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Biomedical subjects

D E Wilson

Publications and source records attributed to D E Wilson.

At least 73 records · Page 4Linked to original sources
PubMed1991

Anxiolytic properties of certain annelated [1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-ones.

Modification of the benzodiazepine (BZ) receptor binding template 2-aryl[1,2,4]triazolo[1,5-c]quinazolin-5(6H)-one by replacement of the annelated benzene ring with various alicyclic and heterocyclic moieties led to novel structures with potent BZ receptor binding affinity. High affinity was found in some cycloalkyl-annelated [1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-ones and in some 7,8,9,10-tetrahydropyrido[3,4-e][1,2,4]triazolo[1,5-c]pyrimidin- 5(6H)-ones, in which the degree of activity was strongly dependent on the N-substituent in the 9-position. Nine compounds with BZ receptor IC50 binding affinity values equal or superior to diazepam were evaluated in secondary screening. One of these, 9-benzyl-2-phenyl-7,8,9,10-tetrahydropyrido[3,4-e] [1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one, showed good activity in rats as a potential anxiolytic agent without sedative liability. However, it increased the rotorod deficit produced by ethanol at anxiolytic doses, an indication of alcohol interaction. Thus, none of the compounds showed an advantage over CGS 9896 (Yokoyama et al. J. Med. Chem. 1982, 25, 337-339), which is free of sedative and alcohol interaction potential as measured by the test procedures described.

Aggression↗
PubMed1991

Role of prostaglandins in gastroduodenal mucosal protection.

Prostaglandins protect the gastroduodenal mucosa from damage caused by diverse noxious agents. This protection (cytoprotection) occurs under experimental conditions where intraluminal acid is required for maximal expression of damage (e.g., stress, aspirin, and bile acids), as well as where damage occurs irrespective of the presence of acid (e.g., 100% ethanol, boiling water, and lye). Prostaglandins stimulate several factors felt to be important in maintaining normal mucosal integrity, such as mucus synthesis and secretion, mucosal bicarbonate secretion, mucosal blood flow, and cellular repair. Inhibition of the prostaglandin synthetic enzyme, cyclooxygenase, by nonsteroidal anti-inflammatory drugs (NSAIDs), is associated with increased gastroduodenal mucosal damage and ulceration. This damage is primarily the result of decreased tissue levels of prostaglandins, but may also be due to direct NSAID actions on the mucosa, as well as with shifting of arachidonic acid metabolism from synthesizing protective prostaglandins to increased production of injurious leukotrienes. There is also evidence that patients with peptic ulcer disease have a deficiency of gastroduodenal mucosal prostaglandin synthesis, so that prostaglandins may play a pathophysiologic role in this disorder. Prostaglandins have a unique ability to prevent NSAID-induced gastric damage in humans, and also appear to improve ulcer healing during the continuation of NSAID therapy.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1991

Intestinal and hepatic cholesterogenesis in hypercholesterolemic dyslipidemia of experimental diabetes in dogs.

We previously reported that dog diabetes results in hypercholesterolemia and the accumulation of a high-density lipoprotein (HDL) subclass, HDL1. Hypercholesterolemic diabetic rodents exhibit hyperphagia, intestinal hypertrophy, and increased intestinal cholesterol synthesis and absorption; intestinal 3-hydroxy-3-methylglutaryl (HMG) CoA reductase activity is increased, whereas hepatic activity is unchanged or reduced. To determine whether similar mechanisms operate in the hypercholesterolemic diabetic dog, we measured hepatic and intestinal cholesterologenesis. Streptozocin-alloxan-induced diabetic dogs allowed access to food ad libitum were hyperphagic and hypercholesterolemic (10.1 vs. 4.47 mM) but normotriglyceridemic. Plasma HDL1 concentrations were markedly increased. Differences in renal and hepatic function were not statistically significant, except serum alkaline phosphatase, which was elevated 4-fold (P = 0.0003). Urinary mevalonate, an index of whole-body cholesterol synthesis, was increased 6-fold. Intestinal and hepatic weights were both increased, and direct measurements showed crypt and villus thickening. The activity of HMG CoA reductase per gram organ weight was increased 1.7-fold in liver and 2.1-fold in intestine. Calculated whole-organ activity in intestine was nearly twice that in liver. These observations provide strong evidence that intestinal cholesterogenesis is involved in the pathogenesis of hypercholesterolemia in dog diabetes and support the conclusion that increased cholesterol synthesis plays a role in the hypercholesterolemia of diabetes.

Animals↗
PubMed1991

Genetic parameters for nuclear and nonnuclear inheritance in three synthetic lines of beef cattle differing in mature size.

Genetic parameters for nuclear and cytoplasmic genetic effects were estimated from preweaning growth data collected on three synthetic lines of beef cattle differing in mature size. Lines of small-, medium-, and large-framed calves were represented in each of two research herds (Rhodes and McNay). Variance components were estimated separately by herd and size line for birth weight and 205-d weight (WW) by REML with an animal mode using an average of 847 and 427 calf records from Rhodes and McNay, respectively. Model 1 included effects of fixed year, sex of calf, age of dam, and random additive direct (a), additive maternal genetic (m), covariance (a,m), permanent environment affecting the dam, and residual error. Model 2 differed from Model 1 by including random cytoplasmic lineage effects and by ignoring permanent environmental effects. Model 1--direct (maternal) heritability estimates for birth weight at Rhodes were .62(.03) for small, .67(.06) for medium, and .30(.11) for large lines. Genetic correlations between direct and maternal effects for birth weight were .67, -.16, and .48 for the respective size groups. For WW at Rhodes, direct (maternal) heritability estimates were .30(.29), .30(.14), and .10(.16) for small, medium, and large lines, respectively, with genetic correlations of -.34 (small), -.12 (medium), and .17 (large). Heritability estimates at McNay were similar to those at Rhodes, except that maternal genetic heritabilities for WW were smaller (.10, small; .01, medium; .00, large). Model 2--estimates for nuclear genetic effects were consistent with the estimates from Model 1. Cytoplasmic variance accounted for 0 to 5% of the total random variance in birth weight. For WW, cytoplasmic variance was negligible at Rhodes and accounted for 4% of the total random variance in the large line at McNay, averaging less than the permanent environment. Results failed to indicate that cytoplasmic variance was important for preweaning performance.

Animals↗
PubMed1991

National sheep improvement program: age adjustment of weaning weight.

Lamb weaning weights at 30 +/- 14, 60 +/- 28, and 90 +/- 28 d were used to evaluate the effect of birth weight on the linear adjustment of weaning weight to a constant age and the effect of deviations from target dates on the accuracy of linear age adjustment. The data consisted of 13,501 birth weights, 3,721 30-d records, 10,988 60-d records, and 3,285 90-d records from the National Sheep Improvement Program data base for the Dorset, Polypay, Rambouillet, Columbia, Hampshire and Suffolk breeds. The effect of using constant vs actual birth weights in a standard linear age adjustment was evaluated using various sex, type-of-birth, and breed type constants. Product moment and rank correlations indicated that a constant birth weight should be used when the actual birth weight is not known, but the choice of constant makes little difference in average bias or maximum adjustment error. The linear age adjustment procedure and the optimal age range for recording weaning weight were examined using a model including effects for contemporary group, sex, type of birth and rearing, age of dam, and breed. The linear age adjustment did not remove the effect of age for the small breed type (Dorset, Polypay, and Rambouillet breeds) at 30 d and the large breed type (Columbia, Hampshire, and Suffolk breeds) at 60 d for age ranges greater than +/- 7 d (P less than .01) but was adequate for all lambs weaned at 30 +/- 7 d, 60 +/- 7 d, and 90 +/- 28 d of age.

Age Factors↗
PubMed1991

The National Sheep Improvement Program: a review.

A nationally organized sheep improvement program for sheep producers in the United States was implemented in 1987 under the name of the National Sheep Improvement Program (NSIP). This program completed a 3-yr Phase I project on February 16, 1990, that involved the definition of a uniform set of performance guidelines, development of an NSIP records processing center with associated performance recording materials and computer software, and the enrollment of both purebred and commercial flocks. Organizers of the NSIP have defined 12 traits of economic importance to the U.S. sheep industry for genetic evaluation: number of lambs born, total ewe productivity, six growth traits, and four wool traits. Genetic evaluations are currently being conducted on a within-flock basis and will move to an across-flock, within-breed basis when sufficient genetic ties between flocks are established. The genetic evaluations use BLUP procedures and provide genetic merit values in the form of expected progeny differences for every animal in a flock.

Animals↗
PubMed1991

Genetic predictions of racing performance in quarter horses.

Research on the racing performance of quarter horses has been used to develop genetic prediction summaries on all horses with at least one start on record at the American Quarter Horse Association. In the 1987 summary, records from a total of 212,065 horses were used to give genetic predictions on stallions, mares, geldings, fillies, and colts. A reduced animal model was used that incorporated the repeated records of individuals. The individual race was the contemporary group after the data were adjusted for distance, sex, and age. Estimates of heritability of .24 and repeatability of .32 suggest that increased racing performance can be achieved if the predictions are used by breeders. Continued research in variance component estimation includes the genetic covariances among the several distances, maternal influence, and genetic parameters for racing longevity.

Animals↗
PubMed1991

Prostaglandins: an overview of the worldwide clinical experience.

Synthetic prostaglandins of the E series have cytoprotective and gastric antisecretory actions. Both actions are relevant to their therapeutic usefulness in treating and preventing gastrointestinal mucosal diseases. Controlled clinical studies have shown prostaglandins to be effective treatment for gastric and duodenal ulcer disease. Although used widely in dozens of foreign countries, however, prostaglandins have not been approved by the United States Food and Drug Administration for use in the treatment of peptic ulcer disease. The use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with an increased incidence of gastric and duodenal ulcers, gastrointestinal bleeding, and increased morbidity and mortality. Misoprostol, a prostaglandin E1 analogue, is effective in preventing and treating NSAID-induced mucosal damage and has been approved by the Food and Drug Administration for the prevention of NSAID-associated gastric ulcers. Controlled studies have not provided convincing evidence that H2-receptor antagonists or sucralfate prevents NSAID-induced gastric ulcer. Preliminary clinical studies indicate that some E-prostaglandins may also be effective in treating and/or preventing stress ulcer, cystic fibrosis, and hepatorenal syndrome and in improving graft survival in renal transplant patients receiving cyclosporine. Additionally, in vitro and animal studies suggest that prostaglandins may have therapeutic value in inflammatory bowel disease, and they may promote cartilage repair by an inhibitory action on interleukin-1. The latter finding could be of major relevance in preventing cartilage destruction in rheumatic patients. Significant side effects associated with the clinical use of prostaglandins include mild to moderate diarrhea and stimulation of uterine contraction during early pregnancy. Prostaglandins are effective for the treatment of peptic ulcer disease and, to date, are the only effective therapy for preventing the total spectrum of NSAID-induced mucosal damage. These compounds may also prove effective in treating various inflammatory disorders.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1990

Primary and secondary structural analyses of glutathione S-transferase pi from human placenta.

The primary structure of glutathione S-transferase (GST) pi from a single human placenta was determined. The structure was established by chemical characterization of tryptic and cyanogen bromide peptides as well as automated sequence analysis of the intact enzyme. The structural analysis indicated that the protein is comprised of 209 amino acid residues and gave no evidence of post-translational modifications. The amino acid sequence differed from that of the deduced amino acid sequence determined by nucleotide sequence analysis of a cDNA clone (Kano, T., Sakai, M., and Muramatsu, M., 1987, Cancer Res. 47, 5626-5630) at position 104 which contained both valine and isoleucine whereas the deduced sequence from nucleotide sequence analysis identified only isoleucine at this position. These results demonstrated that in the one individual placenta studied at least two GST pi genes are coexpressed, probably as a result of allelomorphism. Computer assisted consensus sequence evaluation identified a hydrophobic region in GST pi (residues 155-181) that was predicted to be either a buried transmembrane helical region or a signal sequence region. The significance of this hydrophobic region was interpreted in relation to the mode of action of the enzyme especially in regard to the potential involvement of a histidine in the active site mechanism. A comparison of the chemical similarity of five known human GST complete enzyme structures, one of pi, one of mu, two of alpha, and one microsomal, gave evidence that all five enzymes have evolved by a divergent evolutionary process after gene duplication, with the microsomal enzyme representing the most divergent form.

Alleles↗
PubMed1990

Missense mutation (Gly----Glu188) of human lipoprotein lipase imparting functional deficiency.

Cloning and sequencing of lipoprotein lipase (LPL) cDNA prepared from the adipose tissue of a patient with classical LPL deficiency revealed a G to A transition at nucleotide 818 in all sequenced clones, leading to the substitution of glutamic acid for glycine at residue 188 of the mature protein. Hybridization of genomic DNA with allele-specific oligonucleotides confirmed that the patient was homozygous for this mutation and revealed that carrier status for this mutation among relatives of the patient was significantly associated with hypertriglyceridemia. Assay of the patient's plasma for immunoreactive enzyme and activity demonstrated the presence of a circulating inactive enzyme protein, the concentration of which was further increased by injection of heparin. The mutant sequence was produced by oligonucleotide-directed mutagenesis, and both normal and mutant sequences were cloned into the expression vector pSVL and transfected into COS-1 cells. The normal sequence led to the in vitro expression of an enzyme that bound to heparin-Sepharose and had a specific catalytic activity similar to that of normal postheparin plasma enzyme. By contrast, the mutant enzyme expressed in vitro was catalytically inactive and displayed a lower affinity for heparin than the normal enzyme. We conclude that this single amino acid substitution leads to the in vivo expression of an inactive enzyme accounting for the manifestations of LPL deficiency noted in the patient.

Adipose Tissue↗
PubMed1990

Elevated substance P and accelerated cartilage degradation in rabbit knees injected with interleukin-1 and tumor necrosis factor.

Cytokines, interleukin-1 (IL-1), tumor necrosis factor alpha, and the neurotransmitter, substance P, have been implicated in the pathogenesis of arthritis because they stimulate synovial cells to secrete prostaglandin E2 and collagenase in vitro. We investigated in vivo changes in intraarticular substance P and the degradation of cartilage proteoglycan in response to intraarticular cytokine injections in rabbits. Twenty-four hours after a single injection of 10 ng, 30 ng, or 100 ng of recombinant human IL-1 alpha (rHuIL-1 alpha) per joint, the mean +/- SEM levels of substance P detected in the cell-free joint lavage fluid were 250 +/- 67 fmoles, 480 +/- 60 fmoles, and 530 +/- 130 fmoles (n = 4-5), respectively. The level of substance P in the contralateral knees injected with diluent was 58 +/- 8 fmoles (n = 12). The level of substance P had increased by 2 hours after IL-1 injection and remained elevated in the joint 48 hours after injection. Cytokine-induced proteoglycan depletion was also time- and dose-dependent. Proteoglycan concentrations in articular cartilage dissected from the weight-bearing condyles were calculated as the ratio of sulfated glycosaminoglycan measured using 1,9-dimethylmethylene blue: hydroxyproline. After 48 hours, 10 ng, 30 ng, or 100 ng of rHuIL-1 alpha per joint decreased proteoglycan levels by 9 +/- 4%, 14 +/- 4%, and 21 +/- 3% (n = 8), respectively. Likewise, the injection of recombinant human tumor necrosis factor alpha induced depletion of intraarticular substance P and cartilage proteoglycan.

Animals↗
PubMed1990

Plasma apolipoprotein E, high density lipoprotein1 (HDL1) and urinary mevalonate excretion in pancreatectomized diabetic dogs: effects of insulin and lovastatin.

Hypercholesterolemia and increased concentrations of an apolipoprotein E (apoE)-containing HDL subclass, high density lipoprotein1 (HDL1) have been observed in streptozocin-alloxan diabetic dogs consuming normal amounts of dietary cholesterol. The aim of this study was to characterize the response of HDL1 and its targeting ligand, apoE, to insulin and HMG-CoA reductase inhibitor treatment in pancreatectomized diabetic dogs. Following induction of diabetes, plasma total cholesterol, HDL1, and apoE concentrations were all increased. Urinary mevalonate excretion, an index of cholesterol synthesis in humans, was 6-fold that of nondiabetic controls. Lipoprotein fractionation by Pevikon block electrophoresis and gel filtration chromatography showed that the increased cholesterol and apoE were associated with alpha 2-migrating particles corresponding to HDL1. Insulin treatment, resulting in near normal fasting blood glucose concentrations in the group as a whole (average 5.1 mM, 92 mg/dl), led to variable reductions in apoE, total plasma cholesterol, and HDL1. Uncorrected dyslipidemia during intensified insulin treatment appeared to be related to failure to achieve euglycemia. Despite unremitting hyperglycemia, treatment with lovastatin resulted in pronounced decreases in plasma cholesterol, HDL1 and apoE to concentrations below those observed in nondiabetic animals. Mevalonate excretion also fell, but remained twice normal. Thus neither modality corrected all of the abnormalities in canine diabetic dyslipidemia. Since apoE-containing HDL1 may mediate cholesterol traffic between the periphery and the liver (reverse cholesterol transport), the present observations suggest that increased cholesterol synthesis is accompanied by parallel abnormalities in cholesterol flux through the reverse transport pathway in the canine model.

Animals↗
PubMed1990

CAP 37, a 37 kD human neutrophil granule cationic protein shares homology with inflammatory proteinases.

We have previously shown that a major granule-associated cationic protein CAP 37 (Mr = 37 kD) derived from human PMN is a monocyte-specific chemoattractant. The N-terminal amino acid sequence of this novel chemotactic protein shares significant homology with a number of inflammatory molecules with protease activity including elastase and cathepsin G. However, a critical substitution of a serine for a histidine at position 41, results in its lack of serine protease activity.

Amino Acid Sequence↗
PubMed1990

Mild pantothenate deficiency in rats elevates serum triglyceride and free fatty acid levels.

Pantothenate-derived coenzymes are extensively involved in intermediary metabolism, particularly in the metabolism of lipids. Using a rat model of diet-induced pantothenate deficiency, we hoped in this study to relate pantothenate status, as indicated by serum pantothenate and hepatic coenzyme A, to levels of circulating triglycerides and free fatty acids. Although commercial "vitamin-free" casein contained approximately 3 mg total pantothenate per kilogram, marked changes in serum pantothenate and hepatic CoA still occurred during weeks when rats were fed purified diets supplemented with 0 to 1600 mg pantothenate per kilogram of diet. Conditions in different experiments included ad libitum or pair-feeding of 3- or 6-wk-old rats and blood sampling from 3 to 24 h after feeding. Under most conditions of mild pantothenate deficiency in which weight differences between groups were not statistically significant, serum triglyceride and free fatty acid levels were significantly elevated in pantothenate-deficient groups. Mild pantothenate deficiency appears to have observable in vivo effects on triglyceride metabolism before severe deficiency causes significant weight loss.

Animals↗
PubMed1990

Ultrastructural evidence for differentiation in a human glioblastoma cell line treated with inhibitors of eicosanoid metabolism.

Human glioblastoma cells incubated in the presence of inhibitors of eicosanoid biosynthesis show decreased cellular proliferation without cytotoxicity. We studied the ultrastructural morphology of a human glioblastoma cell line cultured with nordihydroguaiaretic acid (NDGA), a lipoxygenase inhibitor, or 5,8,11,14-eicosatetraynoic acid, a cyclooxygenase and lipoxygenase inhibitor. When glioblastoma cells were treated for 3 days with antiproliferative concentrations of either agent, they shared many morphological characteristics, including evidence for increased astrocytic differentiation with only limited signs of toxicity. The inhibited glioma cells demonstrated an increase in the number and length of astrocytic processes containing greater numbers of glial filaments, and the NDGA-treated cells also demonstrated extensive lateral pseudopod formation along the processes. The glioblastoma cell shape also became more elongated, losing the usual nuclear lobularity and nuclear inclusions, especially in NDGA-treated cells. Many cytoplasmic organelles packed the cytosol of the inhibited glioma cells, including prominent Golgi apparatus, dilated smooth endoplasmic reticulum evolving into dilated vesicles, cytoplasmic vacuoles, and numerous concentric laminations. There was limited evidence for toxicity, however, as the mitochondria were more pleomorphic with some mitochondrial distention and disruption of the cristae along with an increase in cytoplasmic vacuolization. We conclude that the inhibitors of eicosanoid biosynthesis, NDGA and 5,8,11,14-eicosatetraynoic acid, not only suppress glioblastoma cell proliferation, but also induce increased astrocytic differentiation.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed1990

Phenotypic expression of heterozygous lipoprotein lipase deficiency in the extended pedigree of a proband homozygous for a missense mutation.

Familial lipoprotein lipase (LPL) deficiency is a rare genetic disorder accompanied by well-characterized manifestations. The phenotypic expression of heterozygous LPL deficiency has not been so clearly defined. We studied the pedigree of a proband known to be homozygous for a mutation resulting in nonfunctional LPL. Hybridization of DNA from 126 members with allele-specific probes detected 29 carriers of the mutant allele. Adipose tissue LPL activity, measured previously, was reduced by 50% in carriers, but did not reliably distinguish them from noncarriers. Carriers were prone to the expression of a form of familial hypertriglyceridemia characterized by increased plasma triglyceride, VLDL cholesterol and apolipoprotein B, and decreased LDL and HDL cholesterol concentrations. These manifestations were age modulated, with conspicuous differences between carriers and noncarriers observed only after age 40. Several noncarriers exhibited similar lipid abnormalities, but without the inverse relationship between VLDL cholesterol and LDL cholesterol noted among carriers. In addition to age and carrier status, the potentially reversible conditions, obesity, hyperinsulinemia and lipid-raising drug use were contributory. Thus heterozygous lipoprotein lipase deficiency, together with age-related influences, may account for a form of familial hypertriglyceridemia.

Adipose Tissue↗