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Biomedical subjects

G Nguyen

Publications and source records attributed to G Nguyen.

At least 37 records · Page 2Linked to original sources
PubMed1998

Lovastatin modulates in vivo and in vitro the plasminogen activator/plasmin system of rat proximal tubular cells: role of geranylgeranylation and Rho proteins.

Interstitial fibrosis is one of the most deleterious events during the progression of renal deterioration after renal mass reduction. In vivo, hydroxymethylglutaryl CoA reductase inhibitors (HRI) were shown to reduce progression of glomerulosclerosis, but the mechanisms are still unclear. The present study investigates, in vivo, whether lovastatin, a potent HRI, was able to modulate the plasminogen-plasmin pathway, one of the most efficient systems involved in extracellular matrix remodeling, and characterizes in vitro the cellular mechanisms of these effects. Proximal tubules freshly isolated from rats treated for 2 d with lovastatin (4 mg/kg per d) showed increased tissue-type plasminogen activator (tPA) and urokinase (uPA) activities and antigens. Incubation with lovastatin (5 microM) of proximal tubules isolated from untreated rats induced an increase in tPA and uPA and a decrease in plasminogen activator inhibitor-1 (PAI-1) activities. In vitro, supernatants, cytosols, and membranes of renal proximal tubular cells in primary cultures had no detectable uPA activity, and lovastatin (0.1 to 10 microM) induced an increase in tPA and a decrease in PAI-1 activities and antigens. These effects were reversed by mevalonate and geranylgeranyl-pyrophosphate (GGPP) but not by farnesyl-pyrophosphate or LDL cholesterol. C3 exoenzyme, an inhibitor of the geranylgeranylated-activated Rho protein, reproduced the effect of lovastatin on tPA and PAI- activity and blocked its reversion by GGPP. The effect of lovastatin was associated with a disruption of cellular actin stress fibers, which was reversed by GGPP and reproduced by C3 exoenzyme. In conclusion, HRI can modify the fibrinolytic potential of proximal tubules, most likely via inhibition of geranylgeranylated Rho protein and disruption of the cytoskeleton. The resulting increase of proteolytic activity of tubular cells may serve to prevent extracellular matrix deposition and renal interstitial fibrosis.

Animals↗
PubMed1998

[Atenolol/nifedipine combination: efficacy and tolerability of low dose synergistic bitherapy in the treatment of arterial hypertension].

During recent decades, undeniable progress has been made with regard to the management of arterial hypertension. Larger numbers of patients are aware they have hypertension, receive treatment and benefit from this therapy. Furthermore, significant reductions have been observed in morbidity and mortality resulting from cardiovascular diseases. The objectives of hypertension treatment have been formulated on the basis of results of extensive epidemiological studies. Only a few patients receiving monotherapy actually achieve and maintain acceptable blood pressure levels. The complex pathogenesis of essential hypertension, the implications of nervous and humoral counter-regulatory effects, the heterogeneous character of individual responses to any given class of antihypertensive treatment and the onset of adverse effects all account for these failures. The search for a simple, effective and well-tolerated treatment based on a low dose combination of 2 classes of antihypertensive agents is consequently legitimate. The fixed combination of atenolol 50 mg and sustained release nifedipine 20 mg enables patients to benefit from the antihypertensive synergy of a beta-blocker and a calcium antagonist (dihydropyridine). Several open-ended or double-blind, controlled studies have shown that this combination produces a more marked antihypertensive effect than the individual components used alone or other reference monotherapies. Furthermore, it has been shown that this effect persists throughout the entire 24-hour period; this has been confirmed by 24-hour blood pressure monitoring. Short and medium term tolerability is significantly improved: the side effects commonly associated with the 2 drugs when used alone are reduced with the combination formulation since the 2 active substances have different and complementary mechanisms of action. In addition, long term studies have shown that therapeutic efficacy and tolerability remain stable and have even been seen to improve over a 12-month period. The fixed combination of atenolol-nifedipine has a role in strategies for the treatment of mild to moderate hypertension, particularly under the following conditions: when first-line monotherapy has failed to attain specific clearly defined objectives, including stabilised blood pressure levels together with acceptable tolerability. when patient compliance is jeopardised as a result of undesirable side effects. when the vascular burden is aggravated through lack of attention to individual risk factors in hypertensive patients. In more serious forms of hypertension, the atenolol-nifedipine combination can replace sequential monotherapies or other combination treatments that have failed to comply with the various criteria of therapeutic efficacy. Controlling arterial hypertension commonly requires polytherapy with 3 or even 4 different drugs in conjunction with particularly strict rules governing hygiene and diet. The addition of the fixed combination of atenolol-nifedipine simplifies the treatment of patients with arterial hypertension by limiting the daily doses and reducing laboratory monitoring.

Adrenergic beta-Antagonists↗
PubMed1998

[Evidence of a renin receptor on human mesangial cells: effects on PAI1 and cGMP].

Most proteases a receptor or a binding site that serves to concentrate the proteolytic activity on the cell surface and to mediate cellular effects. We looked for such a receptor for renin, an aspartyl protease. The binding of recombinant human renin labelled with 125I was studied on primary and immortalized human mesangial cells. The binding of renin was specific, saturable and was characterized by Kd = 0.4 nM and 8,000 sites/cell and Kd = 1 nM and 2,000 sites/cell for primary and immortalized cells, respectively. The binding did not depend on the active site of the enzyme, was not followed by internalization and degradation of renin and did not modify intracellular Ca2+. Stimulation of primary cells with 100 nM induced a significant increase of 3H thymidine incorporation but was not associated with an increase of the cell number. Furthermore, incubation of mesangial cells 24 h with 100 nM renin provoked an increase of tPA and of PAI1 in the conditioned medium. This increase was not modified neither by captopril nor by angiotensin II receptors antagonists. The tPA antigen elevation was confirmed by fibrin zymography showing an increase of tPA/PAI1 complexes. But, surprisingly, the reverse zymogram showed that PAI antigen increase was associated with decreased PAI activity which was due to PAI clivage in an inactive form. PAI clivage by renin required the presence of the cells and could not be obtained by incubating renin and recombinant human PAI alone. When primary mesangial cells were cultured in the presence of a specific inhibitor of renin active site, RO 42-5982, PAI accumulation in the conditioned medium was reduced by 50-60%, suggesting that endogenous renin plays a role in PAI synthesis and/or secretion. The binding of renin does not induce cAMP and cGMP generation. However, in the presence of renin (100 nM and 1 microM) the extent of cGMP generated by CNP (10 and 100 nM) was reduced by 50%. Preliminary results of the renin receptor purification by affinity chromatography indicate that the receptor Mr is about 57 kDa.

Calcium↗
PubMed1997

A non-aversive approach to reducing hospital absconding in a head-injured adolescent boy.

Patients who abscond from hospital exclude themselves from therapy, and attempts to stop the person can quickly become confrontational with the inherent risk of aggression. Although information is available on absconding in psychiatric settings little is known about the type of person with a head injury who absconds, why such people do so, or how the problem might best be approached. This paper presents a non-aversive approach to hospital absconding in a head-injured adolescent male, discusses how his case relates to the psychiatric literature, and looks at the feasibility of adopting such interventions in general hospital wards.

Adolescent↗
PubMed1996

Motor unit recruitment strategy changes with skill acquisition.

The modifications of motor unit recruitment strategy due to skill acquisition was determined in the elbow flexor-extensor muscles of normal human subjects. The median frequency of the power density spectra of the electromyograms recorded from the biceps and triceps muscles during a 3-s linear increase in flexion force in the range of 0-100% maximal voluntary contraction (MVC) was calculated for each subject, every 2 weeks over a total 6-week period during which subjects practiced linear flexion force increase three times a week. Electromyograms were recorded with two pairs of electrodes of different size and electrode spacing. It was shown that skill acquisition due to the 360 practice trials over the 6-week period caused an increase in the initial motor unit recruitment phase of the agonist's force generation cycle from about 0-65% MVC to about 0-85% MVC. The increase in the recruitment range was gradual and statistically significant for the measurements made every 2 weeks. The recruitment range of the antagonist triceps demonstrated a minor, but statistically insignificant, decrease over the same training period. There was a minor, but statistically insignificant, advantage of using small electrodes and inter-electrode spacing. It was concluded that skill acquisition, due to repeated functional use of a muscle in the same contraction mode, results in a slower, prolonged recruitment of motor units in the initial segment of the force generation cycle, thereby allowing a more precise and accurate control of the increments of force increase. Such conclusions reinforce the concept advocating the plasticity of motor unit control according to the functional demands imposed on the muscle. The results have significant implications in the design of various athletic, occupational and rehabilitation training modalities for optimal performance of various movement functions.

Adult↗
PubMed1996

Specific receptor binding of renin on human mesangial cells in culture increases plasminogen activator inhibitor-1 antigen.

Some proteases possess a membrane receptor that focalizes their proteolytic activity on the cell surface and may mediate a proliferative effect, such as urokinase on glomerular epithelial cells. Since some hypertensive states are associated with high concentrations of renin and proliferation of arteriolar smooth muscle cells, we asked whether renin, an aspartyl-protease, would bind to mesangial cells that are smooth-muscle derived cells, which would induce their proliferation. The binding of 125I labeled recombinant human renin (125I-R) was studied on human primary mesangial cells and mesangial cells immortalized by transfection with SV40-T antigen. At 37 degrees C, the binding of 125I-R was time dependent and reached a plateau after two hours. 125I-R was found to bind in a saturable and specific manner with a Kd = 0.4 nM and 1 nM and 8,000 and 2,000 binding sites/cell, for primary and immortalized cells, respectively. When binding experiments were performed in the presence RO 42-5892, a synthetic inhibitor of renin, RO 42-5892 could inhibit the specific binding of labeled renin only at concentrations 1,000 times superior to the IC 50, indicating that the renin-mesangial receptor interaction did not depend on the active site of renin. Analysis by SDS-PAGE and autoradiography of cross-linking experiments of 125I-R bound to a membrane preparation showed a band of approximately 110 to 120 kDa, suggesting a Mr of 70 to 80 kDa for the renin receptor. Incubation of mesangial cells with 100 nM renin for 24 hours provoked a 100% increase of 3H thymidine incorporation that was not accompanied by an increase of the cell number, even after a seven day period of incubation. However, the incubation of mesangial cells with renin for 24 hours induced a significant increase (170% of control, P = 0.04) of plasminogen activator inhibitor-1 (PAI1) antigen in the conditioned medium. In conclusion, we have shown that human mesangial cells in culture express a specific receptor for renin, and that the binding of renin increases 3H thymidine incorporation independently of renin enzymatic activity. The absence of cell proliferation, the increase of 3H thymidine incorporation and the increase of PAI1 antigen suggest that the binding of renin can induce mesangial cell activation, which is reflected by a change in the fibrinolytic capacity of the cells. The role of this receptor remains to be determined in nephropathies and hypertensive states associated with high plasma/tissue renin concentrations, hypertrophy of mesangial or smooth muscle cells and extracellular matrix remodeling.

Cell Division↗
PubMed1996

Load, length, and velocity of load-moving tibialis anterior muscle of the cat.

Three-dimensional relationships of load, length, and velocity of shortening of the tibialis anterior muscle in the cat were derived experimentally and fitted with an analytic model. Gravitational loads were applied to the isolated muscle, which arrived at an equilibrium with the passive forces before supramaximal tetanic stimulation was delivered to its nerve. Recordings of initial passive muscle length at equilibrium and length changes throughout the shortening phase up to the final length at active equilibrium were taken and numerically differentiated to obtain each load's instantaneous velocity. A three-dimensional surface was constructed by using instantaneous length and the corresponding velocity for each of several loads. Maximal velocity of shortening was shown to gradually decrease, occurring earlier in the shortening phase (at larger muscle lengths) as loads increased. Whereas load-velocity curves were hyperbolic for middle and short muscle lengths, they were nonmonotonic during shortening above the optimal length. The model was found to correlate well with the experimental data (R = 0.98) and allowed for prediction of both muscle performance boundaries and instantaneous shortening velocity for a given length across the physiological load spectrum, thus offering a realistic estimation of the contractile properties exhibited by the tibialis anterior muscle in functions similar to naturally occurring movements against gravitational loads, which are accelerated and decelerated during the movement.

Animals↗
PubMed1996

Increased placental antifibrinolytic potential and fibrin deposits in pregnancy-induced hypertension and preeclampsia.

Preeclampsia is characterized by maternal hypercoagulable state and intravascular coagulation, microthromboses in several organs, and impairment of uteroplacental circulation. Excessive fibrin deposition occurs in the placenta, suggesting that disorders of placental coagulation and fibrinolysis physiologic systems may have a role in hemostasis activation. Term placentas were collected from 17 hypertensive/preeclamptic women and from 17 healthy pregnant women, and processed for both histologic and hemostasis studies. Placental fibrinoid deposition was visualized by cresyl-violet staining and quantified by histomorphometric analysis. The content in hemostasis factors was measured on extracts from homogenized placentas treated by a nonionic detergent. The percentage of villi with fibrinoid deposits was higher in the diseased placentas than in controls: 13.2 +/- 11.2 versus 6.75 +/- 2.7% (p < 0.001) for the total amount of deposits; 4.8 +/- 6.7 versus 1.5 +/- 1.0% (p = 0.04) for perivillous fibrinoid deposits, which are considered as histologic markers of intraplacental fibrin. The content in type 2 plasminogen activator inhibitor (PAI-2) antigen was higher in the diseased placentas than in controls: 124 +/- 8 versus 104 +/- 6 ng/mg placental protein (p = 0.046); there was a negative correlation between PAI-2 antigen and thrombomodulin activity (r = -0.57, p = 0.02) in the diseased placentas. No significant differences were found between the two groups for placental procoagulant tissue factor and anticoagulant thrombomodulin activities, and for the content in plasminogen activators and PAI-1 antigens. Placental antifibrinolytic potential is increased in pregnancy-induced hypertension and preeclampsia. This change, and the association of the highest PAI-2 placental concentrations with the lowest concentrations of thrombomodulin, may contribute to the prethrombotic state and to the excessive placental perivillous fibrin deposition observed in these situations.

Adult↗
PubMed1995

Endothelin-1 induces rapid and long lasting internalization of the thrombin receptor in human glomerular epithelial cells.

Endothelin-1 acts as a potent autocrine and paracrine mediator in the kidney. Glomeruli and renal arterioles also express functional thrombin receptors which mediate the cellular effects of thrombin. Using the binding on glomerular epithelial cells of 125I-labeled ATAP2, a monoclonal antibody raised against the functional thrombin receptor, we demonstrate here that endothelin-1 induces thrombin receptor internalization in a dose- and a time-dependent manner. The maximal effect is observed at 10(-7) M endothelin-1 corresponding to internalization of approximately 25% of thrombin receptors. It is maximal at 20 min and persists for at least 24 h. This effect is mediated by the endothelin receptor subtype A (ETA), and involves a pertussis toxin-sensitive G-protein and protein kinase C activation. Endothelin-1 does not induce thrombin receptor degradation nor change in thrombin receptor mRNA level after 2 h and 24 h of incubation. These results indicate that partial heterologous internalization of the functional thrombin receptor is induced by endothelin-1.

Cells, Cultured↗
PubMed1995

Motor unit recruitment strategy of knee antagonist muscles in a step-wise, increasing isometric contraction.

The purpose of this study was to determine if differences exist between the control strategies of two antagonist thigh muscles during knee flexion and extension muscular coactivation. Surface myoelectric signal (MES) of the quadriceps (rectus femoris) and the hamstrings (semitendinosus) were obtained from both muscles while performing step-wise increasing contractions during flexion and extension with the knee at 1.57 rad of flexion (90 degrees). The median frequency of the power density spectrum, which is related to the average muscle fiber action potential conduction velocity and therefore to motor unit recruitment, was calculated from each MES. The results suggest that, in all the subjects tested, when the muscle acts as antagonist most motor units are recruited up to 50% of the maximal voluntary force, whereas when the muscle acts as antagonist motor units are recruited up to 40% of the maximal voluntary force. The force range past 40-50% of the maximal force is also characterized by differences between the agonist/antagonist.

Adult↗
PubMed1995

[Comparison of different methods in the assessment of the ratio of hypertensive patients responding to antihypertensive treatment].

Identification of a responder to an antihypertensive treatment is helpful and also very difficult in an open uncontrolled study. The existence of many arbitrary methods to define a responder, the placebo effect and the regression to the mean phenomenon coexist and give spurious interpretation. We analysed an open study recruiting 6,530 hypertensive patients (DBP > or = 95 mmHg at entry), treated with the same antihypertensive drug during 3 months. Mean initial and at 3 months blood pressures were respectively 178/101 mmHg and 151/86 mmHg. We observed significant variation in the % of responders (20 to 80%) to a drug when applying different methods. Placebo effect and regression to the mean lead to an overestimation. Without a placebo controlled design, we suggest to increase the BP level for inclusion to determine the % of responders with the standard goal pressure (DBP < 90 mmHg) and to use Oldham's method for adjusting for the regression to the mean unless the coefficient of correlation found is around zero and if upper level of DBP is not selected for inclusion.

Adolescent↗
PubMed1994

Receptor binding and degradation of urokinase-type plasminogen activator by human mesangial cells.

The binding of [125I] labeled urokinase-type plasminogen activator (u-PA) was studied on human mesangial cells (MC) in culture. The binding of active [125I]u-PA at 37 degrees C reached a plateau after 30 minutes of incubation and remained stable for at least four hours. When the supernatant was analyzed with trichloracetic acid (TCA), TCA soluble radioactive material could be detected after a lag phase of 30 minutes, and then increased linearly for four hours. Analysis by electrophoresis on SDS PAGE and autoradiography of the cell associated radioactivity and of the intracellular content showed that active u-PA and u-PA complexed to plasminogen activator inhibitor type-1 (PAI-1) were bound to the cell surface, but only u-PA/PAI-1 complexes were internalized and degraded. Therefore, the Kd and the number of binding sites were determined by competitive inhibition curves at 4 degrees C using diisopropyl-fluorophosphate (DFP) u-PA. Scatchard plots showed a Kd = 400 +/- 30 pM, and Bmax = 240,000 +/- 25,000 sites/cell. Excess of the amino terminal fragment of u-PA (ATF) completely blocked the specific binding of [125I]u-PA, confirming that the binding of u-PA was independent of the presence of the active site and/or of the formation of complexes with PAI-1. 3H thymidine incorporation by mesangial cells after stimulation with 100 nM active u-PA showed that u-PA had a moderate but significant mitogenic effect, in contrast to inactive u-PA and ATF. However, this mitogenic effect was not accompanied by a proliferative effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Binding Sites↗
PubMed1994

Expression of plasminogen/plasmin receptors on human glomerular epithelial cells.

The aim of the present study was to display plasminogen/plasmin receptors on human glomerular epithelial cell (HGEC) membranes and to determine the properties of receptor-bound plasminogen at the cell surface. Using an immortalized human glomerular epithelial cell line (E71-A1), we found a specific, saturable, and reversible binding of 125I-labeled plasminogen and 125I-labeled plasmin to HGEC that involved the lysine binding sites of both ligands. 125I-plasminogen and 125I-plasmin bound to the same receptors with different affinities: Kd = 1.20 +/- 0.08 and 0.30 +/- 0.05 microM, respectively (P < 0.001). The number of binding sites per cell was 6.00 +/- 0.56 x 10(6) for plasminogen and 2.00 +/- 0.47 x 10(6) for plasmin (P < 0.05). Similar receptor affinities were found on isolated glomeruli, on immortalized and nonimmortalized HGEC, and on purified HGEC membranes. The apparent kinetic constants of plasminogen activation by receptor-bound urokinase-type plasminogen activator (u-PA) compared with solution-phase u-PA [Michaelis constant (Km) = 0.80 +/- 0.54 vs. 3.15 +/- 0.78 microM, P < 0.0001; catalytic constant (kcat) = 0.39 +/- 0.17 vs. 0.50 +/- 0.29 s-1, not significant; kcat/Km = 0.57 +/- 0.35 vs. 0.16 +/- 0.11 microM-1.s-1, P < 0.05, respectively] showed a higher efficiency of plasminogen activation at the cell surface. When measured by a chromogenic assay using S22-51, receptor-bound plasmin activity on HGEC was partly protected from its inhibitor, alpha-2-antiplasmin, whereas solution-phase plasmin was not.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Membrane↗
PubMed1994

[Treatment of moderate hypertension: monotherapy or combination?].

The treatment of hypertension must fall within a strategy of the early and strict control of blood pressure levels. Only actual normalisation of blood pressure can offer long term benefit regarding the incidence of cardiovascular morbidity and mortality. While major studies undertaken up to now have already proven the benefit of treatment using classical drugs as monotherapy, it is now necessary to offer all young hypertension patients, even mild, with strict control of levels, a non-pharmacological action on risk factors, and a choice of treatments ensuring no loss of part of the prognostic benefit as a result of persistence or worsening or sub-clinical metabolic disorders. It seems logical, when first-line monotherapy is selected from among the five major drug groups recommended, is neither perfectly effective nor perfectly tolerated, and risks worsening a metabolic disorder in the long term, to use a combination of hypotensive drugs. This should enable blood pressure control in 80 to 90% of cases, and improved acceptability, a major factor in treatment compliance. It is reasonable to hope, in the long term, that the use of a combination of lower doses than as monotherapy, will ensure less interference with major metabolic, endocrine and vascular functions, leading to a further improvement in the prognosis of treated hypertension.

Adrenergic beta-Antagonists↗
PubMed1993

Long-term effects of thrombin require sustained activation of the functional thrombin receptor.

Thrombin is a potent activator of human glomerular epithelial cells (HGEC). Here we compare short-term and long-term effects of thrombin and thrombin receptor agonist peptide (TRAP) which selectively activates the functional thrombin receptor. TRAP, as thrombin, increases intracellular free Ca2+ concentration and acts synergistically with growth factors possessing tyrosine kinase receptors on DNA synthesis. Thrombin induces synthesis of proteins of the fibrinolytic system and cell proliferation if it is present for at least 8 h. TRAP alone does not stimulate protein synthesis and is not mitogenic. However, in the presence of the aminopeptidase inhibitor amastatin all long-term effects of thrombin can be fully mimicked by TRAP. In conclusion, different effects of thrombin and TRAP may be related to the degradation of TRAP by cellular ectoenzymes. The recently cloned thrombin receptor accounts for early intracellular signals and long-term cellular effects that require sustained activation of this receptor.

Anti-Bacterial Agents↗
PubMed1993

A quantitative receptor assay using Triton X-114 for plasminogen activator binding proteins in solubilized membranes from human liver and placenta.

Cell surface binding proteins play an important role in the localization of plasminogen activator (PA) activity at the cell surface or in the clearance of PAs. We describe a rapid and quantitative receptor assay applicable to the quantification and affinity determination of binding proteins for tissue-type PA and urokinase-type PA in solubilized membranes obtained from human liver, human placenta, or human monocyte-like cells. The method is based on the ability of a solution of the nonionic detergent Triton X-114 to phase separate at temperatures above 20 degrees C. After incubation of integral membrane proteins with radiolabeled ligand, a solution of Triton X-114 is added at 4 degrees C and warmed to 37 degrees C to allow phase partitioning. Radiolabeled ligand bound to membrane protein is recovered in the detergent-rich lower phase which is separated by centrifugation from the detergent-poor upper phase containing free radiolabeled ligand.

Carrier Proteins↗
PubMed1993

[Is placebo necessary in a clinical trial on ambulatory blood pressure?].

Placebo has only a slight effect on ambulatory blood pressure (ABP). Some authors have suggested that the use of a placebo is not necessary in a study on the drugs effect on ABP. We demonstrate that even if placebo effect is small, the use of a placebo group is still necessary. Effects of one daily dose of 50 mg atenolol + 20 mg slow-released nifedipine (AN) were investigated. Patients with office DBP 90-110 mmHg received, in a double-blind protocol, either AN (group AN, n = 31) or a placebo (group P, n = 26). Ambulatory BP (ABP) and HR were measured (Spacelabs or Diasys systems) for 24 h before and one month after treatment. The 2 groups were comparable before treatment. After 1 month under treatment, ABP was significantly lower in the AN group, compared to the P group, and this over the whole day (p = 0.03 to p < 0.0001). The effect was the most important between 10-17 h (p < 0.0001). HR was significantly lower in the AN group during daytime (6-22 h), but not during the night (22-6 h). Over the whole group, placebo effect was not significant. However, ABP did decrease under placebo in subjects with high initial pressure. As a result, an analysis without data from the placebo group led to an overestimation of the effects of the drug.

Adult↗