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Biomedical subjects

R Wilson

Publications and source records attributed to R Wilson.

At least 217 records · Page 12Linked to original sources
PubMed1998

Lack of morphine and enkephalin tolerance in 129/SvEv mice: evidence for a NMDA receptor defect.

In contrast to the rapid development of tolerance to morphine in CD-1 mice, tolerance is not seen in 129/SvEv mice implanted with morphine pellets or given daily morphine injections for 5 days. Similarly, the progressive and complete loss of analgesia in CD-1 mice seen with repeated dosing of the delta ligand [D-Pen2, D-Pen5]enkephalin is not observed in 129/SvEv mice. In contrast, tolerance develops normally to both the kappa1 drug U50,488H and the kappa3 agent naloxone benzoylhdrazone. N-methyl-D-aspartate (NMDA) given alone attenuates morphine analgesia in CD-1 mice and accelerates the development of tolerance in CD-1 mice when given daily with morphine. In contrast, NMDA has no significant effect in the 129/SvEv mice in either paradigm. Activation of NMDA receptors can lead to the production of nitric oxide, which also is involved with morphine tolerance. Sodium nitroprusside and L-arginine increase nitric oxide levels and decrease morphine analgesia in both the control CD-1 and 129/SvEv mice. Thus, the defect in the NMDA/nitric oxide cascade responsible for the loss of morphine tolerance in the 129/SvEv mice rests at the level of the NMDA receptor itself or in the steps up to the activation of nitric oxide synthase.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1998

Practice choices of graduating family medicine residents.

OBJECTIVE: To examine the types of practices family medicine residents chose during the first 2 years after residency, and how these choices have changed over a 15-year period. DESIGN: Mailed survey. SETTING: Areas served by graduates of the Queen's University family medicine residency program. PARTICIPANTS: Two hundred thirty (76%) of the 303 graduates from 1977 to 1991 of the Queen's University family medicine residency program responded to the questionnaire. MAIN OUTCOME MEASURES: Type of practices residents entered immediately out of residency: whether they began full-time, part-time, locum tenens, or other type of practice; length of time spent in the first practice situation; and proportion of residents who had settled into a full-time practice within 2 years of completing residency. RESULTS: Residents who graduated before 1985 were significantly more likely to go into full-time practice immediately out of residency (P = .0001). The earlier residents had graduated from the program, the more likely they were to go immediately into full-time practice. This finding was not affected by residents' age, sex, size of community of origin, exposure to rural teaching sites, marital status, or how well prepared for practice they felt. Residents graduating before 1985 were also more likely to be in full-time practice within 2 years of completing their residency program (P = .003). CONCLUSIONS: Recent family medicine residents did not enter full-time practice immediately out of residency as often as those who had graduated earlier, nor did they commit to full-time practice within 2 years of graduating as often as residents graduating before 1985 did.

Career Choice↗
PubMed1997

Myocrisin-mediated oxidative stress.

This study reports on the ability of myocrisin to mediate in the production and detoxification of oxidants (principally hydrogen peroxide) in the monocyte in-vivo and in-vitro. The hydrogen peroxide produced by the monocyte derived from rheumatoid arthritis patients being treated with myocrisin was found to be 14.9 +/- 1.6 nmoles/10(6) cells and is elevated above levels found in monocytes obtained from patients either being treated with non-steroidal anti-inflammatory drugs (NSAIDs) (11.3 +/- 0.4 nmoles/10(6) cells; P < 0.01) or normal healthy volunteers (11.2 +/- 1.2 nmoles/10(6) cells; P < 0.01). A comparative study on glutathione (GSH) oxidation indicated that levels of monocyte GSH were elevated in myocrisin-treated patients (2.4 +/- 0.49 mmol/l) over normal healthy volunteers (0.83 +/- 0.18 mM; P < 0.01) and that levels of monocyte diglutathione (GSSG) were depressed (myocrisin, 0.97 +/- 0.41 micromol/l; normal, 5.71 +/- 0.73 micromol/l; P < 0.01). The non-inhibition of glutathione reductase and the inhibition of glutathione peroxidase by gold provides the link between these two observations. Thus, gold therapy would seem to elevate monocyte hydrogen peroxide, increase monocyte reduced glutathione and decrease plasma glutathione peroxidase activity. Subsequently, the data from this small group of patients (n = 10) provides an indication that, in-vivo, myocrisin contributes to an increase in oxidative stress.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1997

Dietary restriction reduces insulin-like growth factor I levels, which modulates apoptosis, cell proliferation, and tumor progression in p53-deficient mice.

Diet contributes to over one-third of cancer deaths in the Western world, yet the factors in the diet that influence cancer are not elucidated. A reduction in caloric intake dramatically slows cancer progression in rodents, and this may be a major contribution to dietary effects on cancer. Insulin-like growth factor I (IGF-I) is lowered during dietary restriction (DR) in both humans and rats. Because IGF-I modulates cell proliferation, apoptosis, and tumorigenesis, the mechanisms behind the protective effects of DR may depend on the reduction of this multifaceted growth factor. To test this hypothesis, IGF-I was restored during DR to ascertain if lowering of IGF-I was central to slowing bladder cancer progression during DR. Heterozygous p53-deficient mice received a bladder carcinogen, p-cresidine, to induce preneoplasia. After confirmation of bladder urothelial preneoplasia, the mice were divided into three groups: (a) ad libitum; (b) 20% DR; and (c) 20% DR plus IGF-I (IGF-I/DR). Serum IGF-I was lowered 24% by DR but was completely restored in the IGF-I/DR-treated mice using recombinant IGF-I administered via osmotic minipumps. Although tumor progression was decreased by DR, restoration of IGF-I serum levels in DR-treated mice increased the stage of the cancers. Furthermore, IGF-I modulated tumor progression independent of changes in body weight. Rates of apoptosis in the preneoplastic lesions were 10 times higher in DR-treated mice compared to those in IGF/DR- and ad libitum-treated mice. Administration of IGF-I to DR-treated mice also stimulated cell proliferation 6-fold in hyperplastic foci. In conclusion, DR lowered IGF-I levels, thereby favoring apoptosis over cell proliferation and ultimately slowing tumor progression. This is the first mechanistic study demonstrating that IGF-I supplementation abrogates the protective effect of DR on neoplastic progression.

Aniline Compounds↗
PubMed1997

Functionally differentiating two neuronal nitric oxide synthase isoforms through antisense mapping: evidence for opposing NO actions on morphine analgesia and tolerance.

Several isoforms of neuronal nitric oxide synthase (nNOS) have been identified. Antisense approaches have been developed which can selectively down-regulate nNOS-1, which corresponds to the full-length nNOS originally cloned from the brain, and nNOS-2, a truncated form lacking two exons which is generated by alternative splicing, as demonstrated by decreases in mRNA levels. Antisense treatment also lowers nNOS enzymatic activity. Down-regulation of nNOS-1 prevents the development of morphine tolerance. Whereas morphine analgesia is lost in control and mismatch-treated mice given daily morphine injections for 5 days, mice treated with antisense probes targeting nNOS-1 show no decrease in their morphine sensitivity over the same time period. Conversely, an antisense probe selectively targeting nNOS-2 blocks morphine analgesia, shifting the morphine dose-response curve over 2-fold to the right. Both systems are active at the spinal and the supraspinal levels. An antisense targeting inducible NOS is inactive. Studies with NG-nitro-L-arginine, which does not distinguish among NOS isoforms, indicate that the facilitating nNOS-2 system predominates at the spinal level while the inhibitory nNOS-1 system is the major supraspinal nNOS system. Thus, antisense mapping distinguishes at the functional level two isoforms of nNOS with opposing actions on morphine actions. The ability to selectively down-regulate splice variants opens many areas in the study of nNOS and other proteins.

Analgesia↗
PubMed1997

Fringe modulates Notch-ligand interactions.

The Notch family of transmembrane receptor proteins mediate developmental cell-fate decisions, and mutations in mammalian Notch genes have been implicated in leukaemia, breast cancer, stroke and dementia. During wing development in Drosophila, the Notch receptor is activated along the border between dorsal and ventral cells, leading to the specification of specialized cells that express Wingless (Wg) and organize wing growth and patterning. Three genes, fringe (fng), Serrate (Ser) and Delta (Dl), are involved in the cellular interactions leading to Notch activation. Ser and Dl encode transmembrane ligands for Notch, whereas fng encodes a pioneer protein. We have investigated the relationship between these genes by a combination of expression and coexpression studies in the Drosophila wing. We found that Ser and Dl maintain each other's expression by a positive feedback loop. fng is expressed specifically by dorsal cells and functions to position and restrict this feedback loop to the developing dorsal-ventral boundary. This is achieved by fng through a cell-autonomous mechanism that inhibits a cell's ability to respond to Serrate protein and potentiates its ability to respond to Delta protein.

Animals↗
PubMed1997

Quantitative gas chromatography-mass spectrometry isomer-specific measurement of hydroxy fatty acids in biological samples and food as a marker of lipid peroxidation.

We have developed a capillary gas chromatography-mass spectrometry method for the quantitative analysis of individual positional isomers of monohydroxy fatty acids derived from linoleic, arachidonic, eicosapentaenoic, or docosahexaenoic acid. Peroxidation of a particular polyunsaturated fatty acid results already in a complex mixture of positional isomers of hydroperoxy and hydroxy fatty acids. Catalytic hydrogenation of lipid extracts produces stable saturated hydroxy lipids from the complex mixtures typical of oxidized biological samples, simultaneously simplifying the analytical problem and eliminating oxidation artifacts. After saponification and methylation, monohydroxy fatty acid methyl esters are purified by solid-phase extraction and partially resolved using a CP Sil 19 column following on-column derivatization of the hydroxy groups with tetramethylammonium hydroxide. The resulting methoxy fatty acid methyl esters are subjected to electron impact mass spectroscopy. Two characteristic ions are produced for each positional isomer. Quantitative measurements were achieved by using odd chain C17 and C19 monohydroxy fatty acids as internal standards. The limit of detection of individual hydroxy fatty acid isomers is dependent on the total number of ions monitored. Monitoring 11 pairs of ions simultaneously gives limits of detection of 10 ng. Sensitivity is much higher by monitoring fewer ions and as little as 0.2 ng of a single isomer can be detected. The method has been applied for the quantitative analysis of hydroxy (plus hydroperoxy) fatty acids in plasma, adipose tissue, oils, and foods. To date over 1000 samples have been analyzed using the method described in this paper.

Dietary Fats, Unsaturated↗
PubMed1997

Architectural and mechanical properties of the rat adductor longus: response to weight-lifting training.

BACKGROUND: The primary objective of this study was to determine the effects of an 8 week weight-lifting program on the mechanical, histochemical, and architectural properties of the rat adductor longus muscle, a predominantly slow adductor muscle. METHODS: The weight-lifting program was progressive such that the rats were performing three bouts of ten lifts with 300% body weight load every other day during the last 3 weeks of training. The in situ mechanical properties, fiber type composition, and architectural characteristics of the muscle were determined in control and weight-trained rats. Intramuscular electromyographic recordings were used to verify the recruitment of the adductor longus during the lifting task. RESULTS: The adductor longus was composed predominantly of slow fibers (approximately 80% slow oxidative) and had a relatively simple architectural design, i.e., one motor end-plate band near the center of the muscle, virtually no angle of pinnation of the fibers from the line of pull, and a fiber length:muscle length ratio of 0.72. The mean fiber type composition and fiber size, the total fiber number, and the mean physiological cross-sectional area of the adductor longus were similar in the two groups of rats. The mean body weight of weight-lifting rats was significantly less than control. The weight of the adductor longus relative to body weight and its fatigue resistance were higher and the maximum rate of shortening was slower in weight-lifting than in control rats. No other mechanical property was significantly affected by the training program. CONCLUSIONS: The results indicate that approximately 1 minute of over-load every other day by physiological recruitment of motor units can induce remodeling of the adductor longus of growing rats; i.e., the trained muscles were slower and less fatigable than control. Given that the effects on the architectural or force-generating properties of the muscles were small, the marked improvement in the ability to lift heavier loads as the training progressed appears to be more attributable to neurally related than to muscle-related phenomena.

Adenosine Triphosphatases↗
PubMed1997

Resolution of acylated dipeptide stereoisomers by capillary electrophoresis using sulfobutylether derivatized beta-cyclodextrin.

The separation of enantiomerically and diastereomerically related stereoisomers of acylated Asp-Phe dipeptides was explored using capillary electrophoresis (CE). This series of dipeptides included the alpha-L,L parent compound and the three other potential Asp containing stereoisomers (alpha-D,D, alpha-L,D, and alpha-D,L), as well the four possible isoAsp containing stereoisomers (beta-L,L, beta-D,D, beta-L,D and beta-D,L). The separation of these substances was explored using both neutral and charged cyclodextrins as the stereoisomer selector added to the running electrolyte. The major experimental parameters investigated included pH, the cyclodextrin type, and the cyclodextrin concentration. Due to differences in the pKa values of the carboxylic acid groups, adjustment of the separation buffer to between pH 3.0 and 4.0 provided for sufficient electrophoretic mobility differences to result in excellent separations of the diastereomerically related peptides in this pH region. The resolution of the enantiomerically related peptide stereoisomers was accomplished using low concentrations (1 mM) of the anionic cyclodextrin derivative, sulfobutylether-beta-cyclodextrin (SBE-beta-CD). This negatively charged cyclodextrin was found to be superior for the resolution of the enantiomerically related peptides as compared to native beta-cyclodextrin or the neutral derivatives, dimethyl beta-cyclodextrin and hydroxypropyl beta-cyclodextrin. An alternative approach using anionic or neutral surfactants in conjunction with the SBE-beta-CDs was also explored and found to be successful but problematic.

Acylation↗
PubMed1997

The effects of dietary boron on bone strength in rats.

Previous studies from our laboratory found that when boric acid (BA) was administered in the diet to rats, boron levels in bone were approximately fourfold greater than serum levels. The current studies were undertaken to determine if these elevations produced adverse effects on several bone-related measures, including serum electrolyte levels, bone structure, and bone strength. Data from two studies are presented: in the first study, young adult male rats consumed a powdered diet containing 0, 3000, 4500, 6000, or 9000 ppm BA for 9 weeks. Endpoints were serum calcium, phosphorous, potassium, and chloride, as well as blood and bone boron concentrations ([B]) measured weekly during the 9-week exposure period, and at 8, 16, 24, and 32 weeks after the end of exposure. In the second study, the male and female young adult rats diet contained 0, 200, 1000, 3000, or 9000 ppm BA for 12 weeks; endpoints measured weekly were serum levels of calcium, phosphorous, and magnesium, bone [B], and bone structure (humerus) and strength (tibia, femur, and lumbar vertebrae). In treated rats, calcium was reduced in the first study but not the second. Serum phosphorous was reduced in both studies; potassium was unchanged, chloride was increased by 1%, and magnesium was reduced in all BA-exposed groups in the second study, to a maximal 19% reduction. Bone [B] was consistently increased in all treated groups, to concentrations approximately fourfold those of serum. After cessation of exposure, serum and urinary boron concentrations dropped to within control values within a week. However, even 32 weeks after the end of exposure, bone [B] remained threefold greater than controls. Male tibia and femur resistance to bending was unchanged. However, vertebral strength in compression was significantly increased by 5-10% in all dose groups (200 to 9000 ppm). The pattern was substantially similar in females. Only the humerus was examined by light microscopy and was found to be unchanged at any level of BA consumption. These data show that, despite a reduction in some serum electrolyte levels, BA consumption increased vertebral resistance to crush force, without detectably altering the microscopic structure of the humerus or the resistance of femur and tibia to a bending load. This increase in compression resistance occurred at exposure levels substantially below those that were previously reported to be reproductively toxic.

Animals↗
PubMed1997

Ovarian luteal cell toxicity of ethylene glycol monomethyl ether and methoxy acetic acid in vivo and in vitro.

These studies define the site and mechanisms of reproductive toxicity of ethylene glycol monomethyl ether (EGME) in a nongravid female animal model using in vivo and in vitro methods. In vivo studies assessed vaginal cytology and histology, ovarian histology, and serum hormones in 80- to 90-day-old, adult, regularly cycling, female Sprague-Dawley rats treated daily with EGME or vehicle by oral gavage. Dose-response and time-course studies (four to nine rats per group per treatment) determined that 300 mg/kg EGME suppressed cyclicity without systemic toxicity within 3 to 8 days, and doses less than 100 mg/kg had no effect. Pathogenesis studies (six to nine rats per time and treatment) determined that 300 mg/kg EGME elevated serum progesterone within 32 hr after dosing, while serum estradiol, FSH, LH, and prolactin remained at baseline levels. In EGME-treated rats, cyclicity was suppressed, ovulation was inhibited, and corpora lutea were hypertrophied. Thus, EGME appeared to target the ovarian luteal cell. To further examine the toxicity in vitro, luteal cells were recovered from 23-day-old, hCG-primed Sprague-Dawley rats and treated with 0-10 mM methoxy acetic acid (MAA), the proximate toxic metabolite of EGME. MAA (1-10 mM) maintained elevated progesterone levels as production declined in untreated cells at 24 and 48 hr of culture. Progesterone production was maintained independent of LH-stimulated cAMP levels. MAA decreased ATP, but only at 48 hr and at 2.5 mM or greater concentrations. Thus, these studies establish that the ovarian luteal cell is a target of EGME and MAA in vivo and in vitro and that the effect on luteal cell progesterone production is likely independent of LH-stimulated cAMP pathways.

Acetates↗
PubMed1997

Organochlorine pesticides and polychlorinated biphenyls (PCBs) in sediments and biota from four US Arctic lakes.

Organochlorine (OC) concentrations in surface sediment, snails (Lymnea sp.), and two freshwater fish species (grayling, Thymallus arcticus; and lake trout, Salvelinus namaycush) from four lakes in the US Arctic were determined. In surface sediment, chlorinated benzenes (including hexachlorobenzene, HCB), and p,p'-DDT were the primary analytes detected (max = 0.7 ng/g dry wt), while individual polychlorinated biphenyl (PCB) congeners were always below 0.1 ng/g. A wider range of compounds and higher concentrations were found in lake trout, the top predatory fish species in the same lakes. The concentration ranges for hexachlorocyclohexanes (HCHs), chlordane-related compounds (CHLORs), DDTs, and PCBs in lake trout and grayling were similar to those reported for other arctic freshwater fish (1-100 ng/g wet wt), but one to two orders of magnitude lower than Great Lakes salmonids. Nitrogen isotope analysis confirmed that differences in OC concentrations between grayling and lake trout are explained partly by differences in food web position.

Animals↗
PubMed1997

Blockade of morphine-induced hindlimb myoclonic seizures in mice by ketamine.

Morphine administration can lead to a variety of side-effects, including myoclonus. In an animal model, high morphine doses given intrathecally elicit hindlimb myoclonic seizures which are not influenced by traditional opioid receptor antagonists, such as naloxone. Ketamine prevents this seizure-like activity in a dose-dependent manner. The response is stereoselective, with S-ketamine far more potent than R-ketamine. A competitive NMDA antagonist, NPC17742, also prevents the seizures, although less potently than ketamine. Dextromethorphan has limited activity in this model, while haloperidol and pentothal are without any effect.

Amino Acids↗
PubMed1997

Altered interleukin 12 and nitric oxide levels in recurrent miscarriage.

The causes of recurrent miscarriage are not fully understood. Recent studies have suggested that whilst a TH 2 type immune response may be associated with a healthy pregnancy, miscarriage may be associated with a TH 1 type response. Serum levels of nitric oxide (NO) and Interleukin 12 (IL 12) were measured in; healthy non-pregnant women; healthy pregnant women; women suffering spontaneous abortion; pregnant women with a history of recurrent miscarriage; non-pregnant women with a history of recurrent miscarriage. Normal pregnancy was associated with a significant decrease in serum levels of nitrite (13.0 vs. 22.0 P < 0.0001). In women admitted with spontaneous abortion there was a significant increase in the levels of nitrite (16.0 vs. 13.0 P < 0.05), but no change in IL 12 compared to normal pregnant women. In pregnant women with a history of recurrent miscarriage levels of nitrite (16.0 vs. 13.0 P < 0.05) and IL 12 (10.0 vs. 6.0 P < 0.0006) were significantly elevated compared to normal pregnancy. When these women were sampled prior to becoming pregnant the levels of NO were found to be significantly lower than those in the non-pregnant control group (13.1 vs. 22.0 P < 0.05) although levels of IL 12 were unchanged. No correlation was found between serum nitrite and IL 12 levels. This report further supports the idea that polarisation of the immune response during pregnancy may predispose to recurrent miscarriage.

Abortion, Habitual↗
PubMed1997

Electrochemiluminescence flow injection immunoassay for atrazine.

Antibodies to atrazine were labelled with glucose oxidase and used in colorimetric enzyme linked immunosorbent assays. Transparent aminosilanized indium tin oxide coated glass electrodes were derivatized with aminodextran covalently modified with atrazine caproic acid. The labelled antibodies were used to investigate the derivatized electrodes colorimetrically and the electrodes were use in an electrochemiluminescence flow injection analyser. Electrochemiluminescence immunoassay for atrazine in the range 0-10 ppb showed that it was possible to detect less than 0.1 ppb, the precautionary limit for pesticides in drinking water recommended by the European Commission.

Antibodies, Monoclonal↗