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Biomedical subjects

G Reibnegger

Publications and source records attributed to G Reibnegger.

At least 37 records · Page 2Linked to original sources
PubMed1998

Circadian rhythm of the soluble p75 tumor necrosis factor (sTNF-R75) receptor in humans--a possible explanation for the circadian kinetics of TNR-alpha effects.

Circadian alterations of several immune functions in vivo are well established, and may have important physiological and clinical implications. In line with this, tumor necrosis factor (TNF)-alpha has been implicated in the circadian regulation of body temperature. As soluble TNF receptors (TNF-R) act as naturally occurring competitive inhibitors of this cytokine, we investigated plasma levels of the soluble sTNF-R55 and sTNF-R75 in comparison with plasma cortisol and body temperature in nine healthy male volunteers during a defined 16 h light/8 h dark cycle. It was found that sTNF-R75, but not sTNF-R55, exhibited a clear-cut circadian rhythm with a significant (P < 0.01) peak at 7:51 a.m. +/- 58 min. The phase of the sTNF-R75 rhythm preceded that of cortisol by approximately 1 h and inversely corresponded to the circadian rhythm of body temperature. Moreover, the individual amplitudes of sTNF-R75 and body temperature exhibited a significant (P < 0.01) positive correlation. These results suggest that (i) the two sTNF-R are regulated independently, (ii) the sTNF-R75 rhythm is not primarily due to the cortisol rhythm and (iii) the fluctuation of the sTNF-R may contribute to the regulation of body temperature by modulating the availability of free TNF.

Adult↗
PubMed1998

Neopterin concentrations in cerebrospinal fluid and serum as an aid in differentiating central nervous system and peripheral infections in children.

Neopterin is a sensitive indicator for cellular immune activation. Its concentrations were determined in cerebrospinal fluid (CSF) and serum specimens from 91 children with no evidence of central nervous system (CNS) or peripheral inflammations, 43 with definite neuroborreliosis, 51 with other CNS infections, and 33 with peripheral infections. The aim of our study was (a) to establish a range of normal CSF neopterin concentrations in control children, and (b) to inquire into the diagnostic potential of neopterin measurements in both body compartments for aiding in differential diagnosis of inflammatory vs noninflammatory diseases, and CNS vs peripheral inflammations. CSF neopterin concentrations in controls were invariably low (up to 9.3 nmol/L), but in children with neuroborreliosis and, even more so, with other CNS infections neopterin concentrations were significantly (P <0.0001) increased. Children with peripheral infections, however, rarely showed raised CSF neopterin concentrations. Serum concentrations of neopterin, on the other hand, were not significantly different between controls and children with neuroborreliosis. Although serum concentrations were significantly different between controls and children with other CNS infections, diagnostic efficiency was poor for this comparison. Peripheral infections, in contrast, were associated with significantly higher (P <0.0001) serum neopterin concentrations when compared with controls. A classification tree was constructed on the basis of CSF and serum neopterin concentrations, allowing with high accuracy the discrimination between controls, children with CNS infections, and children with peripheral infections. Thus, on the basis of a comparatively large control group, our data underline the diagnostic validity of neopterin as an aid in differential diagnosis of inflammatory vs noninflammatory diseases, and confirm that CSF neopterin concentrations are not correlated with serum neopterin concentrations, and, therefore, CSF neopterin appears to be produced intrathecally.

Adolescent↗
PubMed1997

Periodontitis and concentrations of the cellular immune activation marker neopterin in saliva and urine.

Neopterin concentrations in diverse body fluids provide a well established indication for activation of the cell-mediated immune system. Neopterin concentrations were measured in the saliva and urine of 29 patients with varying numbers of teeth affected by periodontitis. While neopterin concentrations in urine increased slightly but not significantly in parallel with increasing numbers of affected teeth, salivary neopterin levels showed a significant and positive correlation with number of diseased teeth (linear correlation coefficient = 0.48, P = 0.012). Additionally, when the patients were grouped according to the median number of affected teeth (20), salivary specimens of subjects with one to 20 affected teeth showed significantly lower neopterin concentrations than specimens from those with more than 20 diseased teeth (P = 0.0045, Student's t-test). In contrast, urinary neopterin concentrations did not differ significantly among these two groups. This pilot study suggests that salivary neopterin concentrations may reflect local immune activation even in situations where no systemic activation can be detected.

Adolescent↗
PubMed1997

Information theoretical concepts in clinical chemistry: the use of spreadsheet programs for convenient calculation of information theoretical quantities.

Information theoretical concepts can be used as most valuable tools for evaluating clinical chemical tests. They offer several advantages over the conventional test evaluation by Bayesian concepts. Although long known, information theory has failed to gain widespread acceptance among clinical chemists, probably due to the rather laborious computation of the necessary quantities. To resolve this technical problem, this paper demonstrates how commonly available computer spreadsheet programs can assist in the computation of information theoretical quantities such as the diverse entropies and the information content. Two spreadsheet versions are presented: firstly, a working sheet is developed for information theoretical evaluation of a two-by-two contingency table corresponding to a dichotomous diagnostic problem (e.g., diseased versus non-diseased) and a dichotomous diagnostic test outcome (e.g., normal versus abnormal), and secondly, a working sheet is shown for a more general situation with up to ten diagnostic alternatives and up to ten possible test outcomes. Typical examples for application of these tools are demonstrated.

Chemistry, Clinical↗
PubMed1997

NADH stimulates endogenous dopamine biosynthesis by enhancing the recycling of tetrahydrobiopterin in rat phaeochromocytoma cells.

Treatment of Parkinson patients with L-DOPA (3,4-dihydroxy-L-phenylalanine) leads to endproduct inhibition of tyrosine hydroxylase, the key enzyme in dopamine biosynthesis and the enzyme needing tetrahydrobiopterin and iron as cofactors. To overcome this problem an alternative treatment was investigated which attempted to stimulate endogenous dopamine biosynthesis. Incubation of rat PC 12 cells with NADH (beta-nicotinamide adeninedinucleotide) leads to increased dopamine production. We investigated the possibility that this increase of dopamine biosynthesis was due to stimulation of quinonoid dihydropteridine reductase, the enzyme which recycles the inactive dihydrobiopterin to the active tetrahydrobiopterin. The experiments showed that whereas NADH is able to increase dopamine production in PC 12 cells (rat phaeochromocytoma cells, clone PC 12) up to three-fold, no influence is exerted by NADH on pteridine metabolism; neither are tetrahydrobiopterin concentrations nor the de novo-biosynthesis of pteridines from guanosine triphosphate altered by NADH. Further no influence of NADH on protein de novo synthesis of quinonoid dihydropteridine reductase was observed. However, NADH was able to directly increase the catalytic activity of this enzyme. Our results suggest that the stimulation of dopamine biosynthesis by NADH is due to more rapid regeneration of quinonoid dihydrobiopterin to tetrahydrobiopterin.

Animals↗
PubMed1997

Spin trapping study of antioxidant properties of neopterin and 7,8-dihydroneopterin.

Previously, it has been shown that pteridine derivatives are capable of modulating the action of free radicals and both prooxidant and antioxidant properties have been described. However, the mechanism of manifestation of these properties is still unclear. We studied the radical scavenging properties of 7,8-dihydroneopterin and neopterin using the spin trap 5,5-dimethyl-1-pyrroline-1-oxide (DMPO). It was found that dihydroneopterin acts generally as a radical scavenger. In the presence of dihydroneopterin the ESR signal was reduced by 30 to 90% compared to the control signal. The rate constants for the reactions of 7,8-dihydroneopterin with superoxide (10(3) M(-1) s(-1)) and peroxyl radicals (10(7) M(-1) s(-1)) were determined. Neopterin in contrast showed no reduction of the ESR signal except with superoxide radicals produced by xanthine oxidase. However, this effect was shown to be due to an inhibition of enzyme rather than to radical scavenging. Our results provide a basis for understanding previous observations of radical scavenger activity of 7,8-dihydroneopterin.

Antioxidants↗
PubMed1996

A glucose-rich diet shortens longevity of mice.

High plasma levels of glucose and insulin over long-time periods play an important role in the genesis of diabetic complications. There is evidence that the long term consumption of glucose-rich diet by rats is detrimental to insulin sensitivity. We investigated the effect of a glucose-rich diet on longevity of 70 female mice which were compared to 70 mice on a control diet. The average age of death of the control group was 568 +/- 139 days compared to 511 +/- 170 for the glucose group and the seven oldest mice of the control group died at age 890 +/- 52 days, while the seven oldest mice of the glucose group died at 833 +/- 49 days. These differences are statistically significant (P < or = 0.05). Our work shows that a life-long intake of a diet with 20% of total energy derived from glucose leads to a significant reduction of the average and maximal life-span in female mice and thus, supports previous observations of detrimental effects of high glucose intake over long periods.

Animals↗
PubMed1996

The effect of reduced physical activity on longevity of mice.

Reduced physical activity leads, in female mice, to a reduction of the average and maximal life span. The average age at death of the inactive experimental group was 497 +/- 121 days (mean +/- S.D.) compared to 557 +/- 139 days in the active control group, and the six oldest inactive experimental mice died at age 732 +/- 50 days, while the six oldest active control mice died at 890 +/- 52 days. The restriction of mobility was connected with a higher growth rate and a higher body weight in spite of a significant decrease in food intake. In spite of a reduced food intake leading to a reduced whole body metabolism, the results show that mobility restriction shortens life span in female mice.

Analysis of Variance↗
PubMed1996

Self-organizing neural networks--an alternative way of cluster analysis in clinical chemistry.

Supervised learning schemes have been employed by several workers for training neural networks designed to solve clinical problems. We demonstrate that unsupervised techniques can also produce interesting and meaningful results. Using a data set on the chemical composition of milk from 22 different mammals, we demonstrate that self-organizing feature maps (Kohonen networks) as well as a modified version of error backpropagation technique yield results mimicking conventional cluster analysis. Both techniques are able to project a potentially multi-dimensional input vector onto a two-dimensional space whereby neighborhood relationships remain conserved. Thus, these techniques can be used for reducing dimensionality of complicated data sets and for enhancing comprehensibility of features hidden in the data matrix.

Animals↗
PubMed1996

Monoaminergic neurotransmitters, their precursors and metabolites in brains of Alzheimer patients.

The catecholamines dopamine (DA), noradrenaline (NA) and adrenaline (A), their aminoacid precursors tyrosine (Tyr), L-3,4-dihydroxyphenylalanine (L-DOPA), two of their metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and 4-hydroxy-3-methoxy phenyl glycol (MHPG), serotonin (5-HT) and its precursor tryptophan (Trp), were measured by high pressure liquid chromatography (HPLC) with electrochemical detection in seven regions (globus pallidus, putamen, nucleus amygdalae, nucleus caudatus, substantia nigra, gyrus cinguli and raphe) of postmortem brains from eight histologically verified cases with Alzheimer's disease (AD) and six histologically normal controls. Concentrations of L-DOPA, DA, DOPAC, NA and 5-HT were significantly reduced, while Tyr and MHPG concentrations were significantly increased in AD versus control patients. The concentrations of Trp and A in AD patients were not significantly different from controls. Furthermore, for most brain regions examined, significant negative correlations between Tyr and DA as well as between NA and MHPG levels were found. These data confirm and extend findings of monoaminergic systems disturbances in AD, emphasize the significance of dopaminergic deficit for AD and suggest that in pharmacotherapy of AD, attempts to restore deficits of the transmitter systems should be directed to the monoaminergic, in particular the dopaminergic system.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1996

Neural networks as a tool for compact representation of ab initio molecular potential energy surfaces.

Ab initio quantum chemical calculations of molecular properties such as, e.g., torsional potential energies, require massive computational effort even for moderately sized molecules, if basis sets with a reasonable quality are employed. Using ab initio data on conformational properties of the cofactor (6R,1'R,2'S)-5,6,7,8-tetrahydrobiopterin, we demonstrate that error backpropagation networks can be established that efficiently approximate complicated functional relationships such as torsional potential energy surfaces of a flexible molecule. Our pilot simulations suggest that properly trained neural networks might provide an extremely compact storage medium for quantum chemically obtained information. Moreover, they are outstandingly comfortable tools when it comes to making use of the stored information. One possible application is demonstrated, namely, computation of relaxed torsional energy surfaces.

Biopterins↗
PubMed1996

Effects of pteridines on chloramine-T-induced growth inhibition in E. coli strains: correlations with molecular structure.

Little is known about the biological significance of most pteridines, despite their ubiquitous occurrence in living cells. Seventeen different pteridines were tested for their ability to modulate the growth inhibitory effect of the disinfectant chloramine-T on three different strains of Escherichia coli bacteria. We found striking differences between the pteridine derivatives: whereas aromatic pterins with a hydroxy function at side chain atom C2' increased the growth inhibition, those with a 7,8-dihydro structure exerted a suppressive effect. These results are in excellent agreement with previously observed effects of pteridine derivatives on chloramine-T-induced luminol-dependent chemiluminescence, and together, are highly suggestive of a general interaction of these compounds with oxygen or chlorine free radicals. This interaction is likely to have biological significance and might offer an explanation for the widespread occurrence of pteridines.

Anti-Infective Agents, Local↗
PubMed1996

Blockade of swelling-induced chloride channels by phenol derivatives.

1. In NIH3T3 fibroblasts, the chloride channel involved in regulatory volume decrease (RVD) was identified as ICln, a protein isolated from a cDNA library derived from Madin Darby canine Kidney (MDCK) cells. ICln expressed in Xenopus laevis oocytes gives rise to an outwardly rectifying chloride current, sensitive to the extracellular addition of nucleotides and the known chloride channel blockers, DIDS (4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid) and NPPB (5-nitro-2-(3-phenylpropylamino)-benzoic acid). We set out to study whether substances structurally similar to NPPB are able to interfere with RVD. 2. RVD in NIH3T3 fibroblasts and MDCK cells is temperature-dependent. 3. RVD, the swelling-dependent chloride current and the depolarization seen after reducing extracellular osmolarity can be blocked by gossypol and NDGA (nordihydroguaiaretic acid), both structurally related to NPPB. 4. The cyclic AMP-dependent chloride current elicited in CaCo cells is less sensitive to the two substances tested while the calcium-activated chloride current in fibroblasts is insensitive. 5. The binding site for the two phenol derivatives onto ICln seems to be distinct but closely related to the nucleotide binding site identified as G x G x G, a glycine repeat located at the predicted outer mouth of the ICln channel protein.

3T3 Cells↗
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

The conformational flexibility of 5,6,7,8-tetrahydrobiopterin and 5,6,7,8-tetrahydroneopterin: a molecular dynamical simulation.

5,6,7,8-Tetrahydrobiopterin is an essential cofactor of diverse enzymes. Of the eight possible stereoisomers, only the 6R,1'R,2'S-configuration is biologically active. Other stereoisomers, as well as other reduced pterins such as, e.g. 5,6,7,8-tetrahydroneopterin, fail to exhibit significant cofactor activity. Different theoretical models (molecular mechanics, semi-empirical quantum chemical calculations) investigating the stereostructure of tetrahydrobiopterin have yielded diverging answers. It has been claimed on the basis of semi-empirical quantum chemical calculations that conformational properties, and thus particular features in overall shape, might be responsible for the unique biological properties of natural tetrahydrobiopterin in contrast, e.g. to 6R,1'S,2'R-5,6,7,8-tetrahydroneopterin. Molecular dynamical simulations of both molecules at realistic temperatures demonstrate, however, that they possess sufficient conformational flexibility as to render questionable any biological significance of mere conformational properties.

Biopterins↗