Hyperhomocysteinemia in dementia.

Hyperhomocysteinemia is a strong risk factor for atherosclerotic vascular disease, and elevated serum homocysteine is correlated with vitamin B deficiency. In this pilot study, significantly elevated homocysteine levels were found in patients with Alzheimer's disease as well as in patients with vascular dementia, probably indicating similar pathophysiological pathways. We found significant correlations between low folic acid concentrations as well as high homocysteine concentrations and cognitive decline. Supplementation with folic acid may be an inexpensive way to reduce elevated homocysteine levels in demented patients.

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.

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.

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.

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.

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.

Stimulation of dopamine biosynthesis in cultured PC 12 phaeochromocytoma cells by the coenzyme nicotinamide adeninedinucleotide (NADH).

The activity of the tyrosine hydroxylase, the enzyme which is diminished in the brains of Parkinson patients, has been measured in cultured PC 12 rat phaeochromocytoma cells. In the same way dopamine content in the medium after incubating these cells with or without NADH was assayed. The experiment shows that NADH is able to increase the activity of the tyrosine hydroxylase and dopamine - production in PC 12 cells up to 6 times. The results provide evidence that NADH is able to stimulate dopamine - biosynthesis directly.

The coenzyme nicotinamide adenine dinucleotide (NADH) improves the disability of parkinsonian patients.

The coenzyme nicotinamide adenine dinucleotide (NADH) has been used in an open label trial as novel medication in 34 patients with Parkinson's disease, using an intravenous administration technique. In all patients a beneficial clinical effect was observed. 21 patients (61.7%) showed a very good (better than 30%) improvement of disability, 13 patients (38.3%) a moderate (up to 30%) improvement. Concomitant with the improvement of the disability the urine level of homovanillic acid (HVA) increased significantly in all patients (in some patients by more than a 100%). The daily "on phases" of the patients could be increased from 2 up to 9 hours in the individual patients by NADH administration.

Effect of skim milk and whey diets on plasma lipid levels of rabbits in a cross-over study.

The influence of a skim milk and a whey-based diet on plasma lipids and lipoproteins in rabbits was investigated in a crossover design, in which the diets were switched after 12 weeks. The whey diet increased plasma lipid levels regardless of when it was consumed in the feeding protocol. The milk diet, on the other hand, modestly elevated the lipid levels if provided in the first half of the feeding protocol, but reduced lipid levels if given in the second half of the feeding regime. Both diets also induced similar changes in lipoprotein patterns when given in the first half of the feeding protocol, but opposite effects during the second half. Atherosclerotic changes were also observed in the aorta of animals receiving the whey diet during the second half of the experimental protocol.

Quantitative characterization of diet effects on glucose tolerance in rabbits.

Normal, atherogenic and butter-enriched diets were given to three groups of rabbits during six months. The effects of the three forms of diet after six months were examined with the intravenous glucose tolerance test, which was evaluated by computer-aided model-fitting and parameter identification. Long-term effects are reflected in parameters such as pancreas sensitivity and the glucose utilization rate constant as a measure of peripheral insulin sensitivity. In these terms, the atherogenic diet caused a diminution of both pancreatic and peripheral sensitivity, whereas the butter-enriched diet led to an increase in glucose utilization and a decrease in pancreatic sensitivity relative to the system parameters of the normally fed control animals. Related to the findings about metabolic regulation are indications for an endocrinological approach to the problems of cholesterogenesis and atheroma formation.

Role of calcium antagonists in the treatment of essential hypertension.

The calcium antagonists, diltiazem and nifedipine, are effective in mild-to-moderate chronic essential hypertension. The overall responder rate is 80%. Diastolic blood pressure is lowered by 10-15% at rest and during exercise. Systolic blood pressure is reduced only at rest. Heart rate may be unchanged by nifedipine and lowered by diltiazem. Both drugs lead to a decrease of peripheral resistance by 15-20% at rest and 30% during work. As a consequence of afterload reduction, cardiac output, stroke index, and stroke work index increased by 17, 21, and 7% with nifedipine and 34, 26, and 20% with diltiazem. During exercise, these changes are even more pronounced. However, pulmonary artery pressure and pulmonary vascular resistance are reduced only by nifedipine, not by diltiazem. Presumably due to this combined preload and afterload reduction, nifedipine therapy is associated with a reflex activation of the sympathetic nervous system in all cases, with an increase in norepinephrine plasma concentration and, sometimes, tachycardia. Diltiazem, however, has the advantage of being a potent blood pressure-lowering agent, with afterload reduction and increased stroke index, with less pronounced catecholamine increase, and without tachycardia. Side effects with this drug are rare, and long-term therapy is well tolerated.

The influence of an atherogenic, semisynthetic diet on cholesterol metabolism in rabbits.

The influence of a cholesterol-free, semisynthetic diet on the cholesterol content and on the incorporation of radioacetate into cholesterol in liver, aorta and intestinal mucosa of the rabbit was tested over periods of 3 and 6 months. The incorporation of radioacetate in the liver reached a maximum after 3 months. In contrast to this, the rate of acetate incorporation in the aorta and mucosa continued to rise throughout the entire test period. The cholesterol level in serum ran parallel to the hepatic cholesterol synthesis reaching a maximum after 3 months. While the cholesterol content of the liver remained unchanged, it rose in the aorta and mucosa. These results favour the assumption that hypercholesterolemia was not due to a defect in removal of cholesterol from the plasma compartment, but to an increased biosynthesis.

The influence of a cholesterol-free semisynthetic diet on the lipid metabolism in rabbits.

The influence of a cholesterol-free, semi synthetic diet on the total lipid synthesis and on the lipid content of serum, liver, aorta and intestinal mucosa of the rabbit was tested for the duration of three months, and, respectively, six months. Also, the changes in these parameters after a 38-hour period of fasting was examined. The total lipid synthesis in the liver and aorta ran parallel to the lipid level in serum with a peak in radioacetate incorporation into total lipids occuring after three months. In contrast to this the rate of lipid synthesis in the mucosa continued to rise throughout the entire test period. While the lipid content of the mucosa remained unchanged by the diet, it rose in the liver and aorta. The effect of fasting in the three organs was greater after three months than after six months in respect to the incorporation of radioacetate. The serum lipids, too, sank further during fasting after three months than after six.