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Biomedical subjects

M Dumont

Publications and source records attributed to M Dumont.

At least 73 records · Page 4Linked to original sources
PubMed1996

Defect of multidrug-resistance 3 gene expression in a subtype of progressive familial intrahepatic cholestasis.

Disruption of the murine mdr2 (multidrug-resistance) gene, which encodes a phosphatidylcholine flippase, leads to a hepatic disorder because of loss of biliary phospholipid secretion. Among the hereditary human cholestasis, a subtype of progressive familial intrahepatic cholestasis with high gamma-glutamyltranspeptidase (GGT) serum activity shares histological, biochemical, and genetic features with mice lacking mdr2 gene expression (mdr2 -/- mice). No MDR3 (human mdr2 homolog) messenger RNA (mRNA) was detected by Northern blotting in the liver of a patient suffering from this form of PFIC, and the biliary phospholipid level in a second patient was substantially decreased. Thus, the absence of the MDR3 P-glycoprotein may be responsible for this type of PFIC, which, as in the murine model, may be due to a toxic effect of bile acids on the biliary epithelium in absence of biliary phospholipids.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed1996

Interactions of dynorphin A and related peptides with cardiac ouabain binding sites.

The effect of dynorphin A (Dyn A) and related peptides on the binding of [3H]ouabain was examined in rat cardiac sarcolemma. Scatchard analysis of [3H]ouabain binding revealed the existence of two distinct sites: a high affinity (Kd: 20.4 nM) low capacity (Bmax: 1.55 pmol/mg protein) site and a low affinity (Kd: 3695 nM) high capacity (Bmax: 39.3 pmol/mg protein) site. Dyn A-(1-13) (10 microM) interacted selectively with the low affinity [3H]ouabain binding site causing a significant decrease in the Bmax (from 39.3 to 22.2 pmol/mg protein) without altering the Kd. Dyn A-(1-13) inhibited the binding of [3H]ouabain (500 nM) with an IC50 of 2.9 microM and a maximal inhibition of 77% of the specific binding activity. The non-opioid fragments Dyn A-(2-13), Dyn A-(3-13) and Dyn A-(6-10) displayed 36%, 32% and 14% of the potency of Dyn A-(1-13) respectively; whereas 100 microM of Dyn A-(1-8), Leu-enkephalin (Leu-Enk) and selective ligands for kappa (U-50, 488H) mu [(D-Ala2-Me-Phe4.Glyol5]Enk) and delta [(D-Ser2.Thr6]Leu-Enk) opioid receptors caused little or no inhibition of [3H]ouabain binding. The relative potency of various analogs and fragments of Dyn A in inhibiting the binding of [3H]ouabain correlated well (r = 0.89-0.90) with their potency in inhibiting the binding of [3H]Dyn A-(1-13) to non-opioid Dyn sites (Dumont and Lemaire, 1996) and to block [3H]NA uptake by cardiac synaptosomes (Dumont and Lemaire, 1995). In spontaneously hypertensive rats. [3H]ouabain binding displayed a 3.8-fold enhanced sensitivity to the action of Dyn A-(1-13) an effect that correlated with the enhanced ability of the peptide to inhibit Na+/K+-ATPase and [3H]NA uptake. The results indicate that Dyn A and related peptides may modulate cardiac functions through a non-opioid interaction with the low affinity ouabain binding site.

Animals↗
PubMed1996

The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds.

Breast carcinoma is the most common malignancy among women in developed countries. Because family history remains the strongest single predictor of breast cancer risk, attention has focused on the role of highly penetrant, dominantly inherited genes in cancer-prone kindreds (1). BRCA1 was localized to chromosome 17 through analysis of a set of high-risk kindreds (2), and then identified four years later by a positional cloning strategy (3). BRCA2 was mapped to chromosomal 13q at about the same time (4). Just fifteen months later, Wooster et al. (5) reported a partial BRCA2 sequence and six mutations predicted to cause truncation of the BRCA2 protein. While these findings provide strong evidence that the identified gene corresponds to BRCA2, only two thirds of the coding sequence and 8 out of 27 exons were isolated and screened; consequently, several questions remained unanswered regarding the nature of BRCA2 and the frequency of mutations in 13q-linked families. We have now determined the complete coding sequence and exonic structure of BRCA2 (GenBank accession #U43746), and examined its pattern of expression. Here, we provide sequences for a set of PCR primers sufficient to screen the entire coding sequence of BRCA2 using genomic DNA. We also report a mutational analysis of BRCA2 in families selected on the basis of linkage analysis and/or the presence of one or more cases of male breast cancer. Together with the specific mutations described previously, our data provide preliminary insight into the BRCA2 mutation profile.

BRCA2 Protein↗
PubMed1996

Retrograde injections of formaldehyde into the biliary tree induce alterations of biliary epithelial function in rats.

Formaldehyde may induce severe lesions of intrahepatic and extrahepatic bile ducts. The purpose of this study was to examine in vivo the functional consequences of an alteration of the biliary epithelium induced by a retrograde intrabiliary injection of formaldehyde in rats. After basal bile collection, a 10% formaldehyde solution was injected into the biliary tree of anesthetized rats, and the cannula was occluded for 30 minutes. Choleresis was then reestablished, and bile flow, bile acid, and bicarbonate secretion were measured both spontaneously and during ursodeoxycholate infusions. Formaldehyde injections induced a significant increase in bile flow and a marked inhibition of ursodeoxycholate-induced increase in biliary bicarbonate concentration and secretion. Biliary glucose secretion, which is normally very low, was increased about 20-fold in animals injected with formaldehyde. Histological and ultrastructural examination of the liver showed alterations of biliary epithelial cells, whereas hepatocytes, bile canaliculi, and canalicular tight junctions remained normal. Hepatocytic excretory function, as assessed by biliary secretion of bile acids, was not affected. It was concluded that short-term formaldehyde intrabiliary injections cause an inhibition of ursodeoxycholate-induced hypersecretion of bicarbonate, an increase in biliary glucose secretion, and selective structural alterations of biliary epithelial cells. These results suggest that formaldehyde retrograde biliary injection may be a useful model to study alterations of biliary epithelial function in vivo.

Animals↗
PubMed1996

Effect of diethylmaleate on bile secretion and ultrastructural appearance of hepatocytes in normal rats and mutant rats with defective organic anion secretion.

Diethylmaleate is an organic anion secreted into bile as a glutathione conjugate. Its transport by the hepatocyte is associated with dilatation of the Golgi apparatus and the appearance of small vesicles in the pericanalicular area. It has been speculated that the Golgi apparatus could play a role in the intracellular transport and/or the biliary canalicular secretion of diethylmaleate. The purpose of this work was to determine whether the alterations in the Golgi apparatus and the pericanalicular vesicles could mediate the canalicular secretion of diethylmaleate. Diethylmaleate biliary secretion and diethylmaleate-induced bile flow were measured in Sprague-Dawley rats, and in TR- rats which have an inherited defect in the excretion into bile of organic anions, including glutathione conjugates. Livers of both Sprague-Dawley and TR-rats were examined by electron microscopy, to characterize the changes in intracellular organelles. In Sprague-Dawley rats, as previously described, diethylmaleate administration was associated with an increase in bile flow, which was parallel in time to the secretion into bile of diethylmaleate conjugates. Electron microscopic examination of the liver after diethylmaleate administration showed dilatation of the Golgi saccules. In contrast, in TR- rats, the increase in bile flow and the secretion of diethylmaleate conjugated were nearly absent. Nevertheless, electron microscopic examination showed a dilatation of the Golgi saccules similar to that observed in Sprague-Dawley rats. TR- rats, in addition to the changes in the Golgi apparatus, had marked dilatation of the endoplasmic reticulum. These results show that biliary secretion of diethylmaleate conjugates was severely impaired in TR- rats, in spite of a dilatation of the Golgi apparatus and of the endoplasmic reticulum. We conclude that it is unlikely that the alterations in the Golgi apparatus (and the endoplasmic reticulum) induced by diethylmaleate play a role in the canalicular secretion of diethylmaleate. We do not exclude the possibility that these organelles could play a role in intracellular transport of this compound. Alternatively, these alterations could be due to a "toxic" effect of diethylmaleate accumulation in hepatocytes.

Animals↗
PubMed1996

Prospective evaluation of endoscopic ultrasonography and microscopic examination of duodenal bile in the diagnosis of cholecystolithiasis in 45 patients with normal conventional ultrasonography.

The aim of this study was to prospectively evaluate endoscopic ultrasonography and microscopic examination of duodenal bile in the diagnosis of cholecystolithiasis not detected by conventional ultrasonography. Forty five consecutive patients (26 females, 19 males, mean age: 50 years) with suspected cholecystolithiasis and at least two normal transcutaneous ultrasonography examinations were included. Endoscopic ultrasonographic criteria for the diagnosis of cholecystolithiasis were the presence of stones with or without acoustic shadowing or sludge. Criteria of microscopic examination of bile were cholesterol or bilirubinate crystals or spheroliths. Thirty three patients underwent cholecystectomy and lithiasis was found in gall bladder bile in 24. Twelve patients who were not operated on and were followed up (median: 17 months), had no evidence of cholecystolithiasis. Endoscopic ultrasonography and duodenal bile examination were 96% and 67% sensitive, respectively (p < 0.03). The specificity was not different (86 and 91%, respectively). None of the 16 patients with negative results in both procedures had evidence of cholecystolithiasis. It was found that for the diagnosis of cholecystolithiasis in patients with normal conventional ultrasonography, the sensitivity of endoscopic ultrasonography is higher than that of microscopic examination of duodenal bile. If endoscopic ultrasonography and microscopic examination of duodenal bile are negative, the risk of underdiagnosing cholecystolithiasis is negligible.

Adult↗
PubMed1995

Histogranin, a modified histone H4 fragment endowed with N-methyl-D-aspartate antagonist and immunostimulatory activities.

Histogranin is a naturally-occurring pentadecapeptide with a structure 80% homologous with that a fragment-(86-100) of histone H4. First isolated from bovine adrenal medulla, the peptide was also shown to be present in the pituitary, brain, adrenal glands, blood plasma, lungs and spleen. At the subcellular level, histogranin is concentrated in secretory vesicles and it is released from perfused bovine adrenal glands 15-35 min after stimulation with carbamylcholine as opposed to catecholamines and [Leu5]enkephalin which are released immediately after stimulation. Rat brain membranes possess specific binding sites for [125I][Ser1]histogranin with characteristics of a receptor, namely high affinity, saturability, reversibility and sensitivity to heat and proteolytic enzyme treatments. Intracerebroventricular injections of synthetic histogranin (10-100 nmol) in mice protect them against N-methyl-D-aspartate (NMDA)-induced convulsions without affecting convulsions induced by (R,S)-alpha-amino-3-hydroxy -5-methyl-4-isoxazole-propionate (AMPA), kainate and bicuculline. The peptide also binds to specific sites on human peripheral blood mononuclear cells and it evokes the release of tumor necrosis factor-alpha (TNF), interleukin-1 (IL-1) and interleukin-6 (IL-6) from isolated rat macrophages in culture. Since the structure of histone H4 is considered as one of the most conservative, it is presumed that histogranin possesses its own precursor and that its gene is distinctly expressed.

Adjuvants, Immunologic↗
PubMed1995

Cytogenetic analysis of uncleaved oocytes after intracytoplasmic sperm injection.

PURPOSE: This work analyzes the causes of cleavage failure after intracytoplasmic sperm injection (ICSI) and the effect of the procedure on the chromosomes of the oocytes. METHODS: Ninety-seven uncleaved oocytes from 39 patients with severe male infertility or repeated IVF failure were fixed; 79 were analyzable. We checked the decondensation stage of spermatozoa nucleus and the chromosomal abnormalities of the oocytes. RESULTS: Among the fixed oocytes, the spermatozoa nucleus was present in 97% of the cases, and it was undecondensed in 89% of the cases, showing no evolution at all. A low rate (2.6%) of premature chromosome condensation (PCC) of the spermatozoa and a low rate (2.5%) of female diploïdy were observed. Among the oocytes that could be karyotyped, we observed a high rate (45%) of chromosome breakage. CONCLUSION: ICSI fertilization failure was due mostly to the complete lack of evolution of the spermatozoa nucleus. Oocyte selection before ICSI seemed to lower the PCC rate. The high rate of oocyte chromosomal breakage rate has to be confirmed.

Chromosome Aberrations↗
PubMed1995

N-methyl-D-aspartate receptor antagonist activity and phencyclidine-like behavioral effects of the pentadecapeptide, [Ser1]histogranin.

The behavioral and pharmacologic profiles of [Ser1]histogranin ([Ser1]HN) were assessed by monitoring its ability to displace the binding of the specific N-methyl-D-aspartate (NMDA) receptor ligand, [3H]CGP 39653, to block the convulsant effects of NMDA and other excitatory agents in mice, and to produce phencyclidine (PCP)-like behavioral effects in rats. The peptide potently inhibited [3H]CGP 39653 binding to membrane preparations of rat brain with an IC50 of 198 nM and a maximal inhibition of 34% of the specific binding activity. Saturation binding experiments with [3H]CGP 39653 in the absence and presence of [Ser1]HN (2 microM) indicated that the inhibitory effect of the peptide was noncompetititive, producing a decrease in the maximal number of binding sites (Bmax of 62.5 fmol/mg protein as compared with 91.3 fmol/mg protein in control), but no significant change in the affinity (Kd of 4.5 nM as compared with 5.1 nM in control). Intracerebroventricular (ICV) injection of [Ser1]HN (10-100 nmol) in mice evoked a dose-dependent and selective blockade of NMDA-induced convulsions. In rats, [Ser1]HN (2.5-100 nmol, ICV) produced dose-dependent stereotypy, ataxia, and locomotion similar to those observed with PCP, at doses ranging between 50 and 400 nmol. The data indicate that [Ser1]HN noncompetitively interacts with the NMDA receptor, an action that goes along with its in vivo NMDA receptor antagonist activity and PCP-like behavioral effects.

2-Amino-5-phosphonovalerate↗
PubMed1995

Inhibitory effects of dynorphin-A on norepinephrine uptake by cardiac synaptosomal-mitochondrial fractions.

The effect of dynorphin A-(1-13) (Dyn A-(1-13)) on [3H]norepinephrine ([3H]NE) uptake was examined in cardiac synaptosomal-mitochondrial fractions of control rats (Wistar, WR; Wistar-Kyoto, WKY) and spontaneously hypertensive rats (SHR). In adult WR, Dyn A-(1-13) caused naloxone-insensitive dose-dependent inhibition of [3H]NE uptake with an IC50 of 4.0 microM. The nonopioid Dyn A fragments Dyn A-(2-13) and Dyn A-(6-10) displayed 89 and 11% of the potency of Dyn A-(1-13), respectively, whereas Dyn A-(1-8), Leu-enkephalin, and the selective opioid agonists [D-Ala2, N-MePhe4, Glyol5]enkephalin (DAGO, mu), [D-Ser2, Thr6]Leu-enkephalin (DSLET, delta), and U-50488H (kappa) were inactive. The relative potency of various analogues and fragments of Dyn A in inhibiting [3H]NE uptake correlated well (r = 0.96) with their potency in inhibiting binding of [3H]Dyn A-(1-13) to nonopioid sites on cardiac membrane preparations. Dyn A-(1-13) showed the same potency in inhibiting [3H]NE uptake in prehypertensive (4-week-old) SHR as in age-matched WR and WKY. However, at ages 8 and 16 weeks Dyn A-(1-13) was twice as potent in SHR as in WR and WKY. The increased inhibitory potency of Dyn A-(1-13) in 8-week-old SHR was accompanied by a 1.3-fold increase in number of cardiac nonopioid [3H]Dyn A-(1-13) binding sites. Dyn A and related peptides inhibit [3H]NE uptake by cardiac synaptosomes by a nonopioid mechanism. The possible involvement of such a mechanism in development of hypertension in SHR is discussed.

Animals↗
PubMed1995

A 20-h recovery sleep after prolonged sleep restriction: some effects of competing in a world record-setting cinemarathon.

The recovery sleep of a 21-year-old normal woman was assessed after she had endured 11(1/2) days of sleep restriction in a world record-setting film-viewing marathon. An exceptional sleep debt was observed as indicated by an instanteous sleep onset, a high sleep efficiency, and a total sleep duration of over 20 hours. Other striking features of this recovery sleep were very short latencies to stages 3 and 4 sleep, return of Stage 4 sleep after 14.5 h, REM and SWS sleep rebound, and a linear increase in REM sleep efficiency across 14 consecutive REM-NREM episodes. Seven of nine home dreams reported after this recording contained competition themes, but none relating to the marathon films. Comparisons of the present results with those from subjects in previous record-setting events suggest possible explanations for the extremely long recovery sleep. Results also suggest that analyses of multiple consecutive sleep cycles may provide novel ways of assessing hypotheses about regulation of the REM-NREM cycle.

Journal Article↗
PubMed1995

Sleep propensity and sleep architecture after bright light exposure at three different times of day.

The aim of this work was to study the effects of bright light-induced circadian phase shifts on sleep propensity and sleep architecture while the timing of the sleep/wake cycle is kept constant. Twenty-three normal subjects underwent an 11-day study including: (i) baseline sleep and vigilance evaluation; (ii) baseline evaluation of the circadian temperature rhythm with a 40-h constant routine; (iii) five hours of bright light exposure on each of three days; (iv) post-treatment sleep and vigilance evaluation; (v) post-treatment circadian rhythm evaluation with a second 40-h constant routine. Subjects were divided into three groups: eight subjects were exposed to bright light in the morning ('Morning group'), eight subjects were exposed in the evening ('Evening group'), and seven subjects were exposed in the afternoon ('Afternoon group'). After light exposure, the Morning group showed an advance of 1.23 h in the phase of the temperature rhythm, the Evening group showed a delay of 1.62 h, and the Afternoon group showed a non-significant advance of 0.5 h. In support of expectations, early-night sleep propensity was decreased by evening bright light, was increased in almost all subjects exposed to morning bright light, and was not changed by afternoon bright light exposure. The phase shift created by bright light exposure did not seem to be large enough to have a systematic effect on sleep consolidation or on REM sleep parameters in any of the three groups, suggesting that these variables are less sensitive to alterations in phase of the circadian oscillator than early-night sleep propensity.

Journal Article↗
PubMed1994

Dynorphin potentiation of [3H]CGP-39653 binding to rat brain membranes.

Dynorphin A-(1-13) and related peptide fragments were tested for their ability to modulate the binding of the competitive NMDA receptor antagonist, [3H]2-amino-4-propyl-5-phosphono-3-pentanoic acid ([3H]CGP-39653), to rat brain membranes. Dynorphin A-(1-13) produced a dose-dependent (1 nM to 10 microM) potentiation of [3H]CGP-39653 binding. The potentiation was insensitive to the kappa-opioid receptor antagonist norbinaltorphimine and it was also observed with the non-opioid peptides dynorphin A-(2-13) and dynorphin A-(6-10). Among various compounds which interact with distinct sites on the NMDA receptor complex, glycine (Gly; 1 microM) and the Gly receptor antagonist, (+/-)-3-amino-1-hydroxy-2-pyrrolidone ((+/-)-HA-966; 10 microM), blocked the dynorphin A-(1-13) induced potentiation of [3H]CGP-39653 binding. In equilibrium binding experiments, dynorphin A-(1-13) (10 microM) caused a significant increase in the binding capacity (Bmax) of [3H]CGP-39653 (from 111 to 306 fmol/mg protein) but not change in the apparent dissociation constant (Kd of 8.5 nM as compared with 8.7 nM in the absence of the peptide). The results indicate that dynorphin A and related peptides modify the expression of [3H]CGP-39653 binding sites consecutive to a non-opioid interaction with the NMDA receptor complex.

2-Amino-5-phosphonovalerate↗
PubMed1994

Interaction of histogranin and related peptides with [3H]dextromethorphan binding sites in rat brain.

Histogranin (HN) and related peptides were tested for their ability to modulate the binding of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, [3H]dextromethorphan ([3H]DM), to rat brain membranes. HN, [Ser1]HN and the C-terminal fragment HN-(6-15) (0.1 nM-1 microM) potentiated (up to 1.6-fold) the binding of [3H]DM (5 nM) whereas the N-terminal fragment HN-(1-10) had no effect. The potentiation of [3H]DM binding by [Ser1]HN was blocked by NMDA (100 microM) and the NMDA receptor antagonist, CPP (1 microM) but not by the sigma (sigma) receptor ligand, (+)-pentazocine (0.1 microM) and the phencyclidine (PCP) receptor ligand, TCP (1 microM). Equilibrium binding experiments in presence of TCP (1 microM) to block PCP receptors indicated that [Ser1]HN (1 microM) causes a significant increase in the binding capacity (Bmax) of [3H]DM (from 2.46 to 3.46 pmol/mg protein) but no change in the apparent dissociation constant (Kd of 428 nM as compared with 487 nM). The results indicate that HN and related peptides specifically enhance the number of [3H]DM binding sites associated to the NMDA receptor complex.

Animals↗
PubMed1994

Expression of intron-encoded maturase-like polypeptides in potato chloroplasts.

The trnK gene has been identified on a cloned plastid DNA fragment of potato (Solanum tuberosum cv Désirée). This gene codes for a tRNA-Lys and is interrupted by a 2.5-kb intron belonging to the group II organellar introns. In addition, this intervening sequence contains a long open reading frame potentially coding for a 509 amino-acid polypeptide (ORF509) related to mitochondrial intron-encoded maturases from fungi. The translational capacity of the trnK intron was first demonstrated in vitro in a prokaryotic DNA-directed expression system. In order to examine the expression of the intron in the potato plant, a synthetic peptide corresponding to the last nine amino acids of the predicted ORF509 product was used to raise antibodies. Western-blot experiments on chloroplast protein extracts, using a sensitive chemiluminescent detection system, identified polypeptides similar to in-vitro products. These results suggest that the trnK intron is expressed at the protein level in the plant. This is the first report of the in-vivo expression of an intron-encoded polypeptide in higher plant plastids.

Amino Acid Sequence↗