Common variants of multiple genes that control reverse cholesterol transport together explain only a minor part of the variation of HDL cholesterol levels.

It is assumed that the combined effects of multiple common genetic variants explain a large part of variation of high-density lipoprotein cholesterol (HDL-C) plasma levels, but little evidence exists to corroborate this assumption. It was our objective to study the contribution of multiple common genetic variants of HDL-C-related genes to variation of HDL-C plasma levels. A well-characterized cohort of 546 Caucasian men with documented coronary artery disease was genotyped for common functional variants in genes that control reverse cholesterol transport: ATP-binding cassette transporter A1, apolipoprotein A-I and apolipoprotein-E, cholesteryl ester transfer protein, hepatic lipase, lecithin : cholesterol-acyl transferase, lipoprotein lipase, and scavenger receptor class B type 1. Multivariate linear regression showed that these variants, in conjunction, explain 12.4% (95% confidence interval: 6.9-17.9%) of variation in HDL-C plasma levels. When the covariates smoking and body mass index were taken into account, the explained variation increased to 15.3% (9.4-21.2%), and when 10 two-way interactions were incorporated, this percentage rose to 25.2% (18.9-31.5%). This study supports the hypothesis that multiple, mildly penetrant, but highly prevalent genetic variants explain part of the variation of HDL-C plasma levels, albeit to a very modest extent. Multiple environmental and genetic influences on HDL-C plasma levels still have to be elucidated.

A new algorithm for image noise reduction using mathematical morphology.

Morphological openings and closings are useful for the smoothing of gray-scale images. However, their use for image noise reduction is limited by their tendency to remove important, thin features from an image along with the noise. The paper presents a description and analysis of a new morphological image cleaning algorithm (MIC) that preserves thin features while removing noise. MIC is useful for gray-scale images corrupted by dense, low-amplitude, random, or patterned noise. Such noise is typical of scanned or still-video images. MIC differs from previous morphological noise filters in that it manipulates residual images-the differences between the original image and morphologically smoothed versions. It calculates residuals on a number of different scales via a morphological size distribution. It discards regions in the various residuals that it judges to contain noise. MIC creates a cleaned image by recombining the processed residual images with a smoothed version. The paper describes the MIC algorithm in detail, discusses the effects of parametric variations, presents the results of a noise analysis and shows a number of examples of its use, including the removal of scanner noise. It also demonstrates that MIC significantly improves the JPEG compression of a gray-scale image.

Adenosine modulation of dynorphin B release by hippocampal synaptosomes.

A rat hippocampal preparation enriched in mossy fiber synaptosomes was employed in an attempt to expose any relationship between endogenous adenosine and the release of dynorphin B-like immunoreactivity (DynB-LI). Presumptive blockade of purinergic receptors increased the spontaneous release of DynB-LI, and reducing synaptic adenosine by exogenous adenosine deaminase increased the K(+)-evoked release. Evoked release of DynB-LI was reduced by inhibitors of adenosine uptake and 5'-nucleotidase. Taken together, these data suggest that adenosine endogenous to hippocampal mossy fiber synaptosomes serves to inhibit the release of one of the peptide neuromodulators of this preparation, and provide support for the concept of autoregulation of release.

ATP release, adenosine formation, and modulation of dynorphin and glutamic acid release by adenosine analogues in rat hippocampal mossy fiber synaptosomes.

Using a hippocampal subcellular fraction enriched in mossy fiber synaptosomes, evidence was obtained indicating that adenosine derived from a presynaptic pool of ATP may modulate the release of prodynorphin-derived peptides. and glutamic acid from mossy fiber terminals. Synaptosomal ATP was released in a Ca2+-dependent manner by K+-induced depolarization. The rapid hydrolysis of extracellular [14C]ATP in the presence of intact mossy fiber synaptosomes resulted in the production of [14C]adenosine. Micromolar concentrations of a stable adenosine analogue, 2-chloroadenosine, inhibited the K+-stimulated release of both dynorphin B and dynorphin A(1-8). 2-Chloroadenosine failed to suppress the evoked release of glutamic acid, measured in these same superfusates, unless the mossy fiber synaptosomes were pretreated with D-aspartic acid to deplete the cytosolic, Ca2+-independent, pool of this acidic amino acid. In synaptosomes pretreated in this manner, release of the remaining Ca2+-dependent pool of glutamic acid was significantly inhibited by NiCl2, 2-chloroadenosine, 5'-N-ethylcarboxamidoadenosine, cyclohexyladenosine, and R(-)-N6(2-phenylisopropyl)adenosine, but not by ATP. 2-Chloroadenosine-induced inhibition was reversed when the external CaCl2 concentration was raised from 1.8 mM to 6 mM. 8-Phenyltheophylline, an adenosine receptor antagonist, effectively blocked the inhibitory effects of 2-chloroadenosine on mossy fiber synaptosomes and significantly enhanced the K+-evoked release of both glutamic acid and dynorphin A(1-8) when added alone to the superfusion medium. These results support the proposition that depolarized hippocampal mossy fiber synaptosomes release endogenous ATP and are capable of forming adenosine from extracellular ATP, and that endogenous adenosine may act at a presynaptic site to inhibit the further release of glutamic acid and the prodynorphin-derived peptides.

Audiogenic seizures and brain serotonin after L-tryptophan and p-chlorophenylalanine.

Despite intense investigation, the role of serotonergic neurons in audiogenic seizures in mice remains uncertain. In the work reported here, audiogenic seizure susceptibility and brain tryptophan and serotonin concentrations were measured in DBA/2J mice after administration of three doses of L-tryptophan or p-chlorophenylalanine. p-Chlorophenylalanine reduced brain serotonin and significantly prolonged the latency to appearance of all seizure phases. L-tryptophan was largely ineffective in protecting against seizures and in elevating brain serotonin content, despite the fact that it caused a marked increase in brain tryptophan content. Thus, it appears that DBA/2J mice have an impaired ability to synthesize serotonin from tryptophan.

Tryptophan and serotonin metabolism after sustained tryptophan infusion.

In an attempt to elucidate the effects of sustained administration of tryptophan on serotonin synthesis and turnover in mammalian brain, mini-osmotic pumps containing tryptophan or vehicle were implanted in albino mice for 24 and 96 h. Despite the extremely low dose of tryptophan administered by these pumps (8-12 mg/kg-day) statistically significant treatment effects were apparent with both treatment durations. Plasma and brain tryptophan concentrations varied in unison, and were inversely related to the tryptophan degradative capabilities of the liver as reflected in tryptophan pyrrolase activity. After 24 h of tryptophan infusion the hepatic enzyme activity was elevated and tryptophan values were no different from controls, and after 96 h the hepatic enzyme activity was reduced and tryptophan values in treated animals were greater than controls. Serotonin was elevated in treated animals after 24 h, but not after 96 h despite the elevated tryptophan concentration at this time. The turnover of serotonin, as evidenced by 5-hydroxyindoleacetic acid concentrations, was not significantly affected by either treatment. Hepatic degradation of tryptophan thus seemed to be an important determinant of total plasma tryptophan, and brain tryptophan values paralleled plasma tryptophan. It appears that serotonin biosynthesis is regulated by factors other than tryptophan availability when the latter is chronically elevated.

Substrate induced alterations in tryptophan pyrrolase activity in two mouse strains.

Total hepatic L-tryptophan 2,3-dioxygenase activity was studied in 2 mouse strains receiving i.p. injections of L-tryptophan. After a single injection, enzyme activity was increased in albino but not pigmented mice. After 3 injections, enzyme activity was reduced in both strains.

Time-dependent results of amino acid uptake studies of learning in frogs.

Myelencephalic grass frogs were trained to elevate the right forelimb to avoid a shock plate at several times in relation to administration of 3H-leucine and sacrifice. Total radioactivity (excluding 3H2O) and radioactivity in the soluble pool were significantly greater in the trained animals. The differences between trained and yoked animals decreased with increasing time, up to 30 min after training. The opposite trend was apparent in TCA insoluble material; differences between trained and yoked animals increased with increasing time after training. Similar experiments with 3H-inulin provide evidence that the effects were not due to generalized permeability increases or circulatory alterations.