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Biomedical subjects

A Mignon

Publications and source records attributed to A Mignon.

36 records · Page 2Linked to original sources
PubMed1998

Bcl-2 prevents apoptotic mitochondrial dysfunction by regulating proton flux.

We and others have recently shown that loss of the mitochondrial membrane potential (Deltapsi) precedes apoptosis and chemical-hypoxia-induced necrosis and is prevented by Bcl-2. In this report, we examine the biochemical mechanism used by Bcl-2 to prevent Deltapsi loss, as determined with mitochondria isolated from a cell line overexpressing human Bcl-2 or from livers of Bcl-2 transgenic mice. Although Bcl-2 had no effect on the respiration rate of isolated mitochondria, it prevented both Deltapsi loss and the permeability transition (PT) induced by various reagents, including Ca2+, H2O2, and tert-butyl hydroperoxide. Even under conditions that did not allow PT, Bcl-2 maintained Deltapsi, suggesting that the functional target of Bcl-2 is regulation of Deltapsi but not PT. Bcl-2 also maintained Deltapsi in the presence of the protonophore SF6847, which induces proton influx, suggesting that Bcl-2 regulates ion transport to maintain Deltapsi. Although treatment with SF6847 in the absence of Ca2+ caused massive H+ influx in control mitochondria, the presence of Bcl-2 induced H+ efflux after transient H+ influx. In this case, Bcl-2 did not enhance K+ efflux. Furthermore, Bcl-2 enhanced H+ efflux but not K+ flux after treatment of mitochondria with Ca2+ or tert-butyl hydroperoxide. These results suggest that Bcl-2 maintains Deltapsi by enhancing H+ efflux in the presence of Deltapsi-loss-inducing stimuli.

Animals↗
PubMed1998

Regulated expression of mature human insulin in the liver of transgenic mice.

Transgenic mice expressing either human proinsulin cDNA or mutated proinsulin cDNA in the liver were created. The human proinsulin cDNA was mutated to generate a protein cleavable by the ubiquitous prohormone convertase furin, thus leading to mature insulin peptide. All transgenic lines expressed human C-peptide in the blood, whose level varied according to nutritional conditions. High performance liquid chromatography fractionation of mouse serum revealed that mutant proinsulin was effectively processed into mature insulin in vivo. This transgenic mouse model provides a useful tool for further prospects of gene therapy of insulin-dependent diabetes mellitus.

Animals↗
PubMed1998

Selective repopulation of normal mouse liver by Fas/CD95-resistant hepatocytes.

Hepatocyte transplantation might represent a potential therapeutic alternative to liver transplantation in the future; however, transplanted cells have a limited capacity to repopulate the liver, as they do not proliferate under normal conditions. Recently, studies in urokinase (uPA) transgenic mice and in fumarylacetoacetate hydrolase (FAH)-deficient mice have shown that the liver can be repopulated by genetically engineered hepatocytes harboring a selective advantage over resident hepatocytes. We have reported that transgenic mice expressing human Bcl-2 in their hepatocytes are protected from Fas/CD95-mediated liver apoptosis. We now show that Bcl-2 transplanted hepatocytes selectively repopulate the liver of mice treated with nonlethal doses of the anti-Fas antibody Jo2. FK 506 immunosuppressed mice were transplanted by splenic injection with Bcl-2 hepatocytes. The livers of female recipients were repopulated by male Bcl-2 transgenic hepatocytes, as much as 16%, after 8 to 12 administrations of Jo2. This only occurred after anti-Fas treatment, confirming that resistance to Fas-induced apoptosis constituted the selective advantage of these transplanted hepatocytes. Thus, we have demonstrated a method for increasing genetic reconstitution of the liver through selective repopulation with modified transgenic hepatocytes, which will allow optimization of cell and gene therapy in the liver.

Animals↗
PubMed1997

Polyamines inhibit lipopolysaccharide-induced nitric oxide synthase activity in rat liver cytosol.

Liver cells can produce nitric oxide from L-arginine through either constitutive NO synthase or inducible NO synthase (NOS) detected after in vivo or in vitro treatment with cytokines and/or lipopolysaccharide (LPS). The effects of NO on liver cells are associated with protein synthesis and mitochondrial electron transfer inhibition. L-Arginine is also the precursor of L-ornithine and polyamines. The latter are considered to be protective in the liver in several experimental models. The aim of the present work was to test the effects of polyamines on LPS-inducible NOS activity in rat liver cytosol using the test of radioactive L-citrulline synthesis from L-[guanido-14C]arginine. The three polyamines inhibited inducible NO synthase activity with the following hierarchy: spermine > spermidine approximately equal to putrescine. The 0.5 mM spermine was found to inhibit 50% of inducible NO synthase activity. The present data suggest an inhibitory interrelationship in the liver between two metabolites derived from the common precursor L-arginine.

Animals↗
PubMed1996

Bcl-2 protects from lethal hepatic apoptosis induced by an anti-Fas antibody in mice.

Fas is an apoptosis-signalling cell surface antigen that has been shown to trigger cell death upon specific ligand or antibody binding. Treatment of mice with an anti-Fas antibody causes fulminant hepatic failure due to massive apoptosis. To test a putative protective effect of the anti-apoptotic Bcl-2 protein, transgenic mice were generated to express the human bcl-2 gene product in hepatocytes. Early onset of massive hepatic apoptosis leading to death was observed in all nontransgenic mice treated with an anti-Fas antibody. By contrast, hepatic apoptosis was delayed and dramatically reduced in transgenic animals, yielding a 93% survival rate. These results demonstrate that Bcl-2 is able to protect from in vivo Fas-mediated cytotoxicity, and could be of significance for preventing fulminant hepatic failure due to viral hepatitis in humans.

Animals↗
PubMed1996

Transcutaneous cranial electrical stimulation (Limoge's currents) decreases early buprenorphine analgesic requirements after abdominal surgery.

Transcutaneous cranial electrical stimulation with Limoge's currents (TCES) consists of high frequency, low intensity currents which decreased anesthetic requirements during elective surgery. This action is likely to be mediated by the release of central endogenous opioids. In the present study, we hypothesized that TCES applied intraoperatively may decrease early postoperative narcotic requirements. Thirty-nine ASA physical status I and II patients undergoing elective abdominal surgery were enrolled in this prospective, randomized, double-blind, placebo-controlled study. Just before induction of anesthesia, patients were connected to the electrical stimulator and randomly allocated to be either stimulated (TCES group, n = 20) or not (control group, n = 19) during surgery. The managing anesthesiologist was unaware of which group the patient was assigned. Postoperatively, patients were given a patient-controlled analgesia (PCA) device delivering buprenorphine for the first four postoperative hours. The recorded variables included postoperative buprenorphine requirements, pain scores (0-10 visual analog scale [VAS]), sedation (0-4 scale), and intraoperative isoflurane requirements. Patients were comparable with respect to age, sex ratio, weight, duration of surgery, intraoperative hemodynamics, fentanyl requirements, and time from skin closure to tracheal extubation. Buprenorphine requirements were significantly reduced in the TCES group versus the control group (2.36 vs 3.43 micrograms.kg-1.h-1; P = 0.002). Intraoperative isoflurane anesthetic requirements, as well as hourly postoperative scores for pain and sedation, were the same for the two groups. These data indicate that TCES reduces narcotic requirements for early postoperative analgesia. This technique might have potential to facilitate early postoperative analgesia in patients undergoing elective abdominal surgery.

Abdomen↗
PubMed1994

[Ansatipine: only preventive treatment available for opportunistic MAI infections in AIDS. From an interview with Dr. Agnes Mignon].

Ansatipine, the international name of which is rifabutine, is a new specialty that was licensed in February 1993 and marketed in France in June 1993. It is an antibiotic of the rifamycin family, the result of research by Farmitalia Carlo Erba and is now presented by the Laboratoire Pharmacia. Today, rifabutine is the only molecule in the world that has been shown to be efficacious in preventative treatment for infections by the Mycobacterium avium complex (MAC) and to be officially recognised as such. Rifabutine (Ansatipine) was developed for prophylaxis of infections by MAC, because of its bacteriological activity on mycobacteria and especially on the Mycobacterium avium complex, the small number of the MAC which are naturally resistant, its high degree of tissue and intracellular penetration and its long half-life that allows a single daily dose. Clinical tests on more than 1,000 patients have shown the benefit of Ansatipine in the prophylactic treatment of MAC infections: reduction by half on the frequency of surveillance, prolongation of the delay in appearance, significant improvement in general condition and quality of life of the patients. Ansatipine is now dispensed to town pharmacies, which can only ease the daily lives of patients and reinforce the co-operation between hospital teams and general practitioners who specialize in the care of AIDS.

AIDS-Related Opportunistic Infections↗
PubMed1991

Selectivity of juxtaposition between cup-shaped lactotrophs and gonadotrophs from rat anterior pituitary in culture.

Semi-thin sections of three-dimensional reaggregates from adult female rat pituitary, cultured in serum-free defined medium, were stained for prolactin, gonadotropin, thyrotropin, growth hormone and S-100, using the double immunolabelling technique. The frequency of juxtaposition between lactotrophs and gonadotrophs was enumerated and compared with the expected frequency at random distribution of polygonal cell profiles in a hexagonal configuration. The proportions of lactotrophs and gonadotrophs in the aggregate sections were determined using stereometrical analysis. The observed frequency of juxtaposition did not differ significantly from the expected frequency. Hence, no reason was found to assume a selective adhesion between lactotrophs and gonadotrophs in adult female rat pituitary reaggregates. A constant proportion of lactotrophs was found to meet the criteria of a cup-shaped morphology, and 70% +/- 9% (mean +/- S.D.) of these so-called cup-shaped lactotrophs were found to be juxtaposed at their concave side to gonadotrophs. Administration of 0.01 nM 17 beta-oestradiol to the culture medium resulted in a significant reduction of the proportion of cup-shaped lactotrophs but did not affect the selectivity of juxtaposition to gonadotrophs. The selectivity of juxtaposition between cup-shaped lactotrophs and gonadotrophs may be the morphological correlate of the functional relationship between these cells, which are known to be involved in an intra-pituitary paracrine communication system.

Animals↗
PubMed1991

Rifabutin in combination with clofazimine, isoniazid and ethambutol in the treatment of AIDS patients with infections due to opportunist mycobacteria. Groupe d'Etude et de Traitement des Infections à Mycobacteries Résistantes.

96 AIDS patients with fever and either acid-fast bacilli on microscopic examination of bacteriological samples or mycobacteria isolated by culture were treated with a daily 4-drug combination of 7-10 mg/kg rifabutin, 5 mg/kg isoniazid, 20 mg/kg ethambutol and 100 mg clofazimine. 46 patients were excluded from efficacy assessment: 13 died before or within the first days of treatment, 5 had negative initial cultures, 14 had initial cultures positive for M. tuberculosis, 4 for M. kansasii, 1 for M. flavescens, 1 for M. gordonae, 7 were lost to follow-up and 1 received no rifabutin. In the 50 remaining patients, 31 had disseminated disease due to M. avium intracellulare complex (MAIC) and 19 had apparently localised disease, due to MAIC in 15 cases and to M. xenopi in 4 cases. Side-effects led to withdrawal of isoniazid in 1 case (hepatic enzymes increased) and rifabutin in another (thrombocytopenia). After 1 month of treatment, fever decreased from 38.4 +/- 0.6 degrees C to 37.7 +/- 0.5 degrees C (p less than 0.01) and patients stopped losing weight. After 3 months treatment, only 37 patients were alive and still under treatment. Cultures became negative in 16 of 23 patients with available bacteriological data (9 of 14 patients with disseminated disease and 7 of 9 patients with localised disease), relapse occurred before death in 4 patients. 34 patients died before treatment was completed. Death was considered to be related to mycobacterial infection in 5 cases. We conclude that the 4-drug combination is safe and, in some cases, it appears to be effective.

Acquired Immunodeficiency Syndrome↗
PubMedDate not supplied

[Diffuse interstitial pulmonary amyloidosis (author's transl)].

A 56-year-old woman developed diffuse interstitial pulmonary amyloidosis and died two years after the onset of dyspneic symptoms. Lung biopsy confirmed the amyloid nature of the reticulonodular lesions, which were at the origin of the mixed restrictive and obstructive ventilatory deficiency. Investigations showed an obvious hypogamma globulinemia but the etiology of the affection remained unknown. Pathological examination revealed massive infiltration of amyloid material in the lungs, no involvement of the heart, what was unexpected, and minimal deposits in the mediastinal lymph nodes kidneys, and spleen. An immunofluorescence study of the pulmonary amyloid deposits was performed. The authors emphasize the rarity of such diffuse interstitial pulmonary amyloid lesions which differ greatly from nodular amyloidosis and upper respiratory tract amyloid infections.

Amyloid↗