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Biomedical subjects

J Gauthier

Publications and source records attributed to J Gauthier.

At least 19 recordsLinked to original sources
PubMed1995

Peptidomimetic inhibitors of herpes simplex virus ribonucleotide reductase: a new class of antiviral agents.

We have been investigating a new class of antiviral compounds effective against herpes simplex virus (HSV) in vitro and in vivo. Antiviral activity results from inhibition of HSV ribonucleotide reductase (RR). The inhibitors are designed as mimics of the RR small subunit C-terminus, a region essential for RR subunit association and consequently enzymatic activity. Inhibition results from specific binding of the inhibitor to the HSV RR large subunit thereby preventing subunit association. This report details the structure--activity studies that lead to the indentification of BILD 1263, a potent inhibitor of HSV RR subunit association (IC50, 0.2 nM) that also inhibits the replication of HSV types 1 and 2 in cell culture (EC50, 3 and 4 microM) and reduces the severity of HSV-1-induced keratitis in a murine ocular model. The discovery of inhibitors with in vitro antiviral results from a combination of improving inhibitor potency in a RR binding assay and modifying inhibitor physicochemical properties. The importance and possible role of the new structural modifications introduced into this inhibitor series is discussed.

Animals↗
PubMed1995

The zinc-binding site of Escherichia coli glutamyl-tRNA synthetase is located in the acceptor-binding domain. Studies by extended x-ray absorption fine structure, molecular modeling, and site-directed mutagenesis.

The zinc contents of fragments of Escherichia coli glutamyl-tRNA synthetase, as well as the conservation of the CYC sequence only in zinc-containing glutamyl-tRNA synthetases, suggested that the 98CYCX24-CRHSHEHHADDEPC138 includes some or all residues involved in binding its zinc atom (Liu, J., Lin, S.-X., Blochet, J.-E., Pézolet, M., and Lapointe, J. (1993) Biochemistry 32, 11390-11396). Extended x-ray absorption fine structure (EXAFS) shows that this zinc atom has a four-coordinate non-planar coordination environment with 3 sulfur and 1 nitrogen atoms with bond lengths, respectively, 2.37 +/- 0.02 A and 2.01 +/- 0.02 A, presumably belonging to 3 cysteine residues and 1 histidine residue. Conservative replacement of each histidine and cysteine residue of the 98C-138C segment, respectively, with glutamine (Q) and serine (S), yields variants H129Q, H131Q, H132Q, and C138S (which sustain the growth at 42 degrees C of E. coli JP1449, whose glutamyl-tRNA synthetase is thermosensitive) and C98S, C100S, C125S, and H127Q (which do not). The amount of this enzyme in these mutants is at least 1 order of magnitude larger than that in a wild type strain; however, no glutamyl-tRNA synthetase activity is detectable in extracts of the variants C100S and C125S, whereas its specific activity in those of C98S and H127Q is about 10-fold lower than in cells overproducing the wild type enzyme or the variants H129Q, H131Q, H132Q, and C138S. These results indicate that the zinc atom present in E. coli glutamyl-tRNA synthetase is bound by the 2 evolutionarily conserved cysteines at positions 98 and 100, and by Cys125 and His127. Molecular modeling of the N-terminal half of this enzyme, using the known structure of E. coli glutaminyl-tRNA synthetase, supports this conclusion and suggests that the 98C-127H segment does not have the characteristics of the classical zinc fingers.

Absorptiometry, Photon↗
PubMed1995

An evaluation of the N-CAT, a new arterial tonometer.

The N-CAT is a newly developed arterial tonometer (TBP) monitor able to determine systolic, diastolic and mean blood pressures continuously and noninvasively. The aim of this study was to evaluate the accuracy and reliability of the TBP compared with directly measured invasive blood pressure (IBP) in 14 patients before and after elective coronary artery bypass surgery. Although the TBP was able to track changes in systemic pressure, before and after CPB, bias and precision for TBP monitoring did not meet the standard criteria for equivalency for noninvasive blood pressure to invasive blood pressure. We were unable to monitor TBP in two patients. Approximately 40% of all before and after CPB mean TBP pressure values differed from mean IBP by more than 10 mmHg. Moreover, there were discrepancies of sufficient magnitude and duration that limits the clinical usefulness of the N-CAT. Potential users should not rely exclusively on TBP values when making clinical decisions. Technological improvement is needed before its clinical use is recommended.

Aged↗
PubMed1995

Farmer's lung and variables related to the decision to quit farming.

An exploratory strategy was used to investigate why 55% of patients with farmer's lung (FL) disease quit farming. Three groups were recruited: 47 patients with FL disease who quit farming because of the disease (FLq), 76 patients with FL disease who continued farming (FLc), and 123 control farmers without a history of FL disease. The severity of FL disease at diagnosis was similar in both groups of patients. For example, single-breath carbon monoxide diffusion capacity predicted for FLq and FLc was 64.4 +/- 28.2 and 63.9 +/- 22.0, respectively. Relying on a cognitive-behavior theory, numerous physiological, behavioral, cognitive, affective, and social variables were assessed. Results showed that the decision to quit farming was based on cognitive and behavioral motives rather than physiological factors. Subjects in the FLq group showed more negative beliefs toward FL and had more fears of FL disease. FLq subjects also reported that family members, friends, and family doctors were more inclined to consider that FL disease could stop them from farming. However, self-efficacy to continue farming despite having FL disease and perceived hindrance caused by FL disease played the most important roles in the decision to quit farming.

Agriculture↗
PubMed1994

The role of home practice in the thermal biofeedback treatment of migraine headache.

The present study examined the role of home practice of hand warming in the thermal biofeedback treatment of migraine headache. Seventeen female migraine sufferers were randomly assigned to one of the following conditions: thermal biofeedback with regular home practice (HP) or thermal biofeedback without home practice (NHP). Biofeedback treatment consisted of 12 training sessions over a 6-week period, and all subjects completed 5 weeks of headache monitoring before and after treatment. Results indicated that subjects in the HP condition experienced decreases in headache activity and medication intake that were both statistically and clinically significant compared with the NHP condition. None of the outcome measures revealed significant improvement in the NHP condition. Thus, regular home practice appears to enhance the efficacy of biofeedback in the treatment of migraine.

Adult↗
PubMed1994

Effects of intravenous medium-chain triglycerides on pulmonary gas exchanges in mechanically ventilated patients.

OBJECTIVE: In mechanically ventilated patients, pulmonary gas exchange was investigated during the administration of total parenteral nutrition containing medium-chain triglycerides or long-chain triglycerides as fat emulsions. DESIGN: Prospective, randomized, crossover trial (two lipid infusion periods of 8 hrs). SETTING: Intensive care unit in a university hospital. PATIENTS: Six mechanically ventilated patients, using the pressure-support mode. INTERVENTIONS: Total caloric intake was adapted according to measured energy expenditure. Fat emulsion provided 50% of the energy expenditure. Patients were infused with 50% medium-chain/50% long-chain triglycerides or 100% long-chain triglycerides in a random sequence. MEASUREMENTS AND MAIN RESULTS: Oxygen consumption, CO2 production, and minute ventilation were measured by indirect calorimetry. PaO2 and PaCO2 were determined in blood samples. Medium-chain triglycerides increased oxygen consumption by 27.8% and minute ventilation by 14.3% at the end of the protocol. CO2 production, PaO2, and PaCO2 were not different between groups. CONCLUSIONS: Medium-chain triglycerides cause an increase in metabolic demand in mechanically ventilated patients when they are infused over a short period. Postoperative or intensive care unit patients with a low pulmonary reserve should receive infusions of medium-chain triglycerides over a more prolonged period than long-chain triglycerides.

Aged↗
PubMed1993

A static dynamometer measuring multidirectional torques exerted simultaneously at the hip and knee.

The function of a static dynamometer measuring torques exerted simultaneously in the different anatomical planes of the hip (flexion-extension, abduction-adduction and internal-external rotation) and knee (flexion-extension) is described. Muscular torques were calculated in real time using a desktop computer from measurements of orthogonal forces applied at two locations and the lever arm values measured in each subject. The reliability of the force transducers was explored by examining their output, using calibrated weights, on three different days. The results were identical over this period of time, indicating that the transducers are highly reliable. A mechanical simulator of a lower limb was constructed to generate specific or combined torques of known values at the hip and knee. The torques measured by the dynamometer were found to be highly concordant with the known torques applied by the simulator, indicating that the torque measurements were valid. The usefulness of the dynamometer is demonstrated by evaluating the activity of the rectus femoris and biceps femoris muscles during static efforts exerted in various directions at the hip. In addition, the mechanical action of biarticular muscles at the hip was evaluated by quantification of hip torques during efforts exerted at the knee. From these results, it has been concluded that the present biarticular and multidirectional dynamometer is a valid, reliable and precise instrument that may prove to be useful in evaluating the muscular function of the lower limb.

Biophysics↗
PubMed1992

[Acute respiratory insufficiency caused by diffuse pulmonary hemorrhage].

Two cases of adult respiratory distress syndrome due to diffuse pulmonary haemorrhage are reported. The first patient was treated with azathioprine, prednisolone, cyclosporine and ranitidine for haemorrhagic rectocolitis; the second has untreated primary biliary cirrhosis. Haemoptysis only occurred in the latter. Both had severe isolated hypoxaemia. Chest X-rays revealed bilateral alveolar infiltrates. Bronchoscopies showed a diffusely bleeding bronchial tree. Both patients recovered after having been mechanically ventilated with positive end-expiratory pressure for six and eight days respectively. The cause of the diffuse pulmonary haemorrhage was, in the first case, severe thrombocytopaenia (17,000 G.1-1) of central origin, and, in the other patient, an unspecified vasculitis. Diffuse pulmonary haemorrhage should be added to the list of possible causes of the adult respiratory distress syndrome.

Adult↗
PubMed1992

Characterization of contralateral torques during static hip efforts in healthy subjects and subjects with hemiparesis.

Contralateral torques exerted at the hip were measured in healthy subjects and subjects with hemiparesis performing unilateral static hip efforts in abduction, adduction, flexion and extension, in a sitting position, at two torque levels. In general, the ipsilateral hip efforts were accompanied by mirrored contralateral torques in both groups of subjects. The directionality of these contralateral torques indicates that their action at the pelvis is mechanically opposite to the ipsilateral efforts, suggesting that they ensure the stabilization of the pelvis. In healthy subjects, analyses of variance showed no difference in the magnitude of the contralateral torques with regard to which limb was used to perform the task. However, a significant increase in magnitude was demonstrated in the contralateral torques concurrent with the increasing level of effort requested ipsilaterally. In hemiparetic subjects, when performing the tasks with their paretic limb, the magnitude of the contralateral torques was significantly increased in the non-paretic limb when compared with those measured in the paretic limb during non-paretic limb efforts. Based on the present results, a model of postural control is presented to explain the relationship between the ipsilateral and contralateral torques. Using this model, it is hypothesized that the increased contralateral torques observed in hemiparetic subjects when performing the tasks with their paretic limb is related to the weakness of the paretic muscles. The clinical importance of exercises used for the re-education of the paretic lower limb in this population, which consist of resisting the non-paretic hip movements in order to strengthen the paretic hip muscles, is discussed in light of these results.

Adult↗
PubMed1991

Differential synthesis of 5-lipoxygenase in peripheral blood and synovial fluid neutrophils in rheumatoid arthritis.

In order to investigate 5-lipoxygenase enzyme regulation in neutrophils during an inflammatory reaction, we studied 5-lipoxygenase mRNA levels, as well as de novo enzyme synthesis, in resting and activated neutrophils isolated from normal individuals and patients with rheumatoid arthritis. The approach used was to analyze these activities in resting peripheral blood neutrophils of normal individuals on the one hand and in peripheral blood and matched synovial fluid neutrophils isolated from patients with rheumatoid arthritis on the other hand. Our first observation was that resting peripheral blood neutrophils of either normal individuals or patients show detectable levels of 5-lipoxygenase mRNA and are able to synthesize the enzyme de novo. Our second observation was that inflammatory activated neutrophils from synovial fluid reveal lower 5-lipoxygenase mRNA levels and enzyme synthesis than do the patient-matched peripheral blood cells. This is in spite of the fact that, for other proteins, synovial fluid neutrophils are equally or more active than their peripheral blood counterparts. We conclude that peripheral blood neutrophils are capable of synthesizing the enzyme, thus ensuring the turnover of the protein. Furthermore, complex regulatory mechanisms appear to take place in response to inflammation as it occurs in synovial fluids of patients with rheumatoid arthritis, leading to decreased mRNA levels and enzyme synthesis. Possible mechanisms of regulation are discussed and are presently under investigation.

Arachidonate 5-Lipoxygenase↗
PubMed1990

Growth-regulated surface glycoproteins of human bladder cancer.

Clinical studies of human bladder cancer cells with mouse monoclonal antibodies (mAbs) have revealed two surface glycoproteins (T43 and T138) expressed by aggressive cancers and not by normal cells and a differentiation antigen (T16) expressed by normal and tumor cells of urothelial origin (Y. Fradet et al., Proc. Natl. Acad. Sci. USA, 81: 224-228, 1984; Y. Fradet et al. Cancer Res., 46: 5183-5188, 1986). To investigate further the possible association of these antigenic phenotypes with growth advantage of tumor cells, their expression, according to phases of the cell cycle and growth states (exponential and plateau phase) was studied in the human bladder carcinoma cell line T24. Expression of the p21 ras oncogene product, the Thomsen-Friedenreich antigen and the HLA class I antigen were also studied with mAbs. Multiparameter flow cytometry was used to determine antigen expression and DNA content of cells stained with mAbs and propidium iodide. Two antigens, T16 and T43, showed marked variations of their expression according to the growth status of the cells, although with an inverse profile. T16 was expressed on resting cells up to 12.5 times more than on exponentially growing cells. Conversely, T43 expression increased by a factor of 4.5 on actively proliferating cells. However, there was no preferential expression of either antigen in any one phase of the cell cycle. None of the other antigens studied, including the p21 protein, showed any density variation with either cell cycle or growth states. The results of these studies suggest that T43 may be associated with a growth advantage of tumor cells and that T16 has the characteristics of a differentiation antigen whose expression is induced on resting cells. These findings may have implications for the potential clinical use of these mAbs.

Animals↗
PubMed1990

Preparative separation of small molecular weight peptides from casein hydrolysate using gel filtration and immobilized metal ion affinity chromatography.

A two step method consisting of a gel filtration step, followed by a Immobilized Metal Affinity Chromatography (IMAC) step using a IDA-Cu coupled Sephadex G-25 column, on a preparative scale is described for the group separation of peptides from a casein hydrolysate. The 48 groups of peptides thus separated are further characterised by RP-HPLC and amino acid analysis. Some peptides after the analytical RP-HPLC step are further characterised by sequencing. An insight into the mechanism of retention on IMAC of the peptides is attempted. In such complex mixtures as casein hydrolysate, the peptide-peptide interaction can mask the potential sites of interactions in a single peptide. The results obtained using volatile buffers as eluents show the possibility of using IMAC step as an alternative to obtain gram quantities of group of peptides free of salts from complex protein hydrolysates.

Amino Acid Sequence↗
PubMed1990

Electroporation-mediated uptake of proteins into mammalian cells.

Proteins of up to 230 kilodaltons are taken up by chinese hamster ovary fibroblasts exposed to electroporation under conditions generally similar to those used to mediate DNA transfection. The uptake of catalase, ovalbumin, and histone H1 labelled with fluorescein was visualized by fluorescence microscopy. Under the same conditions, the uptake of colloidal gold particles (20 nm diameter) was visualized by electron microscopy. In optimum conditions, about 25% of the cells remained viable and grew normally and about 25% of these retained labelled proteins during two cycles of further growth. About 6 x 10(4) molecules of catalase were retained per cell. Proteins were taken up when presented to the cells up to 4 h after electroporation, suggesting that mechanisms other than classical electropore formation may operate in these conditions. The proteins were localized in the cytoplasm in a predominantly vesicular pattern and histone H1 entered the nucleus in some cells.

Animals↗
PubMed1989

Binding of double-stranded DNA to glomeruli of rats in vivo.

In vivo binding of double-stranded DNA (dsDNA) to renal glomeruli of rats was examined. 125I-dsDNA (600 basepairs) was perfused with 131I-IgG as a blood marker into the right renal artery of normal rats, and blood flow was restored. After 10 minutes, isolated glomeruli showed a specific uptake of DNA, which increased in a saturable fashion with increasing doses of administered DNA. To exclude the possibility that 125I in the glomeruli represented only DNA breakdown products, we extracted the DNA from the glomeruli for analysis by polyacrylamide gel electrophoresis. The extracted DNA was 120-200 bp in size, which is large enough to bind antibodies to DNA. In contrast, the radioactivity of DNA taken up by the liver or renal tissues other than glomeruli was predominantly trichloroacetic acid soluble, i.e., less than 15 bp. Immunofluorescence studies showed that antibodies to DNA, administered after DNA, were present in glomeruli. Our data indicate that dsDNA binds to glomeruli in vivo in a saturable manner, and remains large enough to be antigenic. Therefore, the binding of DNA to glomeruli, followed by interaction with antibodies to dsDNA may be a mechanism for DNA-anti-DNA complex formation in glomeruli in patients with systemic lupus erythematosus.

Animals↗
PubMed1989

Effect of trifluoroacetic acid on the reduction of disulfide bridges in peptides analyzed by fast-atom bombardment mass spectrometry.

Some of the factors that influence the reduction of disulfide-containing peptides under fast-atom bombardment have been investigated using two neurohormonal peptides that include disulfide bridges in their structures. Deaminoarginine-vasopressin (DAVP) and arginine-vasopressin (AVP) have been analyzed as their acetate and trifluoroacetate salts. Results obtained in a thioglycerol matrix indicate that the peptides analyzed as their acetate salts are completely reduced under bombardment, whereas the trifluoroacetate salts show little evidence of reduction. Addition of trifluoroacetic acid to the acetate sample prior to bombardment inhibits reduction whereas addition after bombardment shows no effect on the reduction, thereby indicating the irreversibility of the process. Time-monitoring experiments conducted with the acetate salts of DAVP and AVP in common matrices such as thioglycerol, dithiothreitol + diethioerythritol, glycerol, hydroxyethyldisulfide and nitrobenzyl-alcohol demonstrate an important effect of the chemical nature of the matrix on reduction. In matrices containing thiol groups, the reduction is extensive, whereas it is almost suppressed in matrices such as hydroxyethyldisulfide and nitrobenzylalcohol. However, the addition of trifluoroacetic acid to all of these matrices essentially eliminates reduction and provides measured isotopic peak ratios that are in agreement with theoretically calculated values for these peptides.

Arginine Vasopressin↗