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Biomedical subjects

H Wachter

Publications and source records attributed to H Wachter.

At least 217 records · Page 12Linked to original sources
PubMed1992

Distinct distributions of D-erythro-neopterin in arteries and veins and its recovery by an enterohepatic circulation.

Large amounts of D-erythro-neopterin, a pteridine derivative, are formed from guanosine triphosphate (GTP) by human macrophages upon stimulation with interferon-gamma. In addition, in humans a basal neopterin level in all body fluids is evident also in absence of immunological stimuli. Extremely high concentrations of D-erythro-neopterin were detected in biliary fluid. We therefore investigated, if an enterohepatic circulation might exist for this substance. We quantified concentrations of pteridines in serum obtained from various vessels and in biliary fluid. Samples were collected during surgery of five patients with duodenal ulcer or adenocarcinoma of the stomach. Our data clearly demonstrate the existence of an enterohepatic circulation for the recovery of neopterin which seems to be specific for this substance. The relative distributions of neopterin concentrations in the gastrointestinal tract and vessels were seen invariably in all patients and were consistent with findings in five corpses examined post mortem. In addition, significantly higher neopterin concentrations, were found in arteries than in veins. The data indicate that neopterin derivatives are consumed in the peripheral capillary system and an enterohepatic circulation is established to maintain constant blood levels of neopterin derivatives. Furthermore, we suppose that the liver is the source of constitutive neopterin concentrations.

Adenocarcinoma↗
PubMed1992

The role of neopterin as a monitor of cellular immune activation in transplantation, inflammatory, infectious, and malignant diseases.

The accumulated knowledge about the organization and function of the human immune system contributes to a better understanding of the pathogenesis of most diverse disorders and is opening new avenues for therapeutic regimens. To gain further insight into the complex interactions within the components of the immune system, it has become increasingly necessary to develop rapid and simple methods to monitor the status of the immune system in patients. The determination of neopterin concentrations in human body fluids allows to investigate sensitively the cell-mediated immune status to be investigated with considerable sensitivity. In recent years it was shown that production and release of neopterin is inducible in human monocytes/macrophages by interferon gamma. Increased neopterin levels indicate endogenous formation of gamma interferon, and monitoring of neopterin levels therefore permits the activation status of the cell-mediated immune system to be examined. Neopterin concentrations in serum and in urine increase in parallel to the clinical course of infections with viruses, intracellular bacteria, and parasites. In patients with human immunodeficiency virus infection neopterin concentration in serum and urine is a significant predictor of disease progression, the statistical power being similar to CD4+ T-cell numbers. In patients with autoimmune disorders, neopterin levels correlate with the extent and the activity of the disease. Neopterin concentrations are also sensitive indicators of immunological complications in allograft recipients. In certain malignant diseases neopterin concentrations correlate with the stage of the disease and bear prognostic information. Results of neopterin measurements agree with the important role that the cellular immune system plays in these disorders.

Animals↗
PubMed1992

Trends in HIV infection among intravenous drug users in Innsbruck, Austria.

The first HIV test among intravenous drug users (IVDUs) at the AIDS clinic and/or the drug dependency clinic of the University of Innsbruck was the basis for the calculation of the proportions of those testing HIV seropositive annually over the period 1985-1990. The numbers testing HIV seropositive at the drug dependency clinic declined drastically, from 72.2% in 1985 to 12.5% in 1990 (chi 2 = 29.62, p less than 0.0001), whereas they rose at the AIDS clinic during this period, from 48.4% to 100% (chi 2 = 5.82, p = 0.016). Overall 132 of the 268 (49.2%) individuals examined tested HIV seropositive. There were 102 individuals of the original 146 seronegative IVDUs who were retested, for an overall incidence rate of HIV seroconversion of 5.8/100 persons-years. Risk of seroconversion was associated with a steady sexual partnership with an HIV seropositive IVDU and with an age of less than or equal to 25 years at study entry (13.1 versus 8.7/100 persons-years). No seroconversions occurred in the subgroup of patients treated by the methadone maintenance treatment program. The cumulative incidence (Kaplan-Meier) rate for HIV seropositivity after 64 months was 22%, lower than the proportions testing HIV seropositive found in 1985 at each of the two clinics, which suggests that the speed of the spread of the epidemic of HIV infection among IVDUs has slowed in our region. Counseling of IVDUs should emphasize the risks of sexual acquisition, particularly among persons with steady relationships who may not perceive their risk.

Adult↗
PubMed1992

Patterns of serological markers for cellular immune activation in patients with dilated cardiomyopathy and chronic myocarditis.

We determined serum concentrations of neopterin and beta 2-microglobulin, soluble markers of cellular immune activation, in 27 patients with either dilated cardiomyopathy (DCM) or chronic myocarditis. Neopterin and beta 2-microglobulin concentrations were respectively increased in 2 and 5 of 11 patients with DCM and in 11 and 9 of 16 patients with chronic myocarditis. A higher cardiac functional class (according to the New York Heart Association) was associated with greater neopterin and beta 2-microglobulin concentrations. During follow-up of patients, both neopterin and beta 2-microglobulin concentrations in serum correlated with the course of disease. Additionally, correlations were significant between left ventricular functional tests (end-diastolic volume, end-systolic volume, and ejection fraction) and neopterin and beta 2-microglobulin concentrations. We conclude that measurement of neopterin and beta 2-microglobulin are useful to monitor disease development in patients with myocardial inflammation.

Adult↗
PubMed1992

Iron modulates interferon-gamma effects in the human myelomonocytic cell line THP-1.

This investigation demonstrates that low concentrations (25 microM) of free and transferrin-bound iron reduce the efficiency of the interferon-gamma (IFN-gamma) signal in the human myelomonocytic cell line THP-1, as seen by decreased production of neopterin, reduced degradation of tryptophan, and impaired expression of major histocompatibility complex (MHC) class II antigens. This inhibitory effect of iron, which is not due to an enhanced cytotoxicity towards THP-1 cells, is increased by enhancement of iron concentrations in a dose-dependent relationship and can be partially reversed by increasing amounts of the cytokine. The iron-mediated inhibition of the effects of IFN-gamma is fully reversed when iron is administered concomitantly with equimolar concentrations of the iron chelator deferoxamine. Furthermore, deferoxamine alone is even able to enhance the efficiency of the IFN-gamma signal. Our data provide evidence that there is an inverse correlation between the intracellular amount of iron, which is not bound to ferritin, and the activity of the IFN-gamma signal. This suggests that iron withholding by the immune cells in the course of inflammatory disorders may also contribute to the enhancement of the cytopathic effect of IFN-gamma. This speculation is confirmed by the observation of high concentrations of immune activation markers such as IFN-gamma and neopterin and low serum iron levels in patients with hypoferric anemia in the course of chronic inflammation.

Biopterins↗
PubMed1991

Impact of tumour necrosis factor-alpha and interferon-gamma on tetrahydrobiopterin synthesis in murine fibroblasts and macrophages.

Tumour necrosis factor-alpha causes an up to 30-fold induction of GTP cyclohydrolase I (EC 3.5.4.16) activity in murine dermal fibroblasts in a dose-dependent manner. Owing to the high constitutive activities of 6-pyruvoyltetrahydropterin synthase and sepiapterin reductase (EC 1.1.1.153), this potentiates biosynthesis of tetrahydrobiopterin. Murine macrophages already contain high activities of GTP cyclohydrolase I when unstimulated, and this is further augmented up to 4-fold by tumour necrosis factor-alpha/interferon-gamma. In Western blots an antiserum to murine liver GTP cyclohydrolase I does not stain cell extracts with high enzyme activities, suggesting that the cytokine induced peripheral form of GTP cyclohydrolase I might differ from the liver form.

Animals↗
PubMed1991

Neural networks as a tool for utilizing laboratory information: comparison with linear discriminant analysis and with classification and regression trees.

Successful applications of neural network architecture have been described in various fields of science and technology. We have applied one such technique, error back-propagation, to a medical classification problem stemming from clinical chemistry, and we have compared the performance of two different neural networks with results obtained by conventional linear discriminant analysis or by the technique of classification and regression trees. The results obtained by the various models were tested for robustness by jackknife validation ("leave n out" method). Compared with the two other techniques, neural networks show a unique ability to detect features hidden in the input data which are not explicitly formulated as input. Thus, neural network techniques appear promising in the field of clinical chemistry, and their application, particularly in situations with complex data structures, should be investigated with more emphasis.

Alanine Transaminase↗
PubMed1991

Predictive value of interleukin-6 and neopterin in patients with multiple myeloma.

Concentrations of interleukin-6 and neopterin were measured in sera from 44 patients with multiple myeloma. To judge the relative prognostic value of these analyses, other clinical and laboratory variables were concomitantly determined. The patients were followed up to 9 years, and the abilities of all variables to predict outcome were assessed. Both neopterin (P = 0.0008) and interleukin-6 (P = 0.033) were significantly higher in patients with higher stages of the disease. The correlation between interleukin-6 and neopterin was weak but significant (Spearman's rank correlation coefficient, 0.38; P = 0.019). By univariate survival analysis using the product-limit approach, both neopterin (P = 0.0001) and interleukin-6 (P = 0.025) were identified as significant predictors of survival. Multivariate survival analyses by the proportional hazards technique demonstrated that either stage and neopterin or neopterin and interleukin-6 are useful combinations of predictor variables. Thus, interleukin-6, which is supposed to influence progression of multiple myeloma in an autocrine or paracrine manner, failed to contribute to prediction if stage was included in a model. In contrast, neopterin remained significant in all multivariate models.

Aged↗
PubMed1991

6-Pyruvoyl tetrahydropterin synthase assay in extracts of cultured human cells using high-performance liquid chromatography with fluorescence detection of biopterin.

An assay for 6-pyruvoyl tetrahydropterin synthase, the second enzyme in the conversion of guanosine triphosphate into tetrahydrobiopterin, has been developed. Cell extracts were incubated with enzymatically prepared dihydroneopterin triphosphate (80 microM) in the presence of Mg2+ (12 mM), excess sepiapterin reductase (EC 1.1.1.153) (2 nmol/min) and NADPH (2 mM). 6-Pyruvoyl tetrahydropterin, the product of the reaction, was thus converted into tetrahydrobiopterin. After oxidation of the reduced biopterin derivatives in acidic iodine solution, biopterin was enriched and separated from the abundant neopterin phosphates by solid-phase extraction on a strong cation exchanger. Biopterin was then directly eluted on a reversed-phase liquid chromatographic column and detected fluorimetrically using excitation at 353 nm and emission at 438 nm. The biopterin concentrations formed by the coupled enzyme reaction increased linearly with incubation times up to 90 min. The assay allows the quantification of 6-pyruvoyl tetrahydropterin synthase in cultured human cells.

Alcohol Oxidoreductases↗
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↗