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Biomedical subjects

D Fuchs

Publications and source records attributed to D Fuchs.

At least 181 records · Page 10Linked to original sources
PubMed1995

Conformational investigation of the cofactor (6R,1'R,2'S-)-5,6,7,8-tetrahydrobiopterin.

(6R,1'R,2'S)-5,6,7,8-Tetrahydrobiopterin is an essential cofactor for several enzymes. Different theoretical models (molecular mechanics, semiempirical quantum chemical calculations) investigating its stereostructure have yielded diverging answers. To clarify these issues, combined molecular mechanical and ab initio quantum chemical calculations were performed, investigating both the axial and the equatorial orientation of the dihydroxypropyl side-chain. After geometry optimization, the resulting most stable structures were subjected to systematic variation of two side-chain torsional angles in order to study the conformational flexibility. The axial side-chain orientation is slightly more stable than the equatorial form. Two weak intramolecular hydrogen bonds contribute to stabilization of the axial conformer, while in the equatorial conformer only one hydrogen bond is detected. An 8 ps molecular dynamical simulation at 310 K suggests that, at realistic temperatures, the molecule is flexible enough to undergo internal motions (rotations, vibrations), rendering questionable the biological significance of mere conformational properties.

Biopterins↗
PubMed1995

Effect of neopterin and 7,8-dihydroneopterin on tumor necrosis factor-alpha induced programmed cell death.

Tumor necrosis factor-alpha and the formation of reactive oxygen intermediates are central mediators of apoptosis. Recent data indicated a role of neopterin and 7,8-dihydroneopterin in oxygen radical mediated processes. We have therefore investigated the effect of neopterin-derivatives on TNF alpha induced apoptosis of the monocyte-like cell line U937. At an elevated concentration 7,8-dihydroneopterin was found to superinduce TNF alpha mediated programmed cell death due to the formation of reactive oxygen intermediates. Our results imply that in combination with TNF alpha high concentrations of 7,8-dihydroneopterin enhances apoptosis due to oxidative stress on cells.

Acetylcysteine↗
PubMed1995

Interleukin-13 effectively down-regulates the monocyte inflammatory potential during traumatic stress.

OBJECTIVES: To determine the potential of interleukin-13 (IL-13) to modify in vitro lipopolysaccharide-induced monocyte-macrophage (MO) activity in human cells from individuals who had sustained either major mechanical or burn injury and to investigate whether the effect of IL-13 is different on MOs that have been preactivated under traumatic stress than on monocytic cells from healthy volunteers. DESIGN: Peripheral MOs from 20 controls and 16 patients after major burn or mechanical trauma were separated on days 1, 3, 5, and 7 after injury and incubated with lipopolysaccharide (1 microgram/mL) in the presence or absence of IL-13 (10 ng/mL) for 4 hours and for 20 hours. Thereafter, the following measures were determined from the culture supernatants: neopterin, nitric oxide, tumor necrosis factor alpha, IL-1 beta, IL-6, and IL-8. RESULTS: Ex vivo lipopolysaccharide-activated MOs, compared with control cells, displayed considerably enhanced inflammatory activity during the immediate posttraumatic course, with a substantial and consistent elevation of levels of tumor necrosis factor alpha and IL-6. The addition of human recombinant IL-13 to the MO cultures resulted in an effective down-regulation of the synthesis of tumor necrosis factor alpha, IL-1 beta, and IL-6 as well as IL-8, showing an average reduction of mediator production to two thirds of the value found in corresponding sole lipopolysaccharide-stimulated cultures. The impact of human recombinant IL-13 on control MOs was almost identical for IL-6 and IL-1 beta, slightly lower for IL-8, and nonexistent for tumor necrosis factor alpha. CONCLUSION: From this study and preexisting findings, we conclude that, based on its biologic properties, IL-13 should be tested as a biologic response modifier for acute states of trauma-induced host defense deficiency.

Adult↗
PubMed1995

Neopterin and soluble tumor necrosis factor receptor type I in alcohol-induced cirrhosis.

Alcohol-induced cirrhosis (AC) is accompanied by disturbances of immune function and cytokine production. To better define the pattern of cytokine synthesis in this disease and to relate it to the immune activation state, we measured circulating levels of soluble tumor necrosis factor receptor p55 (sTNFR-55) and neopterin in a group of 85 patients with AC (classified according to the Child-Pugh score of severity of liver disease) and 43 healthy volunteers. Serum concentrations of sTNFR-55 and neopterin were significantly raised in patients with AC. Moreover, concentrations of sTNFR-55 were significantly higher in patients with more severe disease compared with the group with lower severity. There were significant correlations between sTNFR-55 and neopterin levels in patients and controls. The results contribute to affirm the existence of an immune activation state in AC that could be responsible for the development of the disease and clinical complications.

Biopterins↗
PubMed1995

Serum-soluble receptors for tumor necrosis factor-alpha and interleukin-2, and neopterin in acute rheumatic fever.

Immune activation may play an important role in the pathogenesis of acute rheumatic fever (ARF). The objective of the present study was to investigate serum concentrations of various markers of immune activation in ARF patients. Sera of 32 patients with ARF were investigated, 20 of them in follow-up. Radioimmunoassay was used to quantify neopterin and ELISA for the measurement of 55-kDa-type soluble tumor necrosis factor receptor (sTNF-R) and soluble interleukin-2 receptor (sIL2-R). Markers of immune activation were found to be raised in 48% (sTNF-R), 28% (sIL2-R), and 78% (neopterin) of patients at the onset of ARF. There were significant correlations between the concentrations of neopterin and sTNF-R (rs = 0.60, P < 0.001) or sIL2-R (rs = 0.35, P < 0.05). Higher neopterin concentrations were found in patients with combined aortic and mitral insufficiency than in patients with mitral valve lesions alone (U = 2.67, P < 0.05) or without valve lesion (U = 2.36, P < 0.05). Increased concentrations of neopterin, sTNF-R, and sIL2-R demonstrate activation of the cellular immune system in patients with ARF. Higher serum neopterin concentrations are associated with development of combined aortic and mitral insufficiency during the first episode of ARF.

Acute Disease↗
PubMed1995

Linkage of cell-mediated immunity to iron metabolism.

Iron is essential for growing microorganisms and tumour cells, and is also crucial for the proliferation of immune cells. In this review, Günter Weiss, Helmut Wachter and Dietmar Fuchs focus on the complex network of interactions that link iron metabolism with cellular immune effector functions involving cytokines and nitric oxide, and draw a suitable model for the pathogenesis of anaemia of chronic disease.

Animals↗
PubMed1995

Effects of pteridines on luminol-dependent chemiluminescence induced by chloramine-T.

Pteridines are ubiquitous in living organisms, but little is known about their biological functions. Different pteridines were tested for their ability to modulate luminol-dependent chemiluminescence induced by chloramine-T at pH = 7.5 and at a concentration of 100 microM for each pteridine. We observed striking differences between the compounds; whereas reduced pteridine species were generally potent scavengers, aromatic pteridines were weak to strong enhancers of the chemiluminescence. Taking into account the detailed chemical structure of the molecules, by multiple linear regression analysis a simple index was constructed that allows prediction of the effects of the different pteridines with high accuracy (linear correlation coefficient between predicted and observed values r = 0.89). The effects of different pteridines on free radical-induced chemiluminescence might bear biological significance since, for example, certain pteridines take part in enzymic reactions involving free-radical intermediates, or are related to the activation of macrophages in close relationship with the oxidative burst.

Animals↗
PubMed1995

Serum nitrite plus nitrate in infection with human immunodeficiency virus type-1.

To get a measure of the extent of induction of nitric oxide synthase in infection with human immunodeficiency virus type-1 (HIV-1) in vivo, we estimated serum nitrite plus nitrate concentrations in 110 HIV-1 infected individuals compared to 76 blood donors. To monitor cytokine action and to measure induction of pteridine synthesis, we determined in parallel neopterin, biopterin, soluble tumor necrosis factor-alpha receptor 55 and 75, and beta 2-microglobulin. Serum nitrite plus nitrate concentrations were elevated in patients as compared to blood donor controls. In sera of patients, nitrite plus nitrate levels correlated significantly with neopterin, soluble tumor necrosis factor receptor 55 and 75, and beta 2-microglobulin. Nitrite plus nitrate levels were higher and correlations were stronger in groups of patients with lower CD4+ cell count. These results suggest that cytokine-mediated nitric oxide synthesis occurs in individuals with HIV-1 infection.

Adult↗
PubMed1995

Repeated exposure of rhesus macaques to low doses of simian immunodeficiency virus (SIV) did not protect them against the consequences of a high-dose SIV challenge.

As part of an in vivo titration study of the macaque simian immunodeficiency virus (SIVmac) strain 251/spl, macaques were inoculated intravenously with various dilutions of this infectious SIVmac. Seven animals received dilutions from 10(-3) to 10(-6) of SIVmac251/spl. Two monkeys infected with the 10(-3) dilution of SIVmac exhibited a productive infection as indicated by seroconversion, detection of genomic RNA and proviral DNA and positive virus isolation. These animals showed a cytotoxic T cell (CTL) response against different SIVmac proteins without any measurable T cell proliferation. The five macaques receiving higher virus dilutions did not seroconvert and were negative for both viral RNA and for infectious virus, although proviral DNA was detected in their peripheral blood mononuclear cells. In contrast to the animals receiving the 10(-3) virus dilution, these five silently infected monkeys developed an SIV-specific proliferative T cell response but SIV-specific CTL could not be observed. The SIV-specific T cell proliferation of the silently infected animals could be boosted by a second low-dose exposure with a 10(-4) or 10(-5) dilution of SIVmac251/spl. The virological status of the animals was not changed following this second virus inoculation. Four months later these macaques were challenged intravenously with 2 ml of a 10(-4) dilution of SIVmac251/32H containing 10 monkey ID50. After this challenge all SIV-pre-exposed animals and three naive controls became productively infected. In addition, all infected animals developed typical signs of an immunodeficiency within 6 months after infection. These observations indicate that macaques infected silently by a low-dose exposure to infectious virus generated a virus-specific cellular immune response. However, SIV-specific T cell proliferation alone could not protect the monkeys against an intravenous challenge with SIVmac and the subsequent development of AIDS-like symptoms.

Animals↗
PubMed1995

Soluble receptors for tumour necrosis factor in clinical laboratory diagnosis.

Soluble tumour necrosis factor receptors (sTNF-Rs) play a role as modulators of the biological function of tumour necrosis factor-alpha (TNF-alpha) in an agonist/antagonist pattern. In various pathologic states the production and release of sTNF-Rs may mediate host response and determine the course and outcome of disease by interacting with TNF-alpha and competing with cell surface receptors. The determination of sTNF-Rs in body fluids such as plasma or serum is a new tool to gain information about immune processes and provides valuable insight into a variety of pathological conditions. Regarding its immediate clinical use, sTNF-Rs levels show high accuracy in the follow-up and prognosis of various diseases. In HIV infection and sepsis, sTNF-Rs concentrations strongly correlate with the clinical stage and the progression of disease and can be of predictive value. Determination of sTNF-Rs also gives useful information for monitoring cancer and autoimmune diseases. The information provided is often even superior to that obtained with classical disease markers, probably due to the direct involvement of the "TNF system" in the pathogenetic mechanisms in these patients. The available data imply that the measurement of sTNF-Rs, especially of the sTNF-R 75kD type, is a useful adjunct for quantification of the Th1-type immune response, similar to other immune activation markers such as neopterin and beta 2-microglobulin. Endogenous sTNF-Rs concentrations appear to reflect the activation state of the TNF-alpha/TNF receptor system.

Communicable Diseases↗
PubMed1995

Detection of bacterial pyrogens on the basis of their effects on gamma interferon-mediated formation of neopterin or nitrite in cultured monocyte cell lines.

In a number of mammalian cell types, pteridine biosynthesis from guanosine 5'-triphosphate and formation of nitric oxide from L-arginine are induced by gamma interferon (IFN-gamma) and bacterial lipopolysaccharide (LPS). We assessed the possibility of using such metabolic alterations for the in vitro detection of pyrogens. Products from gram-negative and gram-positive bacteria and related synthetic compounds were tested for their potential to induce either of these pathways. Stimulation of pteridine biosynthesis was monitored as the formation of neopterin in the human myelomonocytic cell line THP-1. The formation of nitric oxide was determined as nitrite in murine J774A.1 macrophage cultures. The substances tested included toxic and detoxified parts of LPS and lipid A from Escherichia coli, Salmonella typhimurium, Salmonella minnesota, and Klebsiella pneumoniae as well as lipoteichoic acid and toxic shock syndrome toxin 1 from Staphylococcus aureus. Furthermore, two cell wall compounds from Mycobacterium tuberculosis, trehalose 6,6'-dimycolate and N-acetylmuramyl-L-alanyl-D-isoglutamine, which are active components of Freund's adjuvant, were used. When applied as a single stimulus, only the whole LPS molecule potently stimulated neopterin or nitrite formation. Lipid A and products from gram-positive bacteria were weakly active. For neopterin formation, lipid A required the presence of fetal calf serum. Besides detoxified LPS and independently from the presence of serum, all bacterial compounds tested strongly increased the effects mediated by IFN-gamma. Our results show that bacterial pyrogens can be detected by monitoring the formation of neopterin or nitrite. This may provide a basis for the development of an in vitro assay for the detection of pyrogenic contamination with the aim of replacing the currently used animal test.

Animals↗
PubMed1995

Reactivation of human immunodeficiency virus type 2 in macaques after simian immunodeficiency virus SIVmac superinfection.

By superinfection of human immunodeficiency virus type 2 (HIV-2) strain HIV-2ben-infected macaques with simian immunodeficiency virus (SIV) strain SIVmac, we investigated the mutual influences of an apathogenic and a pathogenic virus in vivo. Four rhesus and two cynomolgus monkeys were infected with HIV-2ben in 1988 and 1989, respectively. Virus could be reisolated from five of six animals 6 weeks after infection. The monkeys remained healthy over the next 2 to 3 years. PCR for viral RNA became negative, and virus could no longer be reisolated by coculture. All six macaques were superinfected with the pathogenic SIVmac251/32H. Subsequently, five monkeys became persistently viremic, while one animal was protected against the SIVmac infection. In the peripheral blood mononuclear cells and cocultures of the five viremic animals, DNA from both HIV-2 and SIVmac was present. The plasma contained RNA from both viruses. Thus, superinfection with SIVmac activated HIV-2. A proliferative T-cell response against both HIV-2 and SIVmac was measured in all animals after superinfection. Such a response was regularly seen after infection with the apathogenic HIV-2 but never when the pathogenic SIVmac alone was administered. While naive control monkeys inoculated with SIVmac251/32H regularly develop AIDS-like symptoms soon after infection and have to be killed, none of the preinfected animals has developed AIDS-like symptoms, but two of six animals developed tumors. After the SIVmac challenge, however, apoptotic lymphocytes were detected in the peripheral blood mononuclear cells of all animals. Thus, the presence of an apathogenic viral variant seems to retard the disease occurring after infection with a pathogenic virus rather than to confirm total protection. This partial protection appears to depend on a specific proliferative T-cell response early after infection.

Animals↗
PubMed1995

vpr deletion mutant of simian immunodeficiency virus induces AIDS in rhesus monkeys.

In previous experiments, animals infected with SIVmac239 containing a point mutation in the vpr and nef genes developed AIDS-like symptoms after early reversion of the vpr and nef genes. Here we show that two animals in which the nef gene but not the vpr gene had reverted in the first few months did not develop disease during a 3-year observation period even after reversion to a functional vpr gene 70 weeks postinfection. To study the influence of a stable vpr mutation on virus load and pathogenesis, a 43-bp deletion was introduced into the vpr gene of SIVmac239on, a nef-open mutant of SIVmac239. Four rhesus monkeys were inoculated with the vpr deletion mutant (SIV delta vpr), and two control animals were infected with SIVmac239on. Both control animals had persistent antigenemia, high cell-associated virus loads, and elevated neopterin levels. They had to be euthanized 20 and 30 weeks postinfection because of AIDS-related symptoms. However, all four rhesus monkeys inoculated with SIV delta vpr showed only transiently detectable antigenemia. The cell-associated virus loads were high in three of the four animals. Two animals with AIDS-like symptoms had to be euthanized 71 and 73 weeks postinfection. The two remaining monkeys infected with SIV delta vpr were still alive 105 weeks postinfection. In contrast to the SIVmac239on-infected animals, SIV delta vpr-infected animals had strong humoral immune responses and intermittent cellular immune responses to SIV antigens. Our data show that a functional vpr gene is not necessary for pathogenesis. However, vpr-deficient SIVmac239 variants might be slightly attenuated, allowing some animals to resist progression to disease for an extended period of time.

Animals↗
PubMed1995

Serum soluble markers of immune activation and disease activity in systemic lupus erythematosus.

We investigated a possible association between markers of immune activation and disease activity in 52 patients with systemic lupus erythematosus (SLE). Serum concentrations of neopterin, beta-2-microglobulin, 55 kD-type soluble tumor necrosis factor receptor, soluble interleukin-2 receptor and soluble CD8 were compared to the Index of European Consensus Lupus Activity Measurement (ECLAM). All markers of immune activation, except sCD8, significantly correlated with ECLAM. Stepwise multiple linear regression analysis revealed erythrocyte sedimentation rate and neopterin to correlate best with ECLAM (multiple correlation coefficient = 0.74, P < 0.001). The study shows that serum neopterin concentrations are a useful independent index for disease activity in SLE. The finding of enhanced concentrations of various parameters of immune activation in patients confirm a role of the T cell and macrophage activation in the pathogenesis of SLE.

Adolescent↗
PubMed1995

Predictive value of urinary neopterin in patients with lung cancer.

Concentrations of neopterin, which is produced by human monocytes/macrophages when stimulated by gamma-interferon, were measured in urine specimens from 72 patients with lung cancer at diagnosis. Other routine clinical and laboratory variables were concomitantly determined. Neither neopterin nor any other laboratory variable studied showed a significant correlation with clinical indicators of the disease (morphologic type, tumour stage, grading, lymph node status, presence of distant metastases). The cancer patients were followed up for up to 10 years, and the abilities of all variable to predict fatal outcome were assessed. In univariate survival analyses, all clinical indicators except morphologic type (P = 0.86) were significant predictors of survival (P < 0.002), but of all the laboratory variables studies, only neopterin was significantly predictive (P = 0.0013). By multivariate survival analysis, a combination of four variables was found to jointly predict survival: lymph node status (P = 0.003), multivariate model), tumour stage (P = 0.0006), grading (P = 0.0047) and neopterin (P = 0.0047). The data suggest that certain aspects of immune activation may have adverse consequences for the prognosis of patients with lung cancer.

Adult↗
PubMed1995

Longitudinal immunological follow-up of HIV infected haemophiliacs in Hungary.

Twenty-five haemophiliacs who had been infected with HIV in 1982 or 1983 were followed up from 1986 to 1993. The absolute number of the CD4+ and CD8+ cells, neopterin levels and more recently the percentage of activated, DR+ T lymphocytes were determined twice a year. In most patients a permanent decline in the CD4+ cell count was observed whereas in two HIV-infected haemophiliacs the absolute number of CD4+ cells did not change during the observation period. In these long-term non-progressor patients no clinical symptoms and no increased neopterin levels were observed. T cells subset and neopterin measurements were found to predict the development of AIDS. AIDS developed only in those patients who exhibited both a CD4+ cell count of < 350/microliter and a serum neopterin concentration of > 20 nmol/l. A negative correlation was observed between the percentage of activated. DR+ T lymphocytes and the CD4+ cell counts.

Adolescent↗