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Biomedical subjects

J Guay

Publications and source records attributed to J Guay.

At least 19 recordsLinked to original sources
PubMed2005

[The neurostimulator for brachial plexus blockade by the axillary approach: a metaanalysis on its efficacy to increase the success rate].

OBJECTIVE: To evaluate the effectiveness of the neurostimulator to improve the success rate of a brachial plexus blockade by the axillary approach. STUDY DESIGN: Metaanalysis. METHODS: Ten prospective randomized studies comparing a neurostimulating technique (NST) of brachial plexus blockade performed by the axillary approach to another technique were kept for analysis. A successful block was defined as blockade of the four following nerves: radial, median, ulnar and musculocutaneous. Data were entered on an intention to treat basis and were analyzed with a random model. A p<0.05 was considered significant. RESULTS: Data were heterogenous (p < 0.001) and the Cochran-Mantel-Haenzel test showed that the neurostimulator does not improve the success rate of brachial plexus blocks performed by the axillary approach when all available studies are considered as a whole (p = 1). For the subgroup of studies where four nerves were stimulated however, the NST decreases the incidence of failed block by 25% (95% CI = 7-42%) (p < 0.0001). There were 12 patients with systemic signs of local anesthetics toxicity when a NST was used compared to 28 when it was not (p = 0.04), relative risk of 0.7 (95% CI= 0.6-0.8). CONCLUSION: This study shows that the neurostimulator improves the success rate of brachial plexus blocks performed by the axillary approach only when three nerves or more are stimulated and its use decreases the incidence of systemic local anaesthetics toxicity.

Anesthetics, Local↗
PubMed2004

Contextual modulation of synchronization to random dots in the cat visual cortex.

Synchronization of neuronal activity has been proposed as a binding mechanism for integration of image properties into one coherent percept. In the present study, we investigated the contextual modulation of synchronization to random dot patterns. Coherent motion of random dots evoked well synchronized responses in area 17 of anaesthetized cats when the stimulus was presented in the compound receptive field of recorded sites. Gradually changing the directional coherence of random dots in the surround while maintaining fully coherent motion of the stimulus in the receptive field significantly suppressed synchronization of neuronal activity for some stimulus conditions. However, usually one or two peaks of increased synchronization were found in the surround coherence tuning curves with low (8-12%) and/or moderate (25-50%) coherence in the surround. At the population level, synchronization was significantly depressed with incoherent motion in the receptive field and when both the surround and the receptive field were jointly stimulated with 0% coherence. The intriguing finding was the discovery of two distinct groups of cells with opposite synchronization changes dependent on the presence or absence of significant synchronization in their spontaneous activity. The latter group of neurons showed peaks of increased synchronization with lower surround coherence, thus probably being more sensitive to the direction of the surround motion. Overall, our findings support the notion that binding of stimulus properties can be achieved by synchronized activity of cortical cells. However, our findings go further than the original hypothesis of feature binding by synchrony to show that synchronization of cortical activity may be directly related to the decision making processes, which in turn are related to the threshold of perception of coherent motion.

Animals↗
PubMed2004

Activation of the renin-angiotensin system contributes significantly to the pathophysiology of oliguria in patients undergoing posterior spinal fusion.

BACKGROUND AND OBJECTIVE: This study was undertaken to investigate the role played by antidiuretic hormone (ADH), the renin-angiotensin system and atrial natriuretic factor (ANF) in the oliguria in patients undergoing spinal fusion. METHODS: Sixteen patients undergoing posterior spinal fusion using isoflurane and fentanyl (n = 8) or sufentanil (n = 8) had renin, aldosterone, ADH and ANF measurements. RESULTS: Compared to the non-oliguric patients, the oliguric patients had a higher number of fused vertebrae 10.5 +/- 1.3 vs. 9.0 +/- 0.5 (P = 0.01) and higher renin values at 12h (3.3 +/- 3.2 vs. 0.7 +/- 0.6 ng L(-1) s(-1), P = 0.04). Hormonal values that had a significant correlation with intraoperative diuresis were: renin at 0.5 h (r2 = 0.26, P = 0.04), aldosterone at 0.5 h (r2 = 0.30, P = 0.03) and ANF at 0.5 h (r2 = 0.32, P = 0.02). Those that had a significant correlation with the mean postoperative diuresis were: renin at 6 h (r2 = 0.29, P = 0.03), 8h (r2 = 0.26, P = 0.04) and 12h (r2 = 0.31, P = 0.03), aldosterone at 6h (r2 = 0.54, P = 0.001), 8h (r2 = 0.40, P = 0.01) and 12h (r2 = 0.32, P = 0.03), ADH at 24h (r2 = 0.38, P = 0.01) and ANF at 6h (r2 = 0.26, P = 0.045). Using stepwise regression, excluding hormonal values, only two continuous variables had a significant correlation with the mean postoperative diuresis: the number of fused vertebrae (P = 0.02) and the length of surgery (P = 0.02). CONCLUSION: Activation of the renin-angiotensin system is the major cause of the early intraoperative oliguria. ADH and the renin-angiotensin system are both involved in the pathophysiology of postoperative oliguria in patients undergoing spinal fusion.

Adolescent↗
PubMed2004

Cardiopulmonary bypass induces significant platelet activation in children undergoing open-heart surgery.

BACKGROUND AND OBJECTIVES: To evaluate the effects of cardiopulmonary bypass (CPB) on platelet function in children undergoing open-heart surgery. METHODS: Data from 16 consecutive children undergoing cardiac surgery with CPB were prospectively collected. Blood samples of 10 mL were collected via the central venous line immediately before and after CPB for CD62 measurements by flow cytometry. RESULTS: Ten children had acyanotic heart disease (median age 3 yr, range 1.8-14) and six had a cyanotic defect (median age 4yr, range 2-14). The platelet count decreased significantly with CPB in both groups: from 163.5 (130-201) to 93.5 (57-186) x 10(3) microL(-1) in acyanotic children and from 139.5 (77-212) to 75 (43-99) x 10(3) microL(-1) in cyanotic children (P < 0.0001). The percentage of activated platelets was significantly lower in acyanotic children at baseline: 1% (0-23%) vs. 5% (3-8%) (P = 0.07). CPB increased the percentage of activated platelets significantly in both groups: post-bypass the values were 10% (range 1-17%) in acyanotic children and 7% (range 1-30%) in cyanotic children (P = 0.03). The increase in the percentage of activated platelets did not differ between the two study groups (P = 0.11). CONCLUSION: CPB induces significant platelet activation in children undergoing open-heart surgery.

Adolescent↗
PubMed2001

Haemostatic disorders during liver transplantation.

Profound and complex coagulation disorders are encountered during liver transplantation. They include preoperative coagulation disorders related to the liver disease and haemostatic changes related to the procedure itself. They commonly lead to increased intraoperative bleeding, especially due to increased fibrinolysis, the contribution of which can be demonstrated by the relative efficacy of antifibrinolytics. Given the multifactorial nature of bleeding in liver transplantation, preoperative coagulation tests cannot predict blood loss even if some statistical relationship is occasionally found. Preoperative correction of coagulation defects has not been shown to be effective in reducing intraoperative bleeding. Throughout the procedure, a rapid and sensitive method for monitoring coagulation is necessary in order to guide the rational use of blood components and pharmacological agents. The usefulness of such a method to assist management of blood loss or blood component requirements is poorly documented and controversial.

Blood Coagulation Disorders↗
PubMed2001

Etoricoxib (MK-0663): preclinical profile and comparison with other agents that selectively inhibit cyclooxygenase-2.

We report here the preclinical profile of etoricoxib (MK-0663) [5-chloro-2-(6-methylpyridin-3-yl)-3-(4-methylsulfonylphenyl) pyridine], a novel orally active agent that selectively inhibits cyclooxygenase-2 (COX-2), that has been developed for high selectivity in vitro using whole blood assays and sensitive COX-1 enzyme assays at low substrate concentration. Etoricoxib selectively inhibited COX-2 in human whole blood assays in vitro, with an IC(50) value of 1.1 +/- 0.1 microM for COX-2 (LPS-induced prostaglandin E2 synthesis), compared with an IC(50) value of 116 +/- 8 microM for COX-1 (serum thromboxane B2 generation after clotting of the blood). Using the ratio of IC(50) values (COX-1/COX-2), the selectivity ratio for the inhibition of COX-2 by etoricoxib in the human whole blood assay was 106, compared with values of 35, 30, 7.6, 7.3, 2.4, and 2.0 for rofecoxib, valdecoxib, celecoxib, nimesulide, etodolac, and meloxicam, respectively. Etoricoxib did not inhibit platelet or human recombinant COX-1 under most assay conditions (IC(50) > 100 microM). In a highly sensitive assay for COX-1 with U937 microsomes where the arachidonic acid concentration was lowered to 0.1 microM, IC(50) values of 12, 2, 0.25, and 0.05 microM were obtained for etoricoxib, rofecoxib, valdecoxib, and celecoxib, respectively. These differences in potency were in agreement with the dissociation constants (K(i)) for binding to COX-1 as estimated from an assay based on the ability of the compounds to delay the time-dependent inhibition by indomethacin. Etoricoxib was a potent inhibitor in models of carrageenan-induced paw edema (ID(50) = 0.64 mg/kg), carrageenan-induced paw hyperalgesia (ID(50) = 0.34 mg/kg), LPS-induced pyresis (ID(50) = 0.88 mg/kg), and adjuvant-induced arthritis (ID(50) = 0.6 mg/kg/day) in rats, without effects on gastrointestinal permeability up to a dose of 200 mg/kg/day for 10 days. In squirrel monkeys, etoricoxib reversed LPS-induced pyresis by 81% within 2 h of administration at a dose of 3 mg/kg and showed no effect in a fecal 51Cr excretion model of gastropathy at 100 mg/kg/day for 5 days, in contrast to lower doses of diclofenac or naproxen. In summary, etoricoxib represents a novel agent that selectively inhibits COX-2 with 106-fold selectivity in human whole blood assays in vitro and with the lowest potency of inhibition of COX-1 compared with other reported selective agents.

Algorithms↗
PubMed2000

Cloning, expression, and up-regulation of inducible rat prostaglandin e synthase during lipopolysaccharide-induced pyresis and adjuvant-induced arthritis.

We have cloned and expressed the inducible form of prostaglandin (PG) E synthase from rat and characterized its regulation of expression in several tissues after in vivo lipopoylsaccharide (LPS) challenge. The rat PGE synthase is 80% identical to the human enzyme at the amino acid level and catalyzes the conversion of PGH(2) to PGE(2) when overexpressed in Chinese hamster ovary K1 (CHO-K1) cells. PGE synthase activity was measured using [(3)H]PGH(2) as substrate and stannous chloride to terminate the reaction and convert all unreacted unstable PGH(2) to PGF(2alpha) before high pressure liquid chromatography analysis. We assessed the induction of PGE synthase in tissues from Harlan Sprague-Dawley rats after LPS-induced pyresis in vivo. Rat PGE synthase was up-regulated at the mRNA level in lung, colon, brain, heart, testis, spleen, and seminal vesicles. Cyclooxygenase (COX)-2 and interleukin 1beta were also up-regulated in these tissues, although to different extents than PGE synthase. PGE synthase and COX-2 were also up-regulated to the greatest extent in a rat model of adjuvant-induced arthritis. The RNA induction of PGE synthase in lung and the adjuvant-treated paw correlated with a 3.8- and 16-fold induction of protein seen in these tissues by immunoblot analysis. Because PGE synthase is a member of the membrane-associated proteins in eicosanoid and glutathione metabolism (MAPEG) family, of which leukotriene (LT) C(4) synthase and 5-lipoxygenase-activating protein are also members, we tested the effect of LTC(4) and the 5-lipoxygenase-activating protein inhibitor MK-886 on PGE synthase activity. LTC(4) and MK-886 were found to inhibit the activity with IC(50) values of 1.2 and 3.2 microm, respectively. The results demonstrate that PGE synthase is up-regulated in vivo after LPS or adjuvant administration and suggest that this is a key enzyme involved in the formation of PGE(2) in COX-2-mediated inflammatory and pyretic responses.

Amino Acid Sequence↗
PubMed2000

Potency and selectivity of inhibition of cathepsin K, L and S by their respective propeptides.

The prodomains of several cysteine proteases of the papain family have been shown to be potent inhibitors of their parent enzymes. An increased interest in cysteine proteases inhibitors has been generated with potential therapeutic targets such as cathepsin K for osteoporosis and cathepsin S for immune modulation. The propeptides of cathepsin S, L and K were expressed as glutathione S-transferase-fusion proteins in Escherichia coli. The proteins were purified on glutathione affinity columns and the glutathione S-transferase was removed by thrombin cleavage. All three propeptides were tested for inhibitor potency and found to be selective within the cathepsin L subfamily (cathepsins K, L and S) compared with cathepsin B or papain. Inhibition of cathepsin K by either procathepsin K, L or S was time-dependent and occurred by an apparent one-step mechanism. The cathepsin K propeptide had a Ki of 3.6-6.3 nM for each of the three cathepsins K, L and S. The cathepsin L propeptide was at least a 240-fold selective inhibitor of cathepsin K (Ki = 0.27 nM) and cathepsin L (Ki = 0.12 nM) compared with cathepsin S (Ki = 65 nM). Interestingly, the cathepsin S propeptide was more selective for inhibition of cathepsin L (Ki = 0.46 nM) than cathepsin S (Ki = 7.6 nM) itself or cathepsin K (Ki = 7.0 nM). This is in sharp contrast to previously published data demonstrating that the cathepsin S propeptide is equipotent for inhibition of human cathepsin S and rat and paramecium cathepsin L [Maubach, G., Schilling, K., Rommerskirch, W., Wenz, I., Schultz, J. E., Weber, E. & Wiederanders, B. (1997), Eur J. Biochem. 250, 745-750]. These results demonstrate that limited selectivity of inhibition can be measured for the procathepsins K, L and S vs. the parent enzymes, but selective inhibition vs. cathepsin B and papain was obtained.

Amino Acid Sequence↗
PubMed2000

[The forgotten actors].

Within the Regional Plans for the Organization of Services, Quebec's mental health reform has tried to redistribute power and influence to mutual aid groups for consumers and their families. However, it has failed to provide them with the financial resources that would allow them to exert that new power. The groups don't have enough personnel to fill the decision-making positions accorded to them under the regional plans while, at the same time, continuing to provide services to consumers. Real partnership requires equality in resources. Social integration being the product of an interaction between consumers and citizens, citizens are the forgotten actors of the interaction. We fail to support them when they are faced with behaviours that they find strange and disturbing. Attitudinal and behavioural changes are interrelated and concomitant; that is, the transformation of citizens' prejudice into acceptance is helped by consumers' efforts to adopt less offensive behaviours.

Canada↗
PubMed1999

Substituted indoles as potent and orally active 5-lipoxygenase activating protein (FLAP) inhibitors.

This paper reports on the SAR investigation of inhibitors of 5-lipoxygenase activating protein (FLAP) based on MK-0591. Emphasis was made on modifications to the nature of the link between the indole and the quinoline moieties, to the substitution pattern around the two heterocycles and to possible replacements of the quinoline moiety. Lead optimization culminated in (3-[1-(4-chlorobenzyl)-3-(t-butylthio)-5-(pyridin-2-ylmethoxy)-ind ol-2-yl]-2,2-dimethylpropanoic acid (18k), as a potent inhibitor of leukotriene biosynthesis that is well absorbed and active in functional models.

5-Lipoxygenase-Activating Proteins↗
PubMed1999

2,3-Diarylcyclopentenones as orally active, highly selective cyclooxygenase-2 inhibitors.

Cyclopentenones containing a 4-(methylsulfonyl)phenyl group in the 3-position and a phenyl ring in the 2-position are selective inhibitors of cyclooxygenase-2 (COX-2). The selectivity for COX-2 over COX-1 is dramatically improved by substituting the 2-phenyl group with halogens in the meta position or by replacing the phenyl ring with a 2- or 3-pyridyl ring. Thus the 3,5-difluorophenyl derivative 7 (L-776,967) and the 3-pyridyl derivative 13 (L-784,506) are particularly interesting as potential antiinflammatory agents with reduced side-effect profiles. Both exhibit good oral bioavailability and are potent in standard models of pain, fever, and inflammation yet have a much reduced effect on the GI integrity of rats compared to standard nonsteroidal antiflammatory drugs.

Analgesics, Non-Narcotic↗
PubMed1999

Cloning and expression of rhesus monkey cathepsin K.

Cathepsin K is a cysteine protease involved in degradation of human type I collagen and plays a primary role in bone resorption. We have cloned rhesus monkey cathepsin K by reverse transcriptase-polymerase chain reaction (RT-PCR) from rhesus ovary poly A+ RNA. The sequence for the rhesus enzyme is 98% identical to that of the human with 100% identity within the mature active form of cathepsin K. Rhesus monkey cathepsin K was transiently expressed in Chinese hamster ovary (CHO) cells and found to be secreted as the proenzyme in the culture media and 50% activated to the mature form intracellularly. The substrate specificity preference of aminomethylcoumarin and rhodamine peptide substrates was Leu > Phe > Pro in the P2 position when tested with constant arginine at P1. The enzyme activity expressed in CHO cell extracts was sensitive to inhibition by E-64 and cystatin with IC50s of 3.5 nmol/L and 13 ng/mL, respectively. The apparent second order rate constants of inactivation by E-64 were 66,000 M(-1) s(-1) and 130,000 M(-1) s(-1) for the recombinantly expressed rhesus monkey and human cathepsin K, respectively. The high similarity between the sequences and the kinetic properties of rhesus monkey and human cathepsin K establishes this monkey species as a suitable animal model for development of novel cathepsin K inhibitors as antiresorptive agents.

Amino Acid Sequence↗
PubMed1999

Rofecoxib [Vioxx, MK-0966; 4-(4'-methylsulfonylphenyl)-3-phenyl-2-(5H)-furanone]: a potent and orally active cyclooxygenase-2 inhibitor. Pharmacological and biochemical profiles.

The discoveries that cyclooxygenase (COX)-2 is an inducible form of COX involved in inflammation and that COX-1 is the major isoform responsible for the production of prostaglandins (PGs) in the gastrointestinal tract have provided a rationale for the development of specific COX-2 inhibitors as a new class of anti-inflammatory agents with improved gastrointestinal tolerability. In the present study, the preclinical pharmacological and biochemical profiles of rofecoxib [Vioxx, also known as MK-0966, 4-(4'-methylsulfonylphenyl)-3-phenyl-2-(5H)-furanone], an orally active COX-2 inhibitor, are described. Rofecoxib is a potent inhibitor of the COX-2-dependent production of PGE(2) in human osteosarcoma cells (IC(50) = 26 +/- 10 nM) and Chinese hamster ovary cells expressing human COX-2 (IC(50) = 18 +/- 7 nM) with a 1000-fold selectivity for the inhibition of COX-2 compared with the inhibition of COX-1 activity (IC(50) > 50 microM in U937 cells and IC(50) > 15 microM in Chinese hamster ovary cells expressing human COX-1). Rofecoxib is a time-dependent inhibitor of purified human recombinant COX-2 (IC(50) = 0.34 microM) but caused inhibition of purified human COX-1 in a non-time-dependent manner that could only be observed at a very low substrate concentration (IC(50) = 26 microM at 0.1 microM arachidonic acid concentration). In an in vitro human whole blood assay, rofecoxib selectively inhibited lipopolysaccharide-induced, COX-2-derived PGE(2) synthesis with an IC(50) value of 0.53 +/- 0.02 microM compared with an IC(50) value of 18.8 +/- 0.9 microM for the inhibition of COX-1-derived thromboxane B(2) synthesis after blood coagulation. Using the ratio of the COX-1 IC(50) values over the COX-2 IC(50) values in the human whole blood assay, selectivity ratios for the inhibition of COX-2 of 36, 6.6, 2, 3, and 0.4 were obtained for rofecoxib, celecoxib, meloxicam, diclofenac, and indomethacin, respectively. In several in vivo rodent models, rofecoxib is a potent inhibitor of carrageenan-induced paw edema (ID(50) = 1.5 mg/kg), carrageenan-induced paw hyperalgesia (ID(50) = 1.0 mg/kg), lipopolysaccharide-induced pyresis (ID(50) = 0.24 mg/kg), and adjuvant-induced arthritis (ID(50) = 0.74 mg/kg/day). Rofecoxib also has a protective effect on adjuvant-induced destruction of cartilage and bone structures in rats. In a (51)Cr excretion assay for detection of gastrointestinal integrity in either rats or squirrel monkeys, rofecoxib has no effect at doses up to 200 mg/kg/day for 5 days. Rofecoxib is a novel COX-2 inhibitor with a biochemical and pharmacological profile clearly distinct from that of current nonsteroidal anti-inflammatory drugs and represents a new therapeutic class of anti-inflammatory agents for the treatment of the symptoms of osteoarthritis and rheumatoid arthritis with improved gastrointestinal tolerability.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗