PubMed Health⌕ Search

Biomedical subjects

E R Werner

Publications and source records attributed to E R Werner.

At least 109 records · Page 6Linked to original sources
PubMed1991

Brain nitric oxide synthase is a biopterin- and flavin-containing multi-functional oxido-reductase.

Brain nitric oxide synthase is a Ca2+/calmodulin-regulated enzyme which converts L-arginine into NO. Enzymatic activity of this enzyme essentially depends on NADPH and is stimulated by tetrahydrobiopterin (H4biopterin). We found that purified NO synthase contains enzyme-bound H4biopterin, explaining the enzymatic activity observed in the absence of added cofactor. Together with the finding that H4biopterin was effective at substoichiometrical concentrations, these results indicate that NO synthase essentially depends on H4biopterin as a cofactor which is recycled during enzymatic NO formation. We found that the purified enzyme also contains FAD, FMN and non-heme iron in equimolar amounts and exhibits striking activities, including a Ca2+/calmodulin-dependent NADPH oxidase activity, leading to the formation of hydrogen peroxide at suboptimal concentrations of L-arginine or H4biopterin.

Amino Acid Oxidoreductases↗
PubMed1991

Induction of indoleamine 2,3-dioxygenase in human cells in vitro.

IFN-gamma is the most effective principle responsible for IDO induction in human cells in vitro. Lymphocyte factors support the effect of other IFN species. Induction of IDO and influence of various factors on IDO is correlated to pteridine synthesis. Cooperative effects of several mediators may account for in vivo observations concerning enhanced excretion of neopterin and tryptophan metabolites in certain disease states.

Biopterins↗
PubMed1991

Neopterin and beta 2-microglobulin as prognostic indices in human immunodeficiency virus type 1 infection.

The great majority of individuals with human immunodeficiency virus type 1 (HIV-1) infection presents with no signs or symptoms, or only lymphadenopathy. To initiate prophylactic measures in time it is necessary to establish risk criteria. CD4+ cell counts are significant predictors. Supplementary methods to improve the predictive information of CD4+ cell counts are still required. In addition, CD4+ cell counting is laborious, expensive, and restricted to specialized laboratories. Thus, there is also a place for more easily performed laboratory tests with similar predictive value as CD4+ cell counts. Neopterin and beta 2-microglobulin levels proved to be significant predictors of AIDS risk in HIV-1 seropositives. The predictive value of both parameters is equal to CD4+ cell counts and both markers are significant joint predictors in addition to CD4+ cell counts. Measurement of the parameters is done in serum (neopterin and beta 2-microglobulin) or urine (neopterin) specimens which reduces the risk of HIV-1 transmission compared to handling of whole-blood samples as it is required for cell counting. Although more studies are needed, especially in developing countries and in persons receiving zidovudine, it can be recommended to use neopterin and beta 2-microglobulin as additional marker to estimate AIDS risk in HIV-1 seropositive individuals. Moreover, both markers may be useful for this purpose without CD4+ cell counts if cell counting is not available.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Increased endogenous interferon-gamma and neopterin correlate with increased degradation of tryptophan in human immunodeficiency virus type 1 infection.

Reduced tryptophan and increased kynurenine concentrations have been reported in patients with human immunodeficiency virus type 1 (HIV-1) infection. From in vitro data it appears that activated indoleamine 2,3-dioxygenase (IDO) is involved in this metabolic change. IDO is inducible by interferon-(IFN)-gamma. We compared serum concentrations of IFN-gamma and neopterin (the biosynthesis of which is also inducible by IFN-gamma) with serum, tryptophan and kynurenine of 42 patients with HIV-1 infection. IFN-gamma, neopterin and kynurenine levels were significantly increased compared to HIV-1 seronegative controls whereas tryptophan was significantly decreased. Various significant correlations were found between tryptophan, kynurenine, IFN-gamma and neopterin concentrations. Highest degree of correlation was found between neopterin, IFN-gamma and the kynurenine per tryptophan quotient which is the ratio between the product and the substrate concentration of IDO. The data indicate that decreased tryptophan in HIV-1 seropositives may result from chronic immune activation and can be referred to increased activation of IDO.

Adult↗
PubMed1991

Negative correlation between blood cell counts and serum neopterin concentration in patients with HIV-1 infection.

Hematopoietic disturbances are common in patients with HIV-1 infection. Recent studies on immune activation markers such as neopterin demonstrate that HIV-1 infection is associated with chronic immune activation. We investigated a possible association between serum neopterin concentrations and blood cell counts (CD4+ T cells, white blood cells, platelets, red blood cells) and hemoglobin and hematocrit in 94 HIV-1-seropositive individuals [52 Walter Reed (WR) stage 1, 31 WR2, one WR5, and 10 WR6]. There were significant negative correlations between neopterin concentrations and CD4+ T cells, hemoglobin, hematocrit and platelets. These correlations were also significant if either only WR1 and WR2 patients or the entire set of data were considered for calculations. Thus, hematological abnormalities are associated with chronic immune activation in patients with HIV-1 infection. Large amounts of neopterin are released by human macrophages on stimulation with interferon-gamma (IFN gamma), and tumor necrosis factor alpha (TNF alpha) further enhances the effect of IFN gamma. Therefore, our data suggest that activated immune cells and specific cytokines such as IFN gamma and TNF alpha are involved inhibiting hematopoiesis.

Biopterins↗
PubMed1991

Posttransplant neopterin excretion in renal allograft recipients--a reliable diagnostic aid for acute rejection and a predictive marker of long-term graft survival.

During the immediate posttransplant period, daily measurements of urinary neopterin, which is produced by stimulated macrophages, were evaluated in 294 consecutive recipients of renal allografts for their diagnostic value in acute graft rejection. The ability of mean and peak neopterin excretion values to predict long-term graft survival was analyzed on the basis of an eight-year follow-up. Immunosuppressive therapy (cyclosporine +/- prednisone versus azathioprine + prednisone) and initial nonfunction did not influence neopterin excretion. In patients with rejection episodes and in those with infections, neopterin levels were significantly increased. Diagnostic sensitivity and specificity with regard to rejection diagnosis were assessed for different levels of neopterin. By statistical analysis, a significant association between increased neopterin and higher risk of rejection was found, which was particularly pronounced in patients receiving cyclosporine. Increase in neopterin excretion preceded clinical rejection diagnosis by up to four days. Peak neopterin values above 800 mumols/mol urinary creatinine observed during the posttransplant period, were associated with significantly poorer graft survival. A multivariate analysis showed that peak neopterin levels, age of patients, and early posttransplant presence/absence of acute rejection were significant and independent joint predictors for long-term graft survival. Measurement of neopterin can be of help as an additional marker in early diagnosis of renal allograft rejection, and high neopterin values during the initial posttransplant period are associated with poorer long-term graft survival.

Adolescent↗
PubMed1991

Change in HIV-antibody seroprevalence rates in i.v. drug dependent prisoners.

In 1985 a high HIV-seroprevalence (44.2%) was found in a cohort of parenteral drug addicted prisoners in Innsbruck, Austria. In a longitudinal study from March 1985 to March 1989 we investigated the epidemiology of HIV-infection as well as possible changes in the drug taking behaviour of this defined population at risk. During the study HIV-seroprevalence rates in drug dependent prisoners showed a statistical decrease to 30%. A concomitant increase in admission to any kind of therapy programmes as well as an increasing change from 'heavy use' (mainly taking heroin i.v.) to 'non-heavy use' (mainly taking drugs orally) could be noted. The influence of preventive measures, such as comprehensive AIDS-information, special therapy programmes including the methadone substitution programme, and the unrestricted availability of needles and syringes is discussed.

Adolescent↗
PubMed1991

Immune activation and the anaemia associated with chronic inflammatory disorders.

Chronic inflammatory disorders are associated with an increased risk of patients developing anaemia. There is some evidence that cytokines released during cell-mediated immune responses are capable of inhibiting bone marrow haematopoiesis. In vitro, interferon gamma and tumour-necrosis factor alpha inhibit growth of erythroid precursor cells. The mode of action of these cytokines is probably associated with their antiproliferative capacity. Decrease of serum iron and increase of storage iron in patients appears to be a consequence of the defense strategy of macrophages during long-lasting inflammatory disorders. Decreased serum iron correlates to decreased haemoglobin concentrations. In view of this, the development of anaemia seems likely to result from the altered iron metabolism induced by stimulated macrophages. Low haemoglobin levels and associated hypoxia up-regulate the release of erythropoietin, which can explain why increased circulating erythropoietin is usually found in patients with anaemia.

Anemia↗
PubMed1991

Biochemistry and function of pteridine synthesis in human and murine macrophages.

We investigated intracellular pteridine concentrations, activities of pteridine biosynthetic enzymes and formation of nitrogen oxides from arginine in human peripheral-blood-derived macrophages and in myelomonocytoma (THP-1) cells, as well as in murine peritoneal and spleen-derived macrophages and in murine macrophage lines (P388-D1, J774-A.1). Interferon-gamma (IFN-gamma) induces the activity of GTP-cyclohydrolase I up to 40-fold in human cells. In human macrophages and THP-1 cells, this induced activity is higher than the constitutively present activity of the subsequent enzyme, the 6-pyruvoyltetrahydropterin synthase. As a consequence, large amounts of neopterin are formed during IFN-gamma-triggered synthesis of tetrahydrobiopterin. Murine macrophages constitutively synthesize tetrahydrobiopterin. The activity of GTP-cyclohydrolase I remains unchanged by treatment with IFN-gamma or tumor necrosis factor-alpha. This activity is lower than the subsequent 6-pyruvoyltetrahydropterin synthase activity, thus explaining the lack of neopterin in murine cells, tissues and body fluids. Inhibition and reconstitution of pteridine synthesis in activated murine macrophages by specific drugs demonstrate that tetrahydrobiopterin regulates the amount of nitrogen oxides formed from arginine in intact cells, thus providing a rationale for therapeutic intervention.

Alcohol Oxidoreductases↗
PubMed1991

Low haemoglobin in haemophilia children is associated with chronic immune activation.

Anaemia is a frequent complication in patients with human immunodeficiency virus type 1 (HIV-1) infection. We tested 14 children with severe haemophilia (9 HIV-1 antibody seropositive CDC stage IIA, 5 seronegative) for haemoglobin and urinary neopterin concentrations and found a negative correlation between neopterin and haemoglobin (rs = -0.745, p = 0.007; Spearman's rank correlation). This finding suggests that chronic immune activation, possibly along with the release of specific cytokines such as interferon gamma and tumor necrosis factor alpha may be involved in the pathogenesis of anaemia.

Adolescent↗
PubMed1991

Neopterin as a marker for activated cell-mediated immunity: application in malignant disease.

A review is presented on studies concerning neopterin determination in patients with malignant neoplastic diseases. Neopterin is produced chiefly by human macrophages through their activation by T-cell-derived interferon gamma. In vivo, determinationof neopterin in various body fluids provides a convenient way to monitor early events that are involved in cell-mediated immune responses. In malignant neoplasia, elevation of neopterin concentrations in body fluids depends on tumor type. Within a given type of tumor, more advanced stages are generally associated with higher levels than early disease. In a variety of different tumor types and sites, a significantly poorer prognosis was associated with high pretherapeutic neopterin concentrations. This predictive value is independent of several possible confounders such as stage or therapy. During follow-up malignant disease, neopterin elevations may predict deterioration of the clinical status of the patients and thereby provide a valuable additional marker for monitoring such patients. Possible immunobiological implications of the results are discussed.

Biomarkers, Tumor↗
PubMed1990

Tetrahydrobiopterin-dependent formation of nitrite and nitrate in murine fibroblasts.

The present study demonstrates that murine dermal fibroblasts produce nitrite (NO2-) and nitrate (NO3-) upon treatment with interferon gamma (IFN-gamma). This formation is dependent on L-arginine and can be inhibited by the L-arginine analogue NG-monomethyl-L-arginine. The effect of IFN-gamma is drastically increased by cotreatment with tumor necrosis factor alpha (TNF-alpha), interleukin 1 (IL-1), or lipopolysaccharide (LPS). The tested cytokines also induce formation of tetrahydrobiopterin in murine fibroblasts. Inhibition of guanosine triphosphate-cyclohydrolase I, the key enzyme of tetrahydrobiopterin de novo synthesis with 2,4-diamino-6-hydroxy-pyrimidine, leads to decreased formation of NO2- and NO3-. This effect can be reversed by addition of sepiapterin, which provides tetrahydrobiopterin via a salvage pathway. Methotrexate, which inhibits the salvage pathway, blocks the restoration of NO2- and NO3- production by sepiapterin. The cytotoxic effect of combinations of IFN-alpha with TNF-gamma, IL-1, or LPS is attenuated by inhibition of tetrahydrobiopterin synthesis. These results show that intracellular concentrations of tetrahydrobiopterin control the amount of NO2- and NO3- produced in situ and suggest that the role of cytokine-induced tetrahydrobiopterin synthesis is to provide cells with the active cofactor for production of nitrogen oxides.

Animals↗
PubMed1990

Neopterin formation and tryptophan degradation by a human myelomonocytic cell line (THP-1) upon cytokine treatment.

Determination of neopterin [D-erythro-6-(1',2',3'-trihydroxypropyl)pterin] in body fluids is a powerful diagnostic tool in a variety of diseases in which activation of cellular immune mechanisms is involved, such as certain malignancies, allograft rejection, and autoimmune and infectious diseases. In vitro, neopterin is released into the supernatant by peripheral blood-derived monocytes/macrophages upon stimulation with gamma-interferon. In parallel, cleavage of tryptophan by indoleamine 2,3-dioxygenase is induced. We report here that the human myelomonocytic cell line THP-1 forms neopterin and degrades tryptophan upon treatment with gamma-interferon. Like in macrophages alpha-interferon and beta-interferon induce these pathways only to a much smaller degree. The action of interferons is enhanced by cotreatment with tumor necrosis factor alpha, lipopolysaccharide, or dexamethasone. gamma-Interferon-induced neopterin formation and indoleamine 2,3-dioxygenase activity are increased by raising extracellular tryptophan concentrations. The pattern of intracellularly formed pteridines upon stimulation with gamma-interferon shows the unique characteristics of human monocytes/macrophages. Neopterin, monapterin, and biopterin are produced in a 50:2:1 ratio. Thus, the THP-1 cell line provides a permanent, easily accessible in vitro system for studying the induction and mechanism of neopterin formation.

Biopterins↗
PubMed1990

Urinary neopterin excretion in patients with uterine sarcomas.

Neopterin, a pyrazinopyrimidine compound, is a marker of activation of cell-mediated immunity. Urinary neopterin concentrations were measured in a total of 44 patients with uterine sarcomas. Pretherapeutic neopterin excretions were elevated in 78% (14/18). The mean neopterin concentration of patients with sarcomas was significantly higher (P less than 0.0001) than that obtained in women with benign myomas and healthy controls. Furthermore, a significant correlation of normal or raised neopterin concentrations with the clinical course of disease was found. These data suggest that urinary neopterin measurement might be a useful immunologic marker for women with uterine sarcomas.

Adolescent↗
PubMed1990

Comparison of serum and urine neopterin concentrations in patients with HIV-1 infection.

Urine and serum neopterin concentrations are now widely used to monitor patients with HIV-1 infection. However, there are no published studies comparing the levels in urine and serum, and relating both to the patients' immune status. Urine and serum neopterin concentrations correlated closely in our study population of 37 HIV-1 seropositive patients (34 homosexuals, 3 drug addicts) and 10 HIV-1 seronegative homosexuals. Our data further show that urine and serum neopterin concentrations correlate almost identically with the clinical and immunological presentation of HIV-1 infected individuals, as expressed by the Walter Reed Staging classification. In addition, there was no difference between the correlation of neopterin concentrations in either serum or urine with the Quetelet indices. It will depend on the clinical situation whether blood or urine sampling is preferred. Collection and handling of urine samples from HIV infected patients is less risky to health care personnel in HIV settings.

Adult↗