV LTR promoter quite efficiently showing that the mechanisms of transactivation and repression by p73 are different. Interestingly, p73 alpha transactivates the IGF-I-R promoter, which is inhibited by wild-type p53; p73 beta has no significant effect on this promoter. This is a unique situation where p73 alpha differs from p73 beta as well as p53.
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PMID:Differential modulation of cellular and viral promoters by p73 and p53. 1117 10

Endocrine dysfunctions have previously been reported in human immunodeficiency virus (HIV) infection. In this study we evaluated the relation of immunological parameters, virus load, clinical stage, and wasting to several parameters of the insulin-like growth factor (IGF) system in 76 patients with HIV infection, of whom 37 had developed acquired immune deficiency syndrome (AIDS). A subgroup of 26 untreated patients was followed during longitudinal testing, while the effects of antiretroviral therapy were evaluated in 34 patients (nucleoside analogs in 9, nucleoside analogs in combination with protease inhibitors in 25). Twenty healthy sex- and age-matched controls were analyzed for comparison. IGF-II was decreased (P = 0.03) and IGF-binding protein-2 (IGFBP-2) and IGFBP-3 protease activity were increased (P < 0.001) in AIDS patients compared with other HIV-infected individuals and controls. Plasma levels of IGFBP-2 and IGFBP-3 protease activity correlated positively to virus load (P < 0.001) and tumor necrosis factor-alpha (P < 0.025) and negatively to CD4(+) and CD8(+) cell counts (P < 0.001). AIDS patients with wasting (n = 13) had lower IGF-II levels (P = 0.001) and higher IGFBP-2 levels (P = 0.001) than other AIDS patients. Although no significant change in any of the IGF-parameters was observed in patients during antiretroviral therapy, patients with elevated IGFBP-3 protease activity before therapy (5 of 34) all had a decrease during treatment. During longitudinal testing in patients followed without antiretroviral therapy, disease progression was associated with increases in IGFBP-3 protease activity and IGFBP-2 levels. Our results reveal several alterations in the IGF system during HIV infection with decreased IGF-II levels, increased concentration of IGFBP-2, and an increased IGFBP-3 protease activity in advanced disease.
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PMID:The insulin-like growth factor system in human immunodeficiency virus infection: relations to immunological parameters, disease progression, and antiretroviral therapy. 1123 5

Tenofovir has been shown to cross the placenta in quantities sufficient to sustain reductions in viral load in simian immunodeficiency virus (SIV)-infected fetal monkeys. With chronic exposure (30 mg/kg), however, significant bone-related toxicity has been shown in approximately 25% of infants studied. Further investigations were conducted to determine whether the bone-related toxicity observed was initiated during fetal life. Gravid rhesus monkeys (n = 4) were administered tenofovir subcutaneously once daily from 20 to 150 days of gestation (30 mg/kg; term: 165 +/- 10 days). Fetuses were monitored sonographically, and maternal and fetal blood and urine samples were collected to assess hematologic parameters, clinical chemistry, insulin-like growth factor (IGF) levels, and bone biomarkers. Fetuses were delivered by hysterotomy near term for necropsy and evaluation of bone-related mechanical properties. Results of these studies have shown 1) normal fetal development, although overall body weights and crown-rump lengths were less than those for age-matched controls (p < or = .03); 2) a significant reduction in circulating IGF-I (p <.001); 3) a small reduction in fetal bone porosity (p < or = .03); and 4) transient alterations in maternal body weights and bone-related biomarkers during the treatment period. The results of these studies suggest that chronic fetal exposure to tenofovir at the maternal dose of 30 mg/kg throughout gestation can alter select fetal parameters and transiently affect maternal bone biomarkers.
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PMID:Fetal and maternal outcome after administration of tenofovir to gravid rhesus monkeys (Macaca mulatta). 1187 70

Increasing evidence has placed hormones and neuropeptides among potent immunomodulators, in both health and disease. Herein, we focus on the effects of growth hormone (GH) upon the thymus. Exogenous GH enhances thymic microenvironmental cell-derived secretory products such as cytokines and thymic hormones. Moreover, GH increases thymic epithelial cell (TEC) proliferation in vitro, and exhibits a synergistic effect with anti-CD3 in stimulating thymocyte proliferation, which is in keeping with the data showing that transgenic mice overexpressing GH or GH-releasing hormone exhibit overgrowth of the thymus. GH also influences thymocyte traffic: it increases human T-cell progenitor engraftment into the thymus; augments TEC/thymocyte adhesion and the traffic of thymocytes in the lymphoepithelial complexes, the thymic nurse cells; modulates in vivo the homing of recent thymic emigrants, enhancing the numbers of fluroscein isothiocyanate (FITC)+ cells in the lymph nodes and diminishing them in the spleen. In keeping with the effects of GH upon thymic cells is the detection of GH receptors in both TEC and thymocytes. Additionally, data indicate that insulin-like growth factor (IGF)-1 is involved in several effects of GH in the thymus, including the modulation of thymulin secretion, TEC proliferation as well as thymocyte/TEC adhesion. This is in keeping with the demonstration of IGF-1 production and expression of IGF-1 by TEC and thymocytes. Also, it should be envisioned as an intrathymic circuitry, involving not only IGF-1, but also GH itself, as intrathymic GH expression is seen both in TEC and in thymocytes, and that thymocyte-derived GH could enhance thymocyte proliferation. Finally, the possibility that GH improve thymic functions, including thymocyte proliferation and migration, places this molecule as a potential therapeutic adjuvant in immunodeficiency conditions associated with thymocyte decrease and loss of peripheral T cells.
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PMID:The thymus gland: a target organ for growth hormone. 1197 55

Lipodystrophy (LD) is a well-recognised clinical syndrome of peripheral fat atrophy and central adiposity, often associated with laboratory abnormalities such as dyslipidemia and glucose intolerance, and probably linked to insulin resistance. The long-term consequences of LD and its potential association with cardiovascular disease remain unknown. The visceral fat accumulation is characterised by the increased, abundant secretion of a number of peptides such as leptin, insulin-like growth factor (IGF), adiponectin and the recently reported resistin and visfatin hormones. Elevated resistin and tumour necrosis factor (TNF-alpha) levels and low levels of adiponectin secretion may have implications for the risk of development of type 2 diabetes and cardiovascular disease. LD is observed not only in rare autosomal syndromes, but also in patients positive for the human immunodeficiency virus (HIV) who have been treated with protease inhibitors. Both the origin of LD and its treatment deserve more attention and further research in clinical settings.
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PMID:Health risks of lipodystrophy and abdominal fat accumulation: therapeutic possibilities with leptin and human growth hormone. 1291 18

Mycobacterium avium is a common opportunistic infection of patients with acquired immunodeficiency syndrome (AIDS). We used the simian immunodeficiency virus (SIV)-infected rhesus macaque (Macaca mulatta) model to examine whether disseminated M. avium is associated with disruption of the somatotropic axis in AIDS. Macaques were followed prospectively, and body composition was determined by dual-energy x-ray absorption. Serum levels of insulin-like growth factor (IGF)-1, IGF binding protein-3, growth hormone (GH), and somatostatin were measured. SIV-infected macaques inoculated with mycobacteria had significant changes in body composition, perturbations of the somatotropic axis (characterized by increased GH/IGF-1 ratios) (day 0 [2.21] vs. day of death [DOD] [28.06]; P=.015, Mann-Whitney rank sum test), and increased serum somatostatin levels (day 0 [2.00 ng/mL] vs. DOD [8.58 ng/mL]; P=.026, Mann-Whitney rank sum test). These data document alterations in the somatotropic axis secondary to experimental disseminated M. avium infection and suggest that similar changes may contribute to alterations in body composition during AIDS.
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PMID:Wasting syndrome and disruption of the somatotropic axis in simian immunodeficiency virus-infected macaques with Mycobacterium avium complex infection. 1555 Dec 19


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