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Biomedical subjects

S Lopez

Publications and source records attributed to S Lopez.

At least 37 records · Page 2Linked to original sources
PubMed2000

An advanced glycation endproduct cross-link breaker can reverse age-related increases in myocardial stiffness.

Decreased elasticity of the cardiovascular system is one of the hallmarks of the normal aging process of mammals. A potential explanation for this decreased elasticity is that glucose can react nonenzymatically with long-lived proteins, such as collagen and lens crystallin, and link them together, producing advanced glycation endproducts (AGEs). Previous studies have shown that aminoguanidine, an AGE inhibitor, can prevent glucose cross-linking of proteins and the loss of elasticity associated with aging and diabetes. Recently, an AGE cross-link breaker (ALT-711) has been described, which we have evaluated in aged dogs. After 1 month of administration of ALT-711, a significant reduction ( approximately 40%) in age-related left ventricular stiffness was observed [(57.1 +/- 6.8 mmHg x m(2)/ml pretreatment and 33.1 +/- 4.6 mmHg x m(2)/ml posttreatment (1 mmHg = 133 Pa)]. This decrease was accompanied by improvement in cardiac function.

Aging↗
PubMed2000

Tumor necrosis factor alpha up-regulates in an autocrine manner the synthesis of plasminogen activator inhibitor type-1 during induction of monocytic differentiation of human HL-60 leukemia cells.

Tumor necrosis factor-alpha (TNFalpha) critically regulates several cellular functions during monocyte/macrophage differentiation. We therefore investigated during the phorbol ester (phorbol 12-myristate 13-acetate (PMA))-induced monocyte/macrophage differentiation of the human HL-60 leukemia cells, if TNFalpha contributed to plasminogen activator inhibitor type-1 (PAI-1) synthesis that is initiated by a protein kinase Cbeta-extracellular signal-regulated kinase 2-dependent pathway (Lopez, S., Peiretti, F., Morange, P., Laouar, A., Fossat, C., Bonardo, B., Huberman, E., Juhan-Vague, I., and Nalbone, G. (1999) Thromb. Haemostasis 81, 415-422). Following PMA treatment, the level of TNFalpha mRNA strongly increased and appeared earlier than PAI-1 mRNA. An anti-TNFalpha antibody significantly inhibited the PMA-induced PAI-1 mRNA and protein levels. The recombinant human TNFalpha, which is inactive on native HL-60 cells in terms of PAI-1 synthesis, optimally potentiates it once HL-60 cells are committed into the differentiation process. The use of 1) the HL-525 cell line, a clone issued from HL-60 cells rendered resistant to PMA-induced differentiation, and 2) the transforming growth factorbeta-1/vitamin D3 differentiative mixture confirmed the relationships between the induction of differentiation and the potency of TNFalpha to up-regulate PAI-1 synthesis. In conclusion, we showed that during the induction of monocyte/macrophage differentiation, TNFalpha and PAI-1 gene expressions are activated and that synthesized TNFalpha up-regulates and prolongs, in an autocrine manner, the synthesis of PAI-1.

Autocrine Communication↗
PubMed2000

The internal rotavirus protein VP6 primes for an enhanced neutralizing antibody response.

We studied in the rotavirus system whether the internal protein VP6 could prime for an enhancement in the production of neutralizing antibodies (NeuAb) against the external proteins, VP7 and VP4. It was found that BALB/c mice immunized with recombinant YM VP6 protein, and challenged i.p. with a heterologous rotavirus had an increase in the production of serum NeuAb compared to the control. This response was both homotypic and heterotypic, and involved an increase of NeuAb belonging to the IgM and IgG isotypes. Mice immunized with the recombinant VP6 and challenged orally with infectious murine rotavirus cleared the infection one day earlier than the control not immunized with VP6, and showed a small increase of total fecal anti-rotavirus IgA. The results suggest that the T-helper (Th) cells specific for VP6 can provide cognate help to B cells specific for neutralizing epitopes on the VP7 and/or VP4 molecules, and that this help can be heterotypic. Finally, we provide evidence that this phenomenon may be happening during infection.

Animals↗
PubMed2000

Effect of atorvastatin and fluvastatin on the expression of plasminogen activator inhibitor type-1 in cultured human endothelial cells.

Inhibitors of HMG-CoA reductase, namely statins, improve endothelial function independently of their cholesterol-lowering effects. Plasminogen activator inhibitor type-1 (PAI-1) plays a critical role in vascular pathophysiology both at the intra- and extravascular levels. We therefore investigated the effects of atorvastatin (ATOR) and fluvastatin (FLU) on PAI-1 and also tissue-type plasminogen activator (t-PA) synthesis in 20% fetal calf serum-cultured human umbilical vein endothelial cells (HUVEC) stimulated or not by recombinant human pro-inflammatory cytokines, i.e. tumor necrosis factor alpha (TNFalpha) and interleukin 1alpha (IL-1alpha). In non-stimulated HUVEC, ATOR and FLU significantly diminished (-50% at 2.0 micromol/l) the constitutive production of PAI-1 (mRNA level and protein secretion). This effect was prevented by addition of mevalonate (100 micromol/l). In HUVEC cultivated in 20% fetal calf serum, the t-PA antigen accumulation was not significantly altered, whereas in low serum concentration (1%) a significant stimulatory effect of ATOR (+30%) and FLU (+76%) was observed. In TNFalpha-stimulated cells, ATOR and FLU had a modest down-modulating effect (-17 and -20%, respectively) on TNFalpha-induced increase in PAI-1 synthesis. No effect of statins was observed in IL-1alpha-stimulated HUVEC, suggesting that statins do not interfere with the up-regulation of PAI-1 synthesis by pro-inflammatory cytokines. However, ATOR and FLU inhibited the TNFalpha-induced decrease in t-PA release. In conclusion, these results show that statins favorably modulate the expression of fibrinolytic factors produced by human endothelial cells.

Anticholesteremic Agents↗
PubMed2000

Estimating the extent of degradation of ruminant feeds from a description of their gas production profiles observed in vitro: comparison of models.

An evaluation of general models that describe gas production profiles is presented. The models are derived from first principles by considering a simple three-pool scheme and permit the extent of ruminal degradation to be calculated, as described in the companion paper. The models evaluated were the generalized Mitscherlich, simple Mitscherlich, generalized Michaelis-Menten, simple Michaelis-Menten, Gompertz, and logistic. Five sets of gas production data consisting of 216 curves, obtained using a wide range of feeds (including straw, hay, silage, grain and various byproducts), were analysed to study the performance of these gas production models. Application of the non-sigmoidal models (simple Mitscherlich and Michaelis-Menten) to the data resulted in convergence problems and these models were found to be inadequate in many cases. Based on results of a pairwise comparison between models (variance ratio test), ranking of residual mean squares, lack-of-fit test, and of analyses of residuals, the generalized Mitscherlich and the generalized Michaelis-Menten models seemed particularly suited because of their flexibility to encompass sigmoidal and non-sigmoidal shapes of gas production profiles, whether symmetrical or not.

Animal Feed↗
PubMed2000

Estimating the extent of degradation of ruminant feeds from a description of their gas production profiles observed in vitro: derivation of models and other mathematical considerations.

Equations to describe gas production profiles, obtained using manual or automated systems for in vitro fermentation of ruminant feeds, were derived from first principles by considering a simple three-pool scheme. The pools represented were the potentially degradable and undegradable feed fractions, and accumulated gases. The equations derived and investigated mathematically were the generalized Mitscherlich, generalized Michaelis-Menten, Gompertz, and logistic. They were obtained by allowing the fractional rate of degradation to vary with time. The equations permit the extent of ruminal degradation (hence the supply of microbial protein to the duodenum) to be evaluated, thus linking the gas production technique to animal production.

Animal Feed↗
PubMed2000

Rotavirus spike protein VP4 is present at the plasma membrane and is associated with microtubules in infected cells.

VP4 is an unglycosylated protein of the outer layer of the capsid of rotavirus. It forms spikes that project from the outer layer of mature virions, which is mainly constituted by glycoprotein VP7. VP4 has been implicated in several important functions, such as cell attachment, penetration, hemagglutination, neutralization, virulence, and host range. Previous studies indicated that VP4 is located in the space between the periphery of the viroplasm and the outside of the endoplasmic reticulum in rotavirus-infected cells. Confocal microscopy of infected MA104 monolayers, immunostained with specific monoclonal antibodies, revealed that a significant fraction of VP4 was present at the plasma membrane early after infection. Another fraction of VP4 is cytoplasmic and colocalizes with beta-tubulin. Flow cytometry analysis confirmed that at the early stage of viral infection, VP4 was present on the plasma membrane and that its N-terminal region, the VP8* subunit, was accessible to antibodies. Biotin labeling of the infected cell surface monolayer with a cell-impermeable reagent allowed the identification of the noncleaved form of VP4 that was associated with the glycoprotein VP7. The localization of VP4 was not modified in cells transfected with a plasmid allowing the expression of a fusion protein consisting of VP4 and the green fluorescent protein. The present data suggest that VP4 reaches the plasma membrane through the microtubule network and that other viral proteins are dispensable for its targeting and transport.

Animals↗
PubMed2000

Repression of virus-induced interferon A promoters by homeodomain transcription factor Ptx1.

Interferon A (IFN-A) genes are differentially expressed after virus induction. The differential expression of individual IFN-A genes is modulated by substitutions in the proximal positive virus responsive element A (VRE-A) of their promoters and by the presence or absence of a distal negative regulatory element (DNRE). The functional feature of the DNRE is to specifically act by repression of VRE-A activity. With the use of the yeast one-hybrid system, we describe here the identification of a specific DNRE-binding protein, the pituitary homeobox 1 (Ptx1 or Pitx1). Ptx1 is detectable in different cell types that differentially express IFN-A genes, and the endogenous Ptx1 protein binds specifically to the DNRE. Upon virus induction, Ptx1 negatively regulates the transcription of DNRE-containing IFN-A promoters, and the C-terminal region, as well as the homeodomain of the Ptx1 protein, is required for this repression. After virus induction, the expression of the Ptx1 antisense RNA leads to a significant increase of endogenous IFN-A gene transcription and is able to modify the pattern of differential expression of individual IFN-A genes. These studies suggest that Ptx1 contributes to the differential transcriptional strength of the promoters of different IFN-A genes and that these genes may provide new targets for transcriptional regulation by a homeodomain transcription factor.

Animals↗
PubMed2000

High-versus low-threshold surfactant retreatment for neonatal respiratory distress syndrome.

UNLABELLED: Surfactant therapy has become an effective standard therapy for infants with respiratory distress syndrome (RDS). The first dose may be given either as prophylaxis immediately after delivery, or as rescue after an infant has developed RDS. Second and subsequent doses are currently recommended by the manufacturers to be administered at minimal levels of respiratory support. PURPOSE: This study compared the relative efficacy of administering second and subsequent doses of Infasurf surfactant at a low threshold (FIO(2) >30%, still requiring endotracheal intubation) versus a high threshold (FIO(2) >40%, mean airway pressure >7 cm H(2)O) of respiratory support. METHODS: A total of 2484 neonates received a first dose of surfactant; 1267 reached conventional retreatment criteria and were randomized to be retreated according to low- or high-threshold criteria. They were then retreated at a minimum of 6-hour intervals each time they reached their assigned threshold until receiving a maximum of 4 total doses. Subjects were stratified by whether they received their first dose by prophylaxis or rescue and by whether their lung disease was considered complicated (evidence of perinatal compromise or sepsis) or uncomplicated. RESULTS: Among the patients randomized, 33% of prophylaxis and 23% of rescue subjects met criteria for the complicated stratum. Although infants allocated to the high-threshold strategy were receiving slightly more oxygen at 72 hours, there was no difference in the number receiving mechanical ventilation at 72 hours or in the secondary respiratory outcomes (requirement for supplemental oxygen or mechanical ventilation at 28 days, supplemental oxygen at 36 weeks' postconceptional age, inspired oxygen concentration >60% at any time). However, there was a significantly higher mortality for infants with complicated RDS who had received retreatment according to the high-threshold strategy. CONCLUSIONS: We conclude that equal efficacy can be realized by delaying surfactant retreatment of infants with uncomplicated RDS until they have reached a higher level of respiratory support than is the current standard. We speculate that this would result in a substantial cost-saving from less utilization of drug. Conversely, we believe that infants with complicated RDS should continue to be treated by the low-threshold retreatment strategy, which is currently recommended by the manufacturers of the commercially available surfactants.

Biological Products↗
PubMed2000

Topical use of papaya in chronic skin ulcer therapy in Jamaica.

The objective of the study was to determine the prevalence of the use of the fruit (papaya) of Carica papaya as topical ulcer dressings by registered nurses in the Spanish Town Hospital (STH), Kingston Public Hospital (KPH) and the University Hospital of the West Indies (UHWI), Jamaica. A ten-item pretested self-administered questionnaire was distributed to 285 randomly selected registered nurses at the UHWI, KPH and STH. There was a 72% response rate. The prevalence of topical papaya use among the respondents was 75%. Comments from the users of papaya suggested that topical application of the unripe fruit promoted desloughing, granulation and healing and reduced odour in chronic skin ulcers. It was cost effective. Papaya was considered to be more effective than other topical applications in the treatment of chronic ulcers. There was some difficulty in preparation of the fruit and occasionally a sensation of burning was reported by the patients. There was concern about the use of a non-sterile, non-standardised procedure but there were no reports of wound infection from its use. Papaya is widely used by nurses as a form of dressing for chronic ulcers and there is need for standardisation of its preparation and application.

Administration, Topical↗
PubMed1999

Presence of proteinase 3 in secretory vesicles: evidence of a novel, highly mobilizable intracellular pool distinct from azurophil granules.

Proteinase 3 (PR3), which is also called myeloblastin, the target autoantigen for antineutrophil cytoplasmic antibodies (ANCA) in Wegener's granulomatosis, is a serine proteinase stored in azurophil granules of human neutrophils. We have previously shown that, in contrast to elastase or myeloperoxidase, PR3 is also expressed at the plasma membrane of a subset of unactivated neutrophils and that a high proportion of neutrophils expressing membrane PR3 is a risk factor for vasculitis. The present study demonstrates that the association of PR3 with the plasma membrane is not an ionic interaction and seems to be covalent. Fractionation of neutrophils shows that, besides the azurophil granules, PR3 could be detected both in specific granules and in the plasma membrane-enriched fraction containing secretory vesicles, whereas elastase and myeloperoxidase were exclusively located in azurophil granules. Electron microscopy confirms that PR3 is present along with CR1 in secretory vesicles as well as in some specific granules. In neutrophils stimulated with an increasing dose of FMLP, membrane PR3 expression increased with the degranulation of secretory vesicles, followed by specific granules, and culminated after azurophil granules mobilization. The presence of a readily plasma membrane-mobilizable pool of PR3 contained in the secretory vesicles might play a relevant role in the pathophysiological mechanisms of ANCA-associated vasculitis.

Autoantigens↗
PubMed1999

A large subset of neutrophils expressing membrane proteinase 3 is a risk factor for vasculitis and rheumatoid arthritis.

It has been shown previously that proteinase 3 (PR3), a neutrophil intracellular protease that is the main antigen of antineutrophil cytoplasm (ANCA) autoantibodies, is present on the plasma membrane of a subset of freshly isolated neutrophils. This study shows that the size of this subset of membrane PR3-positive (mPR3+) neutrophils is a stable feature of a given individual, most likely genetically controlled. It ranges from 0 to 100% of neutrophils and allows us to define a new polymorphism in the healthy population, with three discrete phenotypes corresponding respectively to less than 20% mPR3 + neutrophils (mPR3low) or to a mean percentage of 47% (mPR3intermediate) and 71.5% (mPR3high) mPR3+ neutrophils. The frequency of the mPR3high phenotype was significantly increased in patients with ANCA-associated vasculitis (85% versus 55% in healthy subjects). The percentage of mPR3+ neutrophils was not affected by disease activity, relapses, or therapy, and did not reflect in vivo cell activation. In addition, mPR3+ phenotypes were normally distributed in cystic fibrosis patients, indicating that infection and/or inflammation per se do not lead to a high percentage of mPR3+ neutrophils. The frequency of the mPR3high phenotype was not related to anti-PR3 autoimmunization, since it was increased in vasculitic patients regardless of the ANCA specificity (anti-PR3, anti-myeloperoxidase, or unknown). Interestingly, the frequency of the mPR3high phenotype was also increased in patients with rheumatoid arthritis. It was normal in type I-diabetes, a T cell-dependent autoimmune disease. It is proposed here that a high proportion of membrane PR3-positive neutrophils could favor the occurrence or the progression of chronic inflammatory diseases.

Adult↗
PubMed1999

Activation of plasminogen activator inhibitor-1 synthesis by phorbol esters in human promyelocyte HL-60--roles of PCKbeta and MAPK p42.

HL-60 cells treated by PMA develop the monocyte adherent phenotype and synthesize plasminogen activator inhibitor type-1 (PAI-1). We focused our study on the identification of the PMA-activated protein kinase C (PKC) isoform and its downstream transduction pathway activating PAI-1 synthesis. Acquisition of the monocytic phenotype was evidenced by cell adherence (90-95%) and a sharp increase of CD 36 and receptor for urokinase plasminogen activator (uPAR) surface expression. Ro 31-8220, a specific inhibitor of PKC, prevented PMA-induced PAI-1 synthesis (mRNA and protein levels) and cell adhesion. To identify the PKC isoform, we took advantage of the HL-525 cell line, an HL-60 cell variant deficient in PKCbeta gene expression. This defect prevents PMA to induce the differentiation process. HL-525 stimulated by PMA did not synthesize PAI-1 nor become adherent. However, in HL-525 cells either pretreated by retinoic acid that reinduces PKCbeta gene expression or transfected with PKCbeta cDNA, PMA significantly activated PAI-1 synthesis and adhesion of cells. Immunoblotting of active Mitogen Activated Protein Kinase (MAPK) p42/p44 in HL-60 cells showed a preferential and sustained activation of the p42 isoform by PMA over the p44 isoform. Ro 31-8220 significantly attenuated this activation. PD 098059 and U0126, both highly specific MEK inhibitors, efficiently prevented PMA-induced PAI-1 synthesis (mRNA and protein levels) and cell adhesion whereas SB203580, a specific inhibitor of stress-activated MAPK p38, did not. Results obtained from HL-60 and HL-525 cells indicate that the PMA-activated transduction pathway of uPAR expression involves a PKC isoform other than PKCbeta. In conclusion, we propose that the pathway PKCbeta-MEK-MAPK p42 is a potential linear route for PAI-1 synthesis leading to morphological changes and adherence linked to PMA-induced differentiation in HL-60 cells.

Carcinogens↗
PubMed1998

Characterization of the aldolase B intronic enhancer.

The aldolase B gene is transcribed at a high level in the liver, kidney, and small intestine. This high level of gene expression results from cooperation between a weak but liver-specific promoter and an intronic activator. A deletional study of this activator present in the first intron allowed us to ascribe the maximal enhancer function to a 400-base pair (bp) fragment (+1916 to + 2329). This enhancer is highly liver-specific and enhances the activity of heterologous minimal promoters in a position and distance-independent fashion in transiently transfected Hep G2 hepatoma cells. The aldolase B enhancer is composed of two domains, a 200-bp module (Ba) inactive by itself but which synergizes with another 200-bp module (Bb) that alone retains 25% of the total enhancer activity. The Bb sequence is 76% homologous between human and rat genes and contains several binding sites for liver-enriched nuclear factors. By electrophoretic mobility shift assays, we demonstrated that elements 5 and 7 bind hepatic nuclear factor 1 (HNF1), whereas element 2 binds hepatic nuclear factor 4 (HNF4). A functional analysis of the enhancer whose elements have been mutated demonstrated that mutation of any of the HNF1 sites totally suppressed enhancer activity, whereas mutation of the HNF4-binding site reduced it by 80%.

Animals↗
PubMed1998

Pregnancy outcome and weight gain recommendations for the morbidly obese woman.

OBJECTIVE: To compare pregnancy outcomes between morbidly obese and nonobese women and to determine the effect of gestational weight gain on pregnancy outcome in morbidly obese women. METHODS: A retrospective cohort study was conducted comparing 613 morbidly obese and 11,313 nonobese women who were delivered of a singleton live birth. Morbid obesity was defined as a body mass index greater than 35. The incidence of selected perinatal and neonatal outcomes was assessed for the two groups. Multiple logistic regression analysis was used to evaluate the association between morbid obesity and various measures of outcome while controlling for potential confounders. A subanalysis of the morbidly obese patients was performed to assess the effect of gestational weight gain on pregnancy outcome. RESULTS: Morbidly obese patients were more likely to experience pregnancy complications including diabetes, hypertension, preeclampsia, and arrest-of-labor disorders; however, these were not affected by gestational weight gain. Morbidly obese patients were more likely to experience fetal distress and meconium and to undergo cesarean delivery than their nonobese counterparts (P < .05). Weight gains of more than 25 lb were associated strongly with birth of a large for gestational age (LGA) neonate (P < .01); however, poor weight gain did not appear to increase the risk of delivery of a low birth weight neonate. CONCLUSION: Gestational weight gain was not associated with adverse perinatal outcome, but it did influence neonatal outcome. To reduce the risk of delivery of an LGA newborn, the optimal gestational weight gain for morbidly obese women should not exceed 25 lb.

Adult↗
PubMed1998

[Acute myopericarditis following laparoscopic treatment of gastroesophageal reflux].

A 32-year-old patient experienced a postoperative acute myopericarditis following laparoscopic surgery for gastro-oesophageal reflux (Toupet's fundoplication). His medical history was unremarkable, apart from controlled arterial hypertension. Peroperative circulation was stable, except a short hypertensive episode at CO2 insufflation, controlled with nicardipine. A myopericarditis occurred at the fourth postoperative hour, with apical and inferior hypokinesia at ventriculography, ST-segment elevation with unremarkable coronary arteriography. The patient was discharged at day seven, with a NSAIDs treatment. Echocardiography three and nine months later postoperatively, showed an apical akinesia and persistence of the ST-segment modification, without clinical symptoms. Complications of laparoscopic fundoplication is either specific to surgery (gastro-oesophageal injury, diaphragmatic injury, mediastinitis, stenosis) or secondary to pneumoperitoneum (pneumothorax, carbon dioxide embolism). In this case, following an apparently uncomplicated laparoscopy and, except a direct cardiac trauma from a laparoscopic instrument, either coronary artery spasm, or pneumopericardium with CO2, or delayed gas embolism, or preoperative "silent" myopericarditis could be the potential cause of this cardiac complication.

Acute Disease↗
PubMed1998

Highly purified soybean protein is not hypocholesterolemic in rats but stimulates cholesterol synthesis and excretion and reduces polyunsaturated fatty acid biosynthesis.

The specific effects of soybean protein on lipid metabolism were determined with highly purified soybean protein. At 5 wk of age, growing rats were fed diets containing 20% highly purified soybean protein or casein supplemented or not with 0.1% cholesterol for 2 mo. Plasma and liver lipid composition, fecal steroid excretion and several hepatic enzyme activities were measured. There were no significant dietary protein-related differences in plasma and liver cholesterol concentrations. When diets were cholesterol free, highly purified soybean protein stimulated fecal neutral and acidic steroid excretion associated with concomitantly higher hydroxy methylglutaryl CoA (HMG-CoA) reductase activity, but lower cholesterol 7alpha-hydroxylase activity. Soybean protein lowered the linoleate desaturation index [20:4(n-6)/18:2(n-6)] in liver microsomal lipids and phospholipids. This may have been due to the reduced microsomal Delta6(n-6) desaturase activity in rats fed soybean protein, whereas Delta5(n-6) desaturase activity did not differ between groups fed the two proteins. Cholesterol supplementation (0.1%) did not affect plasma cholesterol but increased liver cholesterol and triacylglycerol concentrations and reduced HMG-CoA reductase activity; this latter effect was greatest in rats fed soybean protein. Cholesterol 7alpha-hydroxylase activity, however, was diminished only in rats fed casein. Desaturase activities, and particularly Delta5(n-6) activity, were lowered by cholesterol supplementation in rats fed both protein diets, including a significantly lower 20:4(n-6)/18:2(n-6) ratio in liver microsomal lipids and liver phospholipids. Thus although dietary proteins have no effect on serum cholesterol in rats, they affect enzyme activities involved in cholesterol metabolism and fatty acid desaturation.

Animals↗