Biomedical subjects

P Aukrust

Publications and source records attributed to P Aukrust.

At least 109 records · Page 6Linked to original sources

PubMed1996

Markedly disturbed glutathione redox status in CD45RA+CD4+ lymphocytes in human immunodeficiency virus type 1 infection is associated with selective depletion of this lymphocyte subset.

We investigated the percentage of CD45RA+ and CD45RO+ T cells in peripheral blood and the intracellular glutathione redox balance in these lymphocyte subsets in patients with human immunodeficiency virus type 1 (HIV-1) infection and healthy controls. In HIV-1-infected patients there was a preferential depletion of CD45RA+CD4+ cells, which was most pronounced in symptomatic patients. In CD4+ lymphocytes from HIV-1-infected patients the glutathione abnormalities were clearly most pronounced in the CD45RA+ subset with a marked increase in level of oxidized glutathione and decreased ratio of reduced to total glutathione as the major characteristics. These abnormalities were shown in CD45RA+ CD4+ lymphocytes from both symptomatic and asymptomatic patients, whereas similar abnormalities in CD45RO+CD4+ cells were found only in symptomatic patients. The glutathione abnormalities in CD45RA+CD4+ lymphocytes were significantly correlated with low numbers of total CD4+ lymphocytes, decreased proportion of CD45RA+CD4+ lymphocytes, and raised serum levels of tumor necrosis factor-alpha. In the CD8+ lymphocytes a decrease in both proportion and absolute numbers of CD45RA+ cells was found, with markedly increased level of oxidized glutathione and decreased ratio of reduced to total glutathione in this subset. These findings suggest that glutathione redox disturbances in CD45RA+ T cells may be of pathogenic importance for the preferential depletion of this subset considered to represent naive T cells, during HIV-1 infection.

CD4 Lymphocyte Count↗

PubMed1996

Persistent activation of the tumor necrosis factor system in a subgroup of patients with common variable immunodeficiency--possible immunologic and clinical consequences.

In patients with common variable immunodeficiency (CVI), we have previously defined a subgroup of patients (CVIHyper) characterized by decreased numbers of CD4+ lymphocytes in peripheral blood, splenomegaly, and persistent immune activation in vivo, particularly of monocytes/macrophages. To further characterize this hyperactivity, parameters of activation of the tumor necrosis factor (TNF) system (TNF alpha and soluble TNF receptors [sTNFRs]) were measured in 24 patients with CVI and 20 healthy controls. Patients with CVI had significantly higher serum levels of TNF alpha and both types of sTNFRs, with the highest levels in the CVIHyper subgroup. In vitro, peripheral blood mononuclear cells (PBMC) and purified monocytes from CVIHyper patients spontaneously released significantly higher levels, and, after lipopolysaccharide (LPS) stimulation, significantly lower levels of TNF alpha and soluble p75-TNFR than cells from both other CVI patients and healthy controls. CVIHyper patients also had significantly higher TNF alpha:sTNFRs ratios in both serum and in unstimulated PMBC supernatants. The present study demonstrates persistent in vivo activation of the TNF system in CVI, particularly in the CVIHyper subgroup. This activation may contribute to the pathogenesis of both clinical and immunologic manifestations in CVI.

Adult↗

PubMed1996

Abnormal levels of circulating adhesion molecules in HIV-1 infection with characteristic alterations in opportunistic infections.

Adhesion molecules enabling leukocytes to communicate and adhere are essential for immunological and inflammatory responses. Circulating forms of these adhesion molecules are detected, although their influence on immunological functions is unknown. We have measured soluble levels of E-selectin, vascular adhesion molecules-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) in sera from 65 HIV-1-seropositive patients and controls. We found significantly higher levels of soluble VCAM-1 (sVCAM-1) and ICAM-1 (sICAM-1) in both symptomatic and asymptomatic HIV-1-infected patients than in controls (P <0.01). Both sICAM-1 and sVCAM-1 correlated to serum levels of neopterin (r = 0.40, P < 0.001; r = 0.46, P <0.001, respectively) and TNFalpha (r = 0.44, P < 0.01; r = 0.49, P < 0.001, respectively), while only sVCAM-1 correlated strongly to CD4+ lymphocyte count (r = -0.46, P < 0.001). Patients infected with Mycobacterium avium intracellular complex had significantly higher levels of sVCAM-1 and sICAM-1 than other AIDS patients (P < 0.05), while patients with cytomegalovirus disease had significantly lower levels both of sE-selectin and sICAM-1 (P < 0.05) than other AIDS patients. In conclusion, we found abnormal levels of circulating adhesion molecules in both symptomatic and asymptomatic HIV-1 infection including AIDS. The correlation to other parameters and clinical events may implicate involvement of circulating adhesion molecules in the immunopathogenesis of HIV-1 infection.

AIDS-Related Opportunistic Infections↗

PubMed1996

Neuropsychological deficits in HIV-1 seropositive and seronegative intravenous drug users (IVDUs): a follow-up study.

Human immunodeficiency virus type 1 (HIV-1) seropositive AIDS free and HIV-1 seronegative intravenous drug users were tested twice with a comprehensive neuropsychological test battery. Only minor group differences were found. Memory difficulties were the most pronounced difference with lower scores in the HIV-1 seropositive group. The memory difficulties were to some degree associated with emotional difficulties, that is, anxiety. The HIV-1 seropositive subjects were tested a third time and there was no further decline in any test with memory content at this testing. The only test that showed a significant decline in the HIV-1 seropositive group was the Trail Making Test.

AIDS Dementia Complex↗

PubMed1996

Elevated plasma concentration of reduced homocysteine in patients with human immunodeficiency virus infection.

Oxidative stress has been suggested to be an important factor in the immunopathogenesis of human immunodeficiency virus (HIV) infection. Reduced plasma thiols may lead to production of reactive oxygen species, thus contributing to the oxidative stress. We quantified the total, reduced, and protein-bound forms of the thiols homocysteine, cysteine, cysteinylglycine, and methionine in plasma from 21 HIV-infected patients and 15 healthy control subjects and compared the results with clinical and immunologic indexes. The HIV-infected patients had significantly higher concentrations of reduced homocysteine in plasma compared with control subjects. No significant differences in reduced homocysteine concentrations were noted when asymptomatic and symptomatic HIV-infected patients were compared, and we did not find any relation between reduced homocysteine concentrations and other markers of immunodeficiency. The HIV-infected patients had normal total homocysteine concentrations. The reduced cysteinylglycine concentration tended to be elevated in the patient group. No differences between HIV-infected patients and control subjects were found for reduced or total cysteine. Compared with control subjects, the HIV-infected patients had lower concentrations of methionine in plasma, and a significant correlation was found between low concentrations of methionine and low CD4+ lymphocyte counts in blood. Elevated concentrations of reduced homocysteine could possibly contribute to formation of reactive oxygen species, leading to accelerated immunologic deterioration and increased HIV replication.

Adult↗

PubMed1996

Disseminated Mycobacterium avium complex infection in AIDS: immunopathogenic significance of an activated tumor necrosis factor system and depressed serum levels of 1,25 dihydroxyvitamin D.

Disseminated Mycobacterium avium complex (MAC) infection is associated with considerable morbidity and mortality in patients with AIDS. Because both tumor necrosis factor-alpha (TNF-alpha) and 1,25-dihydroxyvitamin D3 (1,25D) may be involved in the normal control of MAC infection, these parameters were studied in AIDS patients with disseminated MAC infection. Of 53 AIDS patients studied, 24 had no clinical events, 11 had disseminated MAC infection, and 18 had other clinical events. Patients with disseminated MAC infection had significantly higher serum levels of both TNF-alpha and soluble TNF receptors compared with other AIDS patients; almost half of the MAC-infected patients had TNF bioactivity in serum. MAC-infected patients also had severely decreased serum 1,25D levels compared with all other AIDS patients. The activation of the TNF system was significantly correlated with the degree of 1,25D deficiency. These findings may reflect interaction between vitamin D and the TNF system in the pathophysiology of disseminated MAC infection in AIDS.

AIDS-Related Opportunistic Infections↗

PubMed1996

Reduced, oxidized and protein-bound forms of homocysteine and other aminothiols in plasma comprise the redox thiol status--a possible element of the extracellular antioxidant defense system.

Reduced, oxidized and protein-bound forms of homocysteine (Hcy), cysteine and cysteinylglycine in plasma interact via redox and disulphide exchange reactions, and these aminothiol species comprise a dynamic system referred to as redox thiol status. Notably, in plasma reduced cysteine is the most abundant low molecular weight sulfhydryl compound. Elevation of plasma Hcy (hyperhomocysteinemia) causes changes in redox thiol status. Protein-bound Hcy increases up to a maximum capacity of about 140 micromol/L, and there is a concurrent displacement of protein-bound cysteine. When the Hcy binding approaches saturation, free oxidized and reduced Hcy show a substantial increase. The resulting increase in reduced/total ratio for Hcy causes a parallel change in this ratio for the other aminothiols. These dynamics were observed during both chronic hyperhomocysteinemia (due to cobalamin deficiency or homocystinuria) and acute hyperhomocysteinemia (induced by methionine or Hcy loading). In addition, changes in redox thiol status have been observed in patients with vascular disease (decreased reduced/total ratio for cysteine), renal failure (low reduced/total ratio for aminothiols) or HIV infection (high level of reduced Hcy), which suggest primary imbalance between prooxidant and antioxidant processes in these patients. In conclusion, redox thiol status is a dynamic system which is probably linked to the extracellular antioxidant defence system. This must be taken into account when designing future experimental or epidemiological studies on Hcy and cardiovascular disease.

Animals↗

PubMed1995

Decreased levels of total and reduced glutathione in CD4+ lymphocytes in common variable immunodeficiency are associated with activation of the tumor necrosis factor system: possible immunopathogenic role of oxidative stress.

We have previously shown chronic immune activation and enhanced generation of reactive oxygen species in common variable immunodeficiency (CVI). In the present study, we examined levels of glutathione, the dominant intracellular thiol, that play an important protective role against oxidative and inflammatory stress in plasma and in monocytes and lymphocyte subsets in 20 CVI patients and in 16 healthy controls. CD4+ lymphocytes from CVI patients had significantly lower levels of both total and reduced glutathione as well as a lower ratio of reduced to total glutathione compared with healthy controls. This decrease in glutathione levels in CD4+ lymphocytes was most pronounced in the CD45RA+ subset. Plasma levels of total glutathione were also significantly decreased in CVI. In contrast, monocytes from CVI patients exhibited increased levels of both total and reduced glutathione compared with blood donor monocytes. CVI patients had significantly raised serum levels of tumor necrosis factor alpha (TNF alpha) and TNF alpha concentration was strongly associated with glutathione depletion in CD4+ lymphocytes. Furthermore, the lowest levels of both total and reduced glutathione were found in a subgroup of CVI patients characterized by persistent immune activation in vivo, decreased numbers of CD4+ lymphocytes in peripheral blood, and splenomegaly. Finally, supplementation of cell cultures with glutathione-monoethyl ester did significantly enhance interleukin-2 production from peripheral blood mononuclear cells in CVI patients. These glutathione abnormalities in CVI indicate increased oxidative stress, particularly in CD4+ lymphocytes, and intracellular depletion of reduced glutathione of the demonstrated magnitude may have profound implications for CD4+ lymphocyte function and the immunodeficiency in CVI.

Adult↗

PubMed1995

Increased levels of oxidized glutathione in CD4+ lymphocytes associated with disturbed intracellular redox balance in human immunodeficiency virus type 1 infection.

We investigated the intracellular glutathione redox status in isolated lymphocyte subpopulations and monocytes in patients with human immunodeficiency virus type 1 (HIV-1) infection and in healthy controls. CD4+ lymphocytes from HIV-1-infected patients were primarily characterized by a substantial increase in oxidized glutathione levels and a considerable decrease in the ratio of reduced to total glutathione, in most cases below 0.5 in patients with symptomatic HIV-1 infection, rather than decreased levels of reduced glutathione. The increase in oxidized glutathione was strongly correlated with low numbers of CD4+ lymphocytes in peripheral blood and impaired stimulated interleukin-2 production and proliferation in peripheral blood mononuclear cells, which is compatible with an immunopathogenic role for these redox disturbances. The HIV-1-infected patients with the most advanced clinical and immunologic disease were also characterized by an increase in levels of reduced glutathione in monocytes, suggesting that the glutathione redox cycle may be differentially regulated in CD4+ lymphocytes and monocytes. We could not confirm previous reports suggesting cysteine deficiency as a major cause of disturbed glutathione homeostasis during HIV-1 infection. The demonstrated glutathione abnormalities were correlated with raised serum levels of tumor necrosis factor alpha. These findings suggest that a therapeutical approach, which can restore the glutathione redox dysbalance in CD4+ lymphocytes and decrease the inflammatory stress, may be worthwhile exploring in HIV-1 infection.

CD4-Positive T-Lymphocytes↗

PubMed1995

Reduced serum level of transforming growth factor-beta in patients with IgA deficiency.

Seventeen patients with IgA deficiency, 13 subjects with selective IgA deficiency and 4 with a combined IgA and IgG2 deficiency, were assessed for serum levels of cytokines relevant for B cell differentiation. Transforming growth factor (TGF)-beta was quantified by bioassay and interleukin (IL)-4, IL-6, and IL-7 by immunoassay. The serum levels of TGF-beta were significantly lower in patients with IgA deficiency than in healthy blood donors. Of the patients with IgA deficiency, 4 had detectable IL-4 levels while 4 of the others had detectable IL-6 levels in serum. IL-4 and IL-6 were not detected in the controls. Serum IL-7 levels were similar in patients and controls. A significant, negative correlation was found between serum TGF-beta and the number of circulating B lymphocytes in the patients with IgA deficiency. No association was found between serum cytokine levels and the occurrence of infections at the time of study. Since TGF-beta has been implicated in IgA isotype switching in man, and our study demonstrates an association between low serum TGF-beta levels and IgA deficiency, dysregulation of TGF-beta might be a contributing factor in the pathogenesis of IgA deficiency.

Adult↗

PubMed1994

Release of cytokines, soluble cytokine receptors, and interleukin-1 receptor antagonist after intravenous immunoglobulin administration in vivo.

We investigated the in vivo effects of one bolus injection (400 mg/kg) of intravenous immunoglobulin (IVIG) on a number of cytokines, soluble cytokine receptors, and interleukin-1 receptor antagonist (IL-1Ra) in plasma in 12 patients with primary hypogammaglobulinemia. A significant and rapid increase in plasma levels of IL-6, IL-8, and tumor necrosis factor alpha (TNF alpha) was seen within 1 hour after IVIG infusion. This increase was accompanied by a more prolonged elevation in levels of both types of soluble TNF receptors (sTNFRs), which remained elevated throughout the study period (44 hours) although they reached peak levels within 1 hour. After an initial increase in the ratio between TNF alpha and sTNFRs, this ratio decreased to values significantly lower than baseline values 20 and 44 hours postinfusion with approximately 600-fold molar excess of sTNFRs to TNF alpha (trimer). Although only a modest but statistically significant increase in plasma levels of IL-1 beta was seen, IVIG infusion was followed by a marked increase in plasma levels of IL-1Ra with 1,000-fold molar excess of IL-1Ra to IL-1 beta in some patients. The demonstrated effects of IVIG infusion on the cytokine network, particularly the induction of IL-1Ra and sTNFRs release, might be important for the therapeutic effects of IVIG in several immune-mediated disorders.

Adult↗

PubMed1994

Elevated serum levels of interleukin-4 and interleukin-6 in patients with common variable immunodeficiency (CVI) are associated with chronic immune activation and low numbers of CD4+ lymphocytes.

Serum immunoreactive interleukin (IL-)1 alpha, IL-4, IL-6 and tumor necrosis factor (TNF) alpha were measured in 42 patients with primary hypogammaglobulinemia (25 common variable immunodeficiency (CVI), 10 congenital hypogammaglobulinemia (CH), 7 X-linked agammaglobulinemia (XLA), and in 21 healthy controls. The cytokine levels were correlated to other immunological parameters including serum levels of neopterin and soluble CD8 (sCD8) antigen. IL-6 was detectable in 48% and IL-4 in 36% of the CVI patients, but in none of the controls. Seventy-five percent of the CVI patients with elevated IL-4 levels had detectable IL-6. In contrast, no patients in the XLA group and only three CH patients had detectable IL-4 or IL-6 levels. TNF alpha and IL-1 alpha were detected in only a few serum samples with no significant differences between patients and controls. In the CVI group elevated IL-6 levels were significantly associated to reduced numbers of CD4+ and CD19+ lymphocytes, elevated levels of neopterin and sCD8 antigen, and occurrence of splenomegaly and bronchiectasis. The raised IL-6 levels were confirmed in longitudinal testing, probably reflecting a characteristic immunological dysregulation in these patients. Cytokine alterations may play a role in the pathogenesis of the immunodeficiency and for the clinical manifestations in CVI patients. Alternatively, elevated cytokine levels may be only a marker of chronic immune activation, particularly in monocytes, possibly delineating a distinct subgroup of patients within the heterogeneous CVI group.

Adult↗

PubMed1994

Serum levels of tumor necrosis factor-alpha (TNF alpha) and soluble TNF receptors in human immunodeficiency virus type 1 infection--correlations to clinical, immunologic, and virologic parameters.

Two EIAs (Medgenix and Quantikine) and a bioassay were used to measure tumor necrosis factor-alpha (TNF alpha) in serum samples from 73 human immunodeficiency virus type 1 (HIV-1)-seropositive patients and in samples from 2 control groups. All clinical groups of HIV-1-infected patients, regardless of concurrent illness, had significantly elevated levels of both types of soluble TNF receptors (sTNFRs) and immunoreactive TNF alpha (Medgenix EIA), with the highest concentrations among the AIDS patients. These TNF parameters were significantly correlated with reduced CD4+ lymphocyte counts. Only a few HIV-1-infected patients had detectable TNF alpha levels measured by the Quantikine EIA. TNF alpha bioactivity was significantly raised only in the AIDS group. Serially measured sTNFRs, expressed as sTNFR slopes, were significantly associated with survival in the patient group. The raised levels of immunoreactive TNF alpha and sTNFRs strongly indicate activation of the TNF alpha system during HIV-1 infection. Levels increase with disease progression and degree of immunodeficiency; thus, serially measured sTNFRs may give useful prognostic information in HIV-1 infection.

Adult↗

PubMed1994

Subnormal serum concentration of 1,25-vitamin D in human immunodeficiency virus infection: correlation with degree of immune deficiency and survival.

Vitamin D metabolites, immunologic, virologic, and clinical parameters, and survival time were determined in 22 asymptomatic human immunodeficiency virus (HIV)-infected patients (CDC stage II/III), 31 symptomatic HIV-infected patients (CDC stage IV), and 28 HIV-seronegative controls. Significantly lower serum levels of 1,25-vitamin D (1,25D) were found in symptomatic patients (median, 34 pg/mL; 25th-75th percentile, 21-45) compared with controls (49 pg/mL; 39-59) and asymptomatic patients (45 pg/mL; 42-50). In HIV-infected subjects, the serum level of 1,25D was positively correlated with CD4+ cell counts in peripheral blood (r = .35, P < .05) and negatively correlated with the level of serum neopterin (r = -.36, P < .01). HIV-infected patients with abnormally low 1,25D (< 25 pg/mL) also had shorter survival times than other HIV-infected subjects (P < .01). Low 1,25D levels did not appear to be related to vitamin D deficiency.

Acquired Immunodeficiency Syndrome↗

PubMed1994

Enhanced generation of reactive oxygen species in monocytes from patients with common variable immunodeficiency.

Monocyte and macrophage dysfunction may be important for both immunopathogenesis and clinical manifestations in subgroups of patients with primary hypogammaglobulinaemia. In the present study we examined the ability to generate reactive oxygen species (ROS) in isolated monocytes from these patients by two different methods: superoxide dismutase (SOD) inhibitable cytochrome c reduction by O2- and nitroblue tetrazolium (NBT) reduction. Monocyte from patients with common variable immunodeficiency (CVI) demonstrated significantly enhanced ROS generation both unstimulated and stimulated (unopsonized zymosan and phorbol myristate acetate (PMA)). The enhanced oxidative burst response in CVI patients was found both with and without serum containing medium. Furthermore, serum from CVI patients did significantly enhance the oxidative burst response in monocytes from healthy blood donors compared with the effect of control serum. The enhanced ROS generation in CVI patients was significantly correlated with elevated serum levels of neopterin, reduced numbers of CD4+ lymphocytes in peripheral blood and occurrence of splenomegaly. In contrast to the CVI group, monocytes from patients with X-linked agammaglobulinaemia (XLA) did not show enhanced ROS generation. The increased oxidative burst response in monocytes from CVI patients most probably reflects in vivo activation of these cells. Our observations indicate the presence of a subgroup of CVI patients characterized by chronic immune activation particularly of monocytes. The enhanced ROS generation might be involved in immunopathogenesis (e.g. T cell dysfunction) and in the pathogenesis of clinical manifestations (e.g. malignancies and autoimmune disorders) in these patients.

Adult↗

PubMed1994

Psychological difficulties related to human immunodeficiency virus-1 infection in intravenous drug users.

Psychopathology and emotional changes were examined over a 9-month period in this study of human immunodeficiency virus-1 (HIV-1) infection in seronegative and seropositive intravenous drug users. The HIV-1-seropositive group showed more psychological difficulties and emotional distress at both testings. For the HIV-1-seronegative subjects, a trend for less psychopathology and psychological distress was found. At the second testing, the difference between groups was increased due to improvement of the HIV-1-seronegative group. A more chronic course of psychological distress was found in the HIV-1-seropositive group.

Adult↗

PubMed1994

Elevated serum calprotectin levels in HIV-infected patients: the calprotectin response during ZDV treatment is associated with clinical events.

The calcium-binding myelomonocytic protein calprotectin (L1 protein) was quantified in serum from 51 patients with HIV infection and in 20 HIV-seronegative blood donors. Significantly elevated levels were found both in asymptomatic patients and in people with AIDS compared with controls. The calprotectin level was not related to ongoing or recent opportunistic infections. For patients with CD4+ counts above 50 x 10(6)/L, a significant negative correlation was found between serum calprotectin levels and the CD4+ counts. Serial samples from 24 patients during their first year of zidovudine (ZDV) treatment showed a further elevation of serum calprotectin during the first months of ZDV treatment, with a subsequent decline to pretreatment levels. A low calprotectin response during the first 6 months, determined as area under the curve, was associated with the occurrence of at least one AIDS-defining infection during the first year of antiviral treatment. Also, a low calprotectin maximal response during ZDV therapy was associated with short survival. Similar associations were not found for neopterin, beta 2-microglobulin, HIV p24 antigen, or CD4+ or CD8+ lymphocytes in blood. Our findings in a limited number of patients suggest that calprotectin levels may reflect immune activation and other immune mechanisms correlated with enhanced antimicrobial defense induced at least transiently by antiviral treatment.

AIDS-Related Opportunistic Infections↗

PubMed1993

Neuropsychological deficits in HIV-1 seropositive and seronegative intravenous drug users.

A battery of neuropsychological tests was administered to detoxified HIV-1 seropositive and seronegative intravenous drug users. There were few problems related to administering the test battery to the groups in question. Of the total sample, 28% obtained an Halstead-Reitan Impairment Index > .4, indicating central nervous system deficits. Both groups performed below comparable normative levels on the variables studied. The HIV-1 infection per se could not explain the neuropsychological impairment.

Adult↗