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Biomedical subjects

D L Nelson

Publications and source records attributed to D L Nelson.

At least 253 records · Page 14Linked to original sources
PubMed1992

Sentence encoding and implicitly activated memories.

Some words have fewer direct associates than others, and, when words varying in set size are studied in a list-learning task, those with smaller sets are more likely to be recalled. This set-size effect is found in cued recall when the words are studied in the absence of related words, but not when studied in the presence of related words. Related words provide context and theoretically inhibit irrelevant associates. The present research determined that set-size effects are found when words are encoded in sentence contexts. In contrast to list-learning experiments, the results of three experiments found such effects even when lexically related words were present in the sentences. Other findings indicated that target-set-size effects were determined by the proximity of related words in the sentence and the nature of the test cue. The results are discussed in relation to a model for explaining set-size effects and to selective findings from the sentence-comprehension literature.

Adult↗
PubMed1992

The retrieval of controlled and automatic aspects of meaning on direct and indirect tests.

The literature concerning implicit memory presents conflicting evidence on the importance of meaning in recovering recently studied words. When the same cues are used during testing, indirect instructions reduce levels of processing effects relative to those obtained with direct instructions, suggesting that meaning is not as likely to be retrieved on indirect tests. However, with certain cues, meaning set size of the studied words affects performance even under indirect instructions, suggesting that meaning is retrieved on such tests. The purpose of the present experiments was to resolve this apparent inconsistency. In Experiment 1, the effects of levels of processing and meaning set size were evaluated under direct and indirect test instructions, with the use of stem and word-fragment cues. In other experiments, beginning and ending stem cues were compared, and levels, set size, and instructional effects were evaluated using meaning cues. The findings indicated that levels effects were determined more by test instructions than by test cues, and that set size effects were determined more by test cues than by test instructions. Implications are discussed for transfer-appropriate processing viewpoints and for a model in which it is assumed that performance is determined by searching either explicit or implicit memories.

Adult↗
PubMed1992

Comparison of performance in materials-based occupation, imagery-based occupation, and rote exercise in nursing home residents.

Materials-based occupation, imagery-based occupation, and rote exercise have been examined individually by several researchers. The present study compares all three approaches with one another (i.e., kicking a balloon, imagining kicking a balloon, and a control rote exercise) in nursing home residents. The dependent variable was the number of exercise repetitions. The subjects were 12 women and 3 men between 56 and 93 years of age residing in two nursing homes. All subjects experienced the three approaches but in different orders. One-way analysis of variance for related measures indicated a significant difference among conditions (p = .004). The Tukey procedure (Stevens, 1986) determined that the materials-based occupation condition elicited significantly more repetitions than the other two conditions. The difference between the imagery-based occupation and rote exercise was not statistically significant. These findings support our profession's historical emphasis on the use of physical materials to enhance performance.

Activities of Daily Living↗
PubMed1992

Molecular cloning, functional expression, and pharmacological characterization of a novel serotonin receptor (5-hydroxytryptamine2F) from rat stomach fundus.

Using the polymerase chain reaction amplification technique in conjunction with conventional cloning techniques, we have isolated a novel member of the serotonin [5-hydroxytryptamine (5-HT)] 1C/2 receptor subfamily (designated 5-HT2F) from rat stomach fundus. Two DNA fragments were amplified from cDNA synthesized from rat stomach fundus poly(A)+ RNA using the polymerase chain reaction technique with degenerate oligonucleotide primers derived from sequence comparisons of the second, third, and sixth putative transmembrane domains of known 5-HT receptors. These fragments were used as hybridization probes to isolate full length cDNA clones from rat stomach fundus cDNA libraries. Full length cDNA clones contained one open reading frame encoding a 479-amino acid protein with seven hydrophobic domains, characteristic of members of the guanine nucleotide-binding protein-coupled receptor superfamily. Within these seven putative transmembrane domains, the 5-HT2F receptor shared greatest homology with the rat 5-HT1C and 5-HT2 receptor subtypes (70% and 68%, respectively). Cell lines stably expressing the 5-HT2F receptor were established and demonstrated functional coupling to phosphatidylinositol hydrolysis upon 5-HT stimulation analagous to that observed for the 5-HT1C and 5-HT2 receptors. Membranes from the stably transfected cell lines (but not the untransfected parental lines) exhibited high affinity (Kd = 7.9 nM), saturable binding of [3H]5-HT. Maximum binding ranged from 0.1 to 2.4 pmol/mg of protein, depending on the clonal isolate. Using [3H]5-HT as the basis for a radioligand binding assay, the relative affinities of several tryptamine and piperazine derivatives for the cloned 5-HT2F receptor correlated with their relative potencies to contract the rat stomach fundus. These data suggest a probable relationship between this novel 5-HT2F receptor and the serotonin contractile receptor of the rat stomach fundus.

Amino Acid Sequence↗
PubMed1992

Preclinical studies on LY237733, a potent and selective serotonergic antagonist.

8B-N-cyclohexyl-6-methyl-1(1-methylethyl)ergoline-8-carboxamide (LY237733) is an ergoline with potent and highly selective 5-hydroxytryptamine (5-HT) antagonist activity. The in vitro radioligand displacement studies showed that LY237733 has a preferential affinity for 5-HT1c and 5-HT2 receptors compared to other monoaminergic receptors. This characteristic is shared with other previously described ergoline 5-HT antagonists, such as LY53857 and sergolexole. In parallel ligand displacement assays, LY237733 had a similar potency to sergolexole. LY237733 was equipotent to sergolexole, but slightly less potent than LY53857 in the antagonism of 5-HT-induced elevation in blood pressure and quipazine-induced elevation in corticosterone levels, which are considered to be measures of 5-HT2 and possibly 5-HT1c antagonist activity. LY237733 failed to antagonize pergolide or 8-hydroxy-2-(di-n-propylamino)tetralin-induced elevations in serum corticosterone levels, indicating selectivity for the 5-HT1c/2 receptor, relative to 5-HT1a and D2 dopaminergic receptors. The only in vivo response that could be detected after administration of LY237733 alone in doses less than 1 mg/kg was the amplification of male rat sexual behavior. LY237733 was 10 to 100 times more potent than LY53857 or sergolexole in augmenting sexual responses of male rats with different levels of sexual response capacity. LY237733 has a much longer serum half-life than sergolexole. These studies have provided the pre-clinical rationale to evaluate the effects of this compound in the treatment of sexual disorders such as psychogenic erectile dysfunction, and other therapeutic indications for a 5-HT2 antagonist, including depression, anxiety, schizophrenia and migraine.

Animals↗
PubMed1991

Absence of expression of the FMR-1 gene in fragile X syndrome.

We previously reported the isolation of a gene (FMR-1) expressed in brain at the fragile X locus. One exon of this gene lies within an EcoRI fragment that exhibits length variation in fragile X patients. This exon also contains the CGG repeat within the CpG island hypermethylated in fragile X patients. To study the involvement of the FMR-1 gene in the fragile X syndrome, its expression was studied in lymphoblastoid cell lines and leukocytes derived from patients and normal controls. FMR-1 mRNA was absent in the majority of male fragile X patients, suggesting a close involvement of this gene in development of the syndrome. Normal individuals and carriers all show expression. The methylation status of the BssHII site at the CpG island was also studied by Southern blot analysis of DNA from patients, carriers, and controls. The minority of fragile X affected males that show expression of FMR-1 demonstrated an associated incomplete methylation of the BssHII site.

Base Sequence↗
PubMed1991

Alu-primed polymerase chain reaction for regional assignment of 110 yeast artificial chromosome clones from the human X chromosome: identification of clones associated with a disease locus.

Over 400 yeast artificial chromosome (YAC) clones were isolated from the human X chromosome, and 110 of these were assigned to regions defined by chromosome translocation and deletion breakpoints. Polymerase chain reaction using Alu primers was applied to YAC clones in order to generate probes, to identify overlapping clones, and to derive "fingerprints" and sequence data directly from total yeast DNA. Several clones were identified in regions of medical interest. One set of three overlapping clones was found to cross a chromosomal translocation implicated in Lowe syndrome. The regional assignment of groups of YAC clones provides initiation points for further attempts to develop large cloned contiguous sequences, as well as material for investigation of regions involved in genetic diseases.

Base Sequence↗
PubMed1991

Pharmacology of the novel 5-hydroxytryptamine1A receptor antagonist (S)-5-fluoro-8-hydroxy-2-(dipropylamino)tetralin: inhibition of (R)-8-hydroxy-2-(dipropylamino)tetralin-induced effects.

The selective 5-hydroxytryptamine (5-HT1A) receptor agonist 8-hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT) induces a large number of pharmacological effects. In the present study we demonstrate that a novel 8-OH-DPAT analog, (S)-5-fluoro-8-hydroxy-2-(dipropylamino)tetralin [(S)-UH-301], is able to antagonize completely the following (R)-8-OH-DPAT-induced effects in the rat: 1) reduction in brain 5-HT biosynthesis, measured as a decreased 5-hydroxytryptophan-accumulation after decarboxylase inhibition; 2) induction of the 5-HT1A behavior (flat body posture, forepaw treading and hindlimb abduction) in reserpine-pretreated animals; 3) reduction of body temperature; 4) inhibition of the cage-leaving response; and 5) reduction of 5-hydroxytryptophan- and quipazine-induced wet dog shakes. In addition, (S)-UH-301 reverses the 5-HT-induced inhibition of the forskolin stimulated cyclic AMP production in rat hippocampus without producing any effects per se in this assay. It is shown that high doses of (S)-UH-301 decrease rat brain biosynthesis of dopamine. These and previous data indicate that (S)-UH-301 also is a weakly potent dopamine-receptor agonist, but with a lower affinity for D2 as compared to 5-HT1A receptors. Thus, the data suggest that (S)-UH-301 is a 5-HT1A-receptor antagonist without intrinsic activity. Therefore, it is likely that (S)-UH-301 will become a valuable pharmacological tool in future 5-HT research.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1991

Symptoms of Raynaud's syndrome in patients with fibromyalgia. A study utilizing the Nielsen test, digital photoplethysmography, and measurements of platelet alpha 2-adrenergic receptors.

Twenty-nine female patients with fibromyalgia were questioned about symptoms of cold intolerance and Raynaud's syndrome; objective documentation of cold-induced vasospasm was obtained by a Nielsen test. Twelve patients (41%) had abnormal Nielsen test results, and 11 patients (38%) had elevated levels of platelet alpha 2-adrenergic receptors. There was a positive correlation between the percentage of change in finger systolic pressure on cooling (Nielsen test) and the number of alpha 2-adrenergic receptors. There was poor correlation between Raynaud's syndrome symptoms and an abnormal Nielsen test result. Digital photoplethysmography showed a normal waveform in 2 of 3 patients. We hypothesize that a subgroup of patients with fibromyalgia syndrome have an up-regulation of alpha 2-adrenergic receptors as a cause of their exaggerated reaction to cold.

Adult↗
PubMed1991

An automated assay for quantifying the swimming behavior of Paramecium and its use to study cation responses.

Paramecium tetraurelia is a ciliated protist that alters its swimming behavior in response to various stimuli. Like the sensory responses of many organisms, these responses in Paramecium show adaptation to continued stimulation. For quantitative studies of the initial response to stimulation, and of the time course of adaptation, we have developed a computerized motion analysis assay that can detect deviations from the normal swimming pattern in a population of cells. The motion of an average of ten cells was quantified during periods ranging from 15 to 60 seconds, with a time resolution of 1/15 seconds. During normal forward swimming, the maximum deviation from a straight-line path was less than 17 degrees. Path deviations above this threshold value were defined as changes in swimming direction. The percentage of total path time that cells spent deviating from forward swimming was defined as percent directional changes (PDC). This parameter was used to construct dose-response curves for the behavioral effects of various externally added cations known to induce behavioral changes and also to show the time course of adaptation to a depolarizing K+ stimulus. This assay is a valuable tool for studies of chemoeffectors or mutations that alter the swimming behavior of Paramecium and may also be applicable to other motile organisms.

Animals↗
PubMed1991

Structure-activity relationships at 5-HT1A receptors: binding profiles and intrinsic activity.

The 5-HT1A receptor has been one of the most studied 5-HT receptor subtypes in terms of its pharmacologic profile. Comparisons of various studies of structure-activity relationships (SAR) at this receptor shows an emerging profile for this receptor's pharmacophore. The present discussion focuses on the findings generated with relatively small molecules that can be considered as analogs of serotonin itself and that illustrate some of the structural properties that are important for high-affinity recognition by the receptor. Most of the SAR work has been based on the affinities of compounds for the receptor as determined by the radioligand-binding technique, which has a significant limitation in that it cannot define the intrinsic activity of compounds at the receptor. This problem can be addressed by functional assays, and an example of SAR at the 5-HT1A receptor-coupled adenylate cyclase system is provided.

Animals↗
PubMed1991

Applications of polymerase chain reaction methods in genome mapping.

Important new polymerase chain reaction-based techniques have been developed to assist in genome analysis. Applications range from genetic and physical mapping of DNA to sequence analysis. The polymerase chain reaction has played a significant role in increasing the feasibility of many aspects of genome analysis and positional cloning.

Animals↗
PubMed1991

A 3-D model for 5-HT1A-receptor agonists based on stereoselective methyl-substituted and conformationally restricted analogues of 8-hydroxy-2-(dipropylamino)tetralin.

The enantiomers of cis- and trans-1,2,3,4,4a,5,10,10a-octahydro-9-hydroxy-1- propylbenzo[g]quinolines (10 and 11, respectively) and the enantiomers of trans-1,2,3,4,4a,5,6,10b-octahydro-10- hydroxy-4-propylbenzo[f]quinoline (12) have been synthesized and their stereochemical and conformational characteristics have been studied by use of X-ray crystallography and molecular mechanics (MMP2) calculations. The compounds, which are conformationally restricted analogues of the potent 5-hydroxytryptamine (5-HT) receptor agonist 8-hydroxy-2- (dipropylamino)tetralin (8-OH-DPAT; 1) have been evaluated for central 5-HT and dopamine receptor stimulating activity by use of biochemical and behavioral tests in rats. In addition, we have evaluated the ability of these compounds and a number of previously reported analogues to displace [3H]-8-OH-DPAT from 5-HT1A-binding sites. The enantiomers of 12 behave as potent 5-HT1A-receptor agonists, whereas the octahydrobenzo[g]quinoline derivatives are much less potent or inactive. In general, the affinities of the compounds correlate well with their agonist potencies. The set of compounds under study is accommodated by a novel computer-graphics-derived model for 5-HT1A-receptor agonism. The model consists of a flexible pharmacophore and a partial receptor-excluded volume.

Animals↗
PubMed1991

Choroid plexus protects cerebrospinal fluid against toxic metals.

Although heavy metal ions are known to be toxic to the central nervous system (CNS), the mechanisms by which the CNS may protect itself from initial challenges of such toxic ions is unknown. The choroid plexus is the principal site of formation of the cerebrospinal fluid (CSF) which bathes the brain. We have determined in rats and rabbits that after intraperitoneal administration of lead, cadmium, mercury, and arsenic compounds, these toxic metal ions accumulated in the lateral choroid plexus at concentrations of Pb, Hg, and As that were 70-, 95-, and 40-fold higher, respectively, than those found in the CSF. Cd was not detected in the CSF. In addition, concentrations of these heavy metal ions were found to be many fold greater in the choroid plexus than in the brain or blood. The accumulation of Pb in the choroid plexus was dose-dependent and time-related. When the choroid plexus was preincubated, in vitro, with ouabain (1.5 mM), the uptake of Cd from the CSF side of the choroid plexus was inhibited 57%. Cadmium metallothionein was not found in the choroid plexus. Whereas the concentration of reduced glutathione in the choroid plexus was less than that in the brain cortex, the concentration of cystine was fourfold greater. The lateral choroid plexus sequesters Pb, Cd, As, and Hg. It appears to be one of the important mechanisms that protects the CSF and the brain from the fluxes of toxic heavy metals in the blood.

Animals↗
PubMed1991

Inability of isolated soluble interleukin-2 receptor levels to predict biopsy rejection scores after heart transplantation.

Successful cardiac transplantation requires suppression of rejection, and endomyocardial biopsy is generally used to quantify this and guide immunotherapy. Biopsy, however, is an invasive, costly, cardiac catheterization with repetition limited. Since rejection requires lymphocyte activation, an alternative method of assessing rejection dynamics might be ELISA determination of soluble interleukin-2 receptor (sIL-2R) levels since induction of the interleukin-2 ligand and its receptor is required. Reports suggest that sIL-2R levels rise during kidney, liver, and heart-lung allograft rejection and heart recipients have an adverse prognosis if sIL-2R is elevated postoperatively. It is unclear, however, if serial measurements or single determinations are sufficient or if change from a baseline assessment is important. The purpose of this study was to determine if an isolated sIL-2R level after heart transplant predicted endomyocardial biopsy score at that moment. To do this, we prospectively followed 60 consecutive patients after orthotopic heart transplant and correlated 479 endomyocardial biopsy scores (McAllister scale 0-10) with matched sIL-2R levels. Regression analysis demonstrated minimal relationship between sIL-2R level and biopsy score (r =.11, r2 =.01, P=.009). When the maximum sIL-2R level for each individual patient was compared with the matched biopsy score, regression analysis revealed r=.04, r2=.001, P=.8. Likewise, when all biopsy scores and sIL-2R levels for each patient were meaned, analysis showed r=.14, r2=.02, P=.26. Thus in heart transplant patients, there is poor correlation between an isolated biopsy score and matched sIL-2R level. However, when mean +/- SEM sIL-2R was determined for severe rejection (score 7-10) and compared with sIL-2R for all other grades, it was significantly higher (1600 +/- 257 vs. 423 +/- 57 U/ml; P=.012). Still, the sensitivity, specificity, and predictive value of an sIL-2R level above 1000 U/ml predicting severe rejection was only 52%, 63%, and 8%. It would be difficult, therefore, to use a single sIL-2R determination after heart transplant to foretell the endomyocadial biopsy score. Serial measurements or quantification of a change in sIL-2R level from baseline might be more predictive of rejection severity.

Biomarkers↗
PubMed1991

Dexamethasone inhibits human interleukin 2 but not interleukin 2 receptor gene expression in vitro at the level of nuclear transcription.

Glucocorticosteroids have an inhibitory effect on the expression of interleukin 2 (IL-2) and interleukin 2 receptor (IL-2R) genes. To determine the mechanisms of this inhibition, human T lymphocytes were stimulated with mitogens in the presence of dexamethasone. Nuclear transcription run-off assays showed that high doses of dexamethasone inhibited the transcription of the IL-2 gene but not that of the IL-2R gene. Post-transcriptionally, high doses of dexamethasone (10(-4) M) were required to inhibit IL-2R mRNA levels by 50%, whereas lower doses (10(-6) M) inhibited by greater than 70% the accumulation of IL-2 mRNA. IL-2 mRNA half-life decreased in the presence of dexamethasone (10(-6) M) by approximately 50%. At the protein product level, dexamethasone inhibited both IL-2 production, as well as cell surface and soluble forms of IL-2R. IL-2R gene expression was inhibited for at least 72 h after exposure of cells to dexamethasone. In the presence of exogenous IL-2, dexamethasone failed to exert a significant effect on the production of IL-2R protein. These data indicate that dexamethasone has a greater effect on the expression of the IL-2 gene than on the IL-2R gene. Dexamethasone both inhibits transcription of the IL-2 gene and decreases the stability of IL-2 mRNA. The effect of dexamethasone on the IL-2R gene is post-transcriptional and may result indirectly from decreased IL-2 production.

Dexamethasone↗
PubMed1991

Multiple families of proteins in the secretory granules of Paramecium tetraurelia: immunological characterization and immunocytochemical localization of trichocyst proteins.

Paramecium tetraurelia has thousands of secretory granules (trichocysts), which release their protein contents by regulated exocytosis. The secretory proteins that fill the granule comprise the condensed trichocyst matrix (ctmx), a paracrystalline structure that, upon exocytosis, expands about eightfold in length within milliseconds. The resulting needle-like extended trichocyst matrix (xtmx), also paracrystalline, is released outside the cell. Both ctmx and xtmx are composed of 35 or more small (Mr 14-25 x 10(3)), acidic (pI 4.4-5.8) proteins. We used monoclonal antibodies (mAbs) raised against proteins of the xtmx to study the relationship among these proteins, and to determine their locations within the paracrystalline ctmx and xtmx. The antibodies defined four distinct protein groups. Group I proteins (defined by mAb A1-3 and B5-5) showed a relatively wide range of pI values, and existed in xtmx as disulfide-linked heterodimers. They were distributed throughout the matrix of condensed and extended trichocysts, as judged by electron-microscopic immunocytochemistry. Group II proteins (defined by mAb B4-4 and B3-5) were more acidic, also present as heterodimers and specifically localized in a 150 nm wide cortex in ctmx and in a much thinner cortex in xtmx. In xtmx, antibodies against group II proteins stained the outer surface on the regions between the electron-dense striations with 55 nm intervals. However, these regions were not accessible to antibody B4-4 in ctmx. Group III proteins (defined by mAb B7-4) are monomeric proteins; group IV are two subunits of heterodimers. Proteins of groups IV are two subunits of heterodimers. Proteins of groups III and IV were localized in the core of ctmx, but were distributed uniformly in xtmx. Our results show that these very similar tmx proteins are not structurally equivalent. Within the highly regular structures of condensed and extended tmx, immunologically distinct families of tmx proteins occupy specific and different positions in the paracrystalline array. One family of tmx proteins (group II) is buried in the condensed tmx and only becomes accessible to antibodies upon trichocyst extension. Our results suggest that the 150 nm cortex of condensed tmx expands lengthwise, while decreasing in the thickness, to form the outer shell of extended tmx, and the core expands in length without decreasing in diameter to form the inside structure of the extended tmx.

Animals↗