Search PubMed⌕ Search

Biomedical subjects

M W Wilson

Publications and source records attributed to M W Wilson.

At least 55 records · Page 3Linked to original sources
PubMed1995

Effect of phenobarbital and the peroxisome proliferator ciprofibrate on gamma-Glutamyltranspeptidase activity and leukotriene C4 concentration in cultured rat hepatocytes.

Peroxisome proliferators induce hepatocellular carcinomas in rodents by an unknown mechanism. gamma-Glutamyltranspeptidase (GGT), a biochemical marker for identifying putative preneoplastic lesions in the liver, is highly expressed in phenobarbital (PB)-promoted altered hepatic foci but not in those promoted by peroxisome proliferators. One of the substrates of GGT is the eicosanoid LTC4. Because peroxisome proliferators and PB have differing effects on eicosanoid metabolism in vivo, we hypothesized that PB would similarly increase LTC4 concentrations, whereas the peroxisome proliferator ciprofibrate (CIP) would not. Cultured hepatocytes were treated with the peroxisome proliferator ciprofibrate (CIP: 100 and 400 microM) or PB (PB: 0.5 and 2 mM). Competitive radioimmunoassay (RIA) was used to determine the concentration of LTC4 in extracts of cultured hepatocytes. CIP decreased the concentration of LTC4 throughout the culture period, but PB increased the LTC4 concentration. Both doses of CIP significantly inhibited the induction of GGT activity at 48 and 72 hours, whereas PB enhanced GGT activity. We therefore hypothesized that LTC4, a substrate of GGT, may induce GGT activity. LTC4, however, did not enhance GGT activity and inhibited it at very high concentrations. The results of this experiment show that CIP and PB have different effects on GGT activity and LTC4 concentration. LTC4, however, does not induce GGT in cultured hepatocytes.

Animals↗
PubMed1995

Altered hepatic eicosanoid concentrations in rats treated with the peroxisome proliferators ciprofibrate and perfluorodecanoic acid.

Several hypolipidemic drugs, plasticizers, and other chemicals induce hepatic peroxisome proliferation and hepatocellular carcinomas in rodents. These agents induce and promote hepatocarcinogenesis by unknown mechanisms, since most studies have not found them to be genotoxic. Peroxisome proliferators increase the expression of several genes, including those for the enzymes of the peroxisomal beta-oxidation pathway and the cytochrome P-450 4A family, which metabolize lipids, including eicosanoids and their precursor fatty acids. The peroxisome proliferators ciprofibrate and perfluorodecanoic acid (PFDA) were therefore examined for their ability to alter hepatic eicosanoid concentrations. Rats received injections of 3 or 10 mg PFDA/kg body weight every 14 days or were fed 0.01% ciprofibrate for 10 days, 24 days, 6 weeks, 26 weeks, or 54 weeks. The activity of the peroxisomal enzyme fatty acyl CoA oxidase was significantly increased by both ciprofibrate and PFDA at all times. Hepatic concentrations of prostaglandins E2 and F2a (PGE2, PGF2a), thromboxane B2 (TXB2), and leukotriene C4 (LTC4) were measured by immunoassay. Concentrations of PGE2, PGF2a, and TXB2 were decreased in livers of rats receiving ciprofibrate or PFDA compared to livers of control rats, with ciprofibrate exerting a greater effect than PFDA at the doses used. Hepatic LTC4 concentrations were significantly increased by ciprofibrate at 10 days and PFDA at 54 weeks, and significantly decreased by PFDA at 26 weeks. These alterations in eicosanoid concentrations may be important in the natural history of peroxisome proliferator-induced hepatocarcinogenesis.

Acyl-CoA Oxidase↗
PubMed1995

Bone formation in hydroxyapatite orbital implants.

PURPOSE: We examined the histopathologic features of two hydroxyapatite orbital implants that were removed from two patients. METHODS: Two surgically removed hydroxyapatite orbital implants were decalcified and processed for routine light microscopic examination. RESULTS: Both implants demonstrated fibrovascular ingrowth and foci of bone formation. CONCLUSION: Bone may form in hydroxyapatite orbital implants.

Adult↗
PubMed1995

Murine model of anterior and posterior ocular melanoma.

Iris melanomas are less likely to metastasize than ciliary body or choroidal melanomas. In order to study this difference in metastatic rate, we developed a murine model of anterior chamber (AC) and posterior compartment (PC) melanoma. Eighteen C57BL6 mice were inoculated in the AC (n = 6) or PC (n = 12) with B16F10 melanoma cells and eleven mice were inoculated in the AC (n = 3) or PC (n = 8) with Queens melanoma cells. The animals were sacrificed at 12 to 14 days post inoculation and histologically examined. Results were that 8 of 9 AC tumors and 10 of 20 PC tumors grew. One PC tumor metastasized to the lungs. This model may be used to study anterior versus posterior ocular melanoma differences.

Animals↗
PubMed1994

Increased 8-hydroxydeoxyguanosine in hepatic DNA of rats treated with the peroxisome proliferators ciprofibrate and perfluorodecanoic acid.

In this study we examined the ability of peroxisome proliferators to induce oxidative DNA damage in the form of 8-hydroxydeoxyguanosine (OHdG). We studied the hypolipidemic drug ciprofibrate, which is among the most potent and efficacious of the peroxisome proliferators, and perfluorodecanoic acid (PFDA), which is an inhibitor of peroxisomal beta-oxidation. Rats were fed 0.01% ciprofibrate in the diet, or were injected with PFDA at doses of 3 or 10 mg/kg every 14 days (controls and ciprofibrate-fed rats were given equivalent doses of corn oil). Rats were maintained for 10 days, 24 days, 6 weeks, 26 weeks, or 54 weeks. DNA was isolated from the liver at these times and hydrolysed to nucleosides, and the levels of OHdG as well as normal nucleosides were analysed by high-performance liquid chromatography with electrochemical detection. Ciprofibrate increased OHdG concentrations at all times except for the initial 10-day timepoint. Both doses of PFDA increased OHdG levels at all times except the last timepoint, at which only the higher dose produced a significant increase. This study shows that both ciprofibrate and PFDA induce oxidative DNA damage in the form of OHdG. Furthermore, the inhibition of peroxisomal beta-oxidation by PFDA does not affect the development of OHdG.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1994

Inhibitors of acyl-CoA:cholesterol O-acyl transferase (ACAT) as hypocholesterolemic agents. 8. Incorporation of amide or amine functionalities into a series of disubstituted ureas and carbamates. Effects on ACAT inhibition in vitro and efficacy in vivo.

A series of disubstituted ureas containing amide or amine groups was prepared and evaluated for their ability to inhibit acyl-CoA:cholesterol O-acyl transferase in vitro and to lower plasma total cholesterol in a variety of cholesterol-fed rat models in vivo. The presence of polar or ionizable functionalities within this class of compounds may impart greater aqueous solubility to those compounds and thus allow improved transport to the enzyme location within the intestinal enterocyte. Compounds from this class exhibit good cholesterol lowering in a chronic cholesterol-fed rat model of hypercholesterolemia even when dosed in an aqueous vehicle. In general, the amine-containing compounds were more potent and efficacious than the amides in the acute rat model of hypercholesterolemia. Further structure-activity relationship studies showed that the preferred position of the amide/amine group was beta to the urea moiety and not alpha, and that in this series, the presence of a secondary amine (or amide) proton is required for good in vitro potency. One of these compounds, 9n(-), lowered plasma total cholesterol (-47%) and elevated high-density lipoprotein cholesterol (+256%) when dosed in an aqueous vehicle to rats with preestablished hypercholesterolemia.

Amides↗
PubMed1994

Effect of the peroxisome proliferators ciprofibrate and perfluorodecanoic acid on hepatic cell proliferation and toxicity in Sprague-Dawley rats.

The objective of this study was to compare the effects of perfluorodecanoic acid (PFDA) and ciprofibrate on the induction of hepatic toxicity and on hepatocellular proliferation in rats. In the first study, rats were first subjected to partial hepatectomy and then injected with [3H]thymidine (20 microCi/injection) at 23, 24, 25, 47, 48 and 49 h afterwards. After a 2 week recovery period, rats were injected with one of four levels of PFDA (0.3, 1.0, 3.0 or 10 mg/kg/injection) in four i.p. doses every 14 days, or were fed 0.01% or 0.003% ciprofibrate. Six days after the last PFDA injection and three days before the animals were killed, an osmotic minipump containing 20 mg/ml 5-bromo-2'-deoxyuridine (BrdU) was implanted s.c. for the measurement of DNA synthesis. Peroxisomal fatty acyl-CoA oxidase activity was significantly enhanced in both PFDA and ciprofibrate-treated groups in a dose-dependent manner. Hepatotoxicity, measured as the loss of [3H]thymidine from hepatic DNA, was not significantly affected by any of the treatments. Hepatic DNA synthesis was significantly increased only in rats receiving the highest dose of PFDA. In order to determine the time course of ciprofibrate- and PFDA-induced cell proliferation, we conducted another study with more time points. Rats were fed 0.01% ciprofibrate or were injected every 14 days with 3 or 10 mg PFDA/kg body weight for 10 days, 24 days, 6 weeks, 26 weeks or 54 weeks. Cell proliferation was quantified as in the first study. Ciprofibrate increased cell proliferation at the early but not the later time points, whereas PFDA increased cell proliferation at most times throughout the study. This study demonstrates that PFDA and ciprofibrate do not selectively induce hepatic toxicity and that their effects on cell proliferation do not correlate with their carcinogenic or promoting activities.

Acyl-CoA Oxidase↗
PubMed1993

Design of 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3,4-thiadiazoles, -1,3,4-oxadiazoles, and -1,2,4-triazoles as orally-active, nonulcerogenic antiinflammatory agents.

To discover dual inhibitors of 5-lipoxygenase (LO) and cyclooxygenase (CO) with improved pharmacokinetic properties, we have designed and synthesized series of 1,2,4-triazole, 1,3,4-oxadiazole, and 1,3,4-thiadiazole di-tert-butylphenol derivatives which exhibit a wide range of log P (2.3 to > 4) and pKa (5.5-12) values. From this work 5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2(3H)- thione, choline salt (12a, CI-986) was found to be a potent inhibitor of 5-LO (IC50 = 2.8 microM) and CO (IC50 = 0.8 microM), orally active in rat models of inflammation and nonulcerogenic.

Animals↗
PubMed1992

Unusual clinical presentation and scintigraphic pattern in myositis ossificans.

Myositis ossificans, or heterotopic bone formation, is a possible sequela of musculoskeletal trauma. Its radiographic and scintigraphic appearances have been well documented. Specifically, plain film radiographs usually show soft tissue calcification in the muscle groups adjacent to the trauma. The three-phase bone scan may demonstrate an area of nonspecific increased tracer uptake in all three phases. The authors present a case of radiographically demonstrated heterotopic bone formation in the leg of a retired football player.

Adult↗
PubMed1991

Pre- and post-operative cerebral blood flow changes in subarachnoid haemorrhage.

Assessment of cerebral perfusion on patients with subarachnoid haemorrhage (SAH) in the Neurologic Intensive Care Unit is difficult since nuclear medicine imaging modalities capable of measuring cerebral blood flow (CBF) are not generally available. We performed 101 quantitative (ml 100g-min) bedside CBF measurements on 40 individual patients to correlate SAH grade with CBF and to assess the effect of surgical intervention on CBF. Global CBF (G-CBF) and bihemispheric CBF (B-CBF) asymmetry were correlated with the grade of SAH pre- and post-operatively. Data analysis showed that pre-operative patients with low grade SAH (Hunt and Hess grades 0 to 2) had higher mean G-CBF values [44.2 +/- 71] than those with high grade SAH (Hunt and Hess grades 3 to 4): [mean G-CBF = 34.1 +/- 1.7]. Post-surgery there was a significant improvement in G-CBF; CBF increased [5.3 +/- 1.07] in the group of patients with low grade SAH. Patients with high grade SAH showed no significant improvement in their G-CBF during the first week post-operatively compared to pre-operative values. We conclude that portable units capable of measuring bedside CBF values are useful in monitoring CBF changes in patients with SAH. Patients with low grade SAH have G-CBF within normal limits both pre-operatively and post-operatively, with a statistically significant increase in CBF during two weeks post-operatively. Patients with high grade SAH show no significant increase in CBF one week post-operatively compared to their pre-operative measures.

Adult↗
PubMed1991

Intravascular ultrasound imaging of vascular responsiveness in isolated perfused canine arteries.

We investigated the feasibility of using intravascular ultrasound imaging to analyze vascular physiology in various arterial beds. Canine superficial femoral, external iliac, and common carotid arteries were harvested and suspended and perfused in a bath of oxygenated, heated, physiologic salt solution. A 6-Fr, 20-MHz ultrasound imaging catheter was inserted into the lumen of the arteries and serial images were acquired after bolus injections of either serotonin or normal saline into the extravascular bathing medium. Serotonin resulted in a significant time- and dose-dependent decrease in cross-sectional area in muscular femoral arteries (P less than .001): -5.2% with 10(-8) M serotonin, -15% with 10(-7) M, and -28% with 10(-6) M. Histologically transitional iliac arteries demonstrated less marked changes, while elastic carotid arteries demonstrated no significant changes. Our results indicate that intravascular ultrasound may be used to quantify and differentiate responses to vasoconstrictive agents in different vascular beds.

Animals↗
PubMed1991

Clinical SPRINT imaging. Preliminary results compared to conventional SPECT brain scanning using Tc-99m HMPAO.

We have performed initial clinical studies using the high resolution single photon ring tomograph (SPRINT) and Tc-99m HMPAO. To determine what additional anatomic detail can be depicted using this high resolution, dedicated head, multidetector SPECT device compared to conventional SPECT, six patients with stroke and one normal volunteer were imaged after the injection of 20 mCi Tc-99m HMPAO on a conventional rotating Anger gamma camera (GE-400AC), followed immediately by imaging on SPRINT. Imaging acquisition on the GE-400AC gamma camera was performed using 360 degrees rotation, 64 stops, at 30 sec/stop, yielding an average of 985,714 counts for a 10.0 mm thick slice. GE-400AC images were of good quality, having in-plane full width half maximum (FWHM) resolution of approximately 15 mm. SPRINT acquisition of image data was performed using both the high resolution and high sensitivity apertures, with data collection over 15 or 20 minutes of imaging time accumulating approximately 500,000 counts and 1,000,000 counts, respectively, from patients in a 10.0 mm thick slice, achieving an in-plane FWHM resolution of approximately 8 mm and 10 mm for the two apertures, respectively. Both image resolution and contrast for visualization of gray, white, and cerebral spinal fluid filled brain structures were improved using SPRINT compared with the GE-400AC. We conclude that SPRINT is well suited for brain imaging with Tc-99m HMPAO and is of particular value for applications demanding high resolution.

Adult↗
PubMed1990

Inhibitors of cholesterol biosynthesis. 1. trans-6-(2-pyrrol-1-ylethyl)-4-hydroxypyran-2-ones, a novel series of HMG-CoA reductase inhibitors. 1. Effects of structural modifications at the 2- and 5-positions of the pyrrole nucleus.

A novel series of trans-6-(2-pyrrol-1-ylethyl)-4-hydroxypyran-2-ones and their dihydroxy acid derivatives were prepared and evaluated for their ability to inhibit the enzyme HMG-CoA reductase in vitro. A systematic study of substitution at the 2- and 5-positions of the pyrrole ring revealed that optimum potency was realized with the 2-(4-fluorophenyl)-5-isopropyl derivative 8x, which possessed 30% of the in vitro activity of the potent fungal metabolite compactin (I). A molecular modeling analysis led to the description of a pharmacophore model characterized by (A) length limits of 5.9 and 3.3 A for the 2- and 5-substituents, respectively, as well as an overall width limit of 10.6 A across the pyrrole ring from the 2- to the 5-substituent and (B) an orientation of the ethyl(ene) bridge to the 4-hydroxypyran-2-one ring nearly perpendicular to the planes of the parent pyrrole, hexahydronaphthalene, and phenyl rings of the structures examined (Figure 3, theta = 80-110 degrees). Attempts to more closely mimic compactin's polar isobutyric ester side chain with the synthesis of 2-phenylpyrroles containing polar phenyl substituents resulted in analogues with equal or slightly reduced potencies when compared to the 2-[(unsubstituted or 4-fluoro)phenyl]pyrroles, supporting the hypothesis that inhibitory potency is relatively insensitive to side-chain polarity or charge distribution in this area.

Animals↗
PubMed1990

Inhibitors of cholesterol biosynthesis. 2. 1,3,5-trisubstituted [2-(tetrahydro-4-hydroxy-2-oxopyran-6-yl)ethyl]pyrazoles.

A series of 1,3,5-trisubstituted pyrazole mevalonolactones were prepared and evaluated for their ability to inhibit the enzyme HMG-CoA reductase in vitro. Since previous studies suggested that the 5-(4-fluorophenyl) and 3-(1-methylethyl) substituents afforded optimum potency, attention was focused on variations in position 1 of the pyrazole ring. Biological evaluation of analogues bearing a variety of 1-substituents suggested that, although most substituents were tolerated, none afforded an advantage over phenyl, which exhibited potency comparable to that of compactin in vitro.

Animals↗
PubMed1989

Positron emission tomographic evaluation of cerebral blood flow during state anxiety in simple phobia.

The present study was undertaken to clarify some of the conflicting findings of previous reports on the effect of state anxiety on cerebral blood flow (CBF). Seven subjects with simple phobia of small animals were studied to permit the generation of wide ranges of anxiety. Each subject received five positron emission tomography (PET) scans in a rest-fear-rest-fear-rest, repeated-measures paradigm. A population of eight normal controls was employed. The phobic stimuli produced significant increases in state anxiety during fear and significant differences in physiologic measurements between the fear and rest scans. Absolute global and regional CBF was significantly lower during fear scans than during rest scans; however, when hypocapnia resulting from anxiety-induced hyperventilation was taken into account, the pattern vanished, and all global and regional CBF differences among scans became not significant. Resting global and regional CBF values in the phobic subjects did not significantly differ from those of the normal controls. That a relationship between anxiety and CBF was not found in 35 scans among seven subjects strongly suggests that CBF changes induced by state anxiety are either not presently measurable by PET techniques or that such a relationship may not exist. These findings should also reduce concerns that subject anxiety may confound CBF measurements during routine PET scanning.

Anxiety Disorders↗
PubMed1988

Managemental influences on the selective proliferation of two strains of haemolytic Escherichia coli in weaned pigs.

In an experimental study on a piggery it was found that haemolytic Escherichia coli of O-serotypes 138 or 139 proliferated in the intestinal tracts of pigs following weaning, with E. coli of the O-138 type also being occasionally recovered from unweaned pigs, and once from a sow. Organisms of the O-138 type produced heat labile enterotoxin and their presence in weaned pigs was associated with the development of severe post-weaning diarrhoea. E. coli of O-139 type produced a vero cell cytotoxin and were associated with a milder diarrhoea in weaned pigs. Under various managemental circumstances the O-138 type E. coli almost invariably proliferated after weaning. The O-139 strain of E. coli did however proliferate rather than the O-138 strain following the movement of weaned pigs to new accommodation, after weaned pigs were returned to their sow and then weaning again 5 days later, and very occasionally in pigs weaned at 5 weeks of age. In all these cases earlier proliferation of the O-138 E. coli had been detected, suggesting that this may be a prerequisite for proliferation of the O-139 strain.

Animals↗