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Biomedical subjects

G Tanguy

Publications and source records attributed to G Tanguy.

At least 19 recordsLinked to original sources
PubMed2005

[Leber congenital amaurosis: comprehensive survey of genetic heterogeneity. A clinical definition update].

Leber congenital amaurosis (LCA) is the earliest and most severe form of all inherited retinal dystrophies, responsible for congenital blindness. Disease-associated mutations have been hitherto reported in seven genes. These genes are all expressed preferentially in the photoreceptor cells or the retinal pigment epithelium, but they are involved in strikingly different physiologic pathways, resulting in an unforeseeable pathophysiologic variety. This broad genetic and physiologic heterogeneity, which could greatly increase in the coming years, hinders molecular diagnosis in LCA patients. Genotyping is, however, required to establish genetically defined subgroups of patients ready for therapy. Here we report a comprehensive mutational analysis of all the known genes in 179 unrelated LCA patients, including 52 familial and 127 sporadic (27/127 consanguineous) cases. Mutations were identified in 47.5% of patients. GUCY2D accounted for by far the largest part of the LCA cases in our series (21.2%), followed by CRB1 (10%), RPE65 (6.1%), RPGRIP1 (4.5%), AIPL1 (3.4%), TULP1 (1.7%) and CRX (0.6%). The clinical history of all patients with mutations was carefully revisited in the search for phenotype variations. Genotype-phenotype correlations were found that made it possible to divide patients into two main groups. The first one includes patients whose symptoms fit the traditional definition of LCA, i.e., congenital or very early cone-rod dystrophy, while the second group gathers patients affected with severe yet progressive rod-cone dystrophy. In addition, objective ophthalmologic data subdivided each group into two subtypes. Based on these findings, we have drawn decisional flowcharts directing the molecular analysis of LCA genes in a given case. These flowcharts will hopefully lighten the onerous task of genotyping new patients, but only if the most precise clinical history since birth is available.

Animals↗
PubMed2001

Is up-regulation of phosphodiesterase 4 activity by PGE2 involved in the desensitization of beta-mimetics in late pregnancy human myometrium?

Elevation of cAMP content resulting from stimulation of the receptor-adenylyl cyclase complex is involved in maintaining the quiescence of the human myometrium during pregnancy. The magnitude of this elevation is critically influenced by the rate of cAMP hydrolysis by phosphodiesterase (PDE) isoenzymes. In the present study we report that in term myometrium, enhanced cAMP-specific PDE4 activity takes part in the heterologous desensitization to the beta-mimetic, salbutamol. Indeed, pretreatment with a PDE4-selective inhibitor potentiates the relaxant effect of salbutamol on myometrial strips of women at term. Furthermore, the reduced relaxant effect of salbutamol after long-term treatment of myometrial strips with PGE2, a potent myometrial effector, can be reversed by PDE4 inhibition. Using a model of cultured myometrial cells, we also demonstrated that PGE2 is able to up-regulate PDE4 activity, at least through the induction of synthesis of PDE4B and PDE4D short forms, which, in turn, dampen the cAMP accumulation provoked by the stimulation of adenylyl cyclase. Such data suggest that in late pregnancy endogenous PGE2 might up-regulate PDE4 activity and lessen the responsiveness of myometrium to beta-mimetic activation. Accordingly, coapplication of a selective PDE4 inhibitor might greatly improve the usefulness of beta-mimetic in tocolysis.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2001

Total and structured water in cancer: an NMR experimental study of serum and tissues in DMBA-induced OF1 mice.

Total water and structured water (fraction of total water which remains unfrozen below the transition point from the semisolid to solid state) were characterized by 1H NMR relaxometry in the sera and tissues of 3 groups of 30 female mice (C, H and L) receiving a single administration of DMBA and different diets. Mice given the diet H, containing the highest proportion of saturated fatty acids and processed starch, and the lowest phytochemicals content, presented the highest tumor incidence (lymphoma). This allowed 3 subgroups to be defined: subnormal (SN), small (T+) and large tumor (T++). Spin-lattice relaxation times of total water (Tlobs) in the sera and tissues did not significantly differ between C, H and L groups, and SN, T+ and T++ subgroups. In T+ mice, a decrease in the relative amount of structured water was noticed in the serum, liver and heart, while changes in the temperature dependence of the Tl of structured water (Tlsw) were observed between -21 degrees C and -42 degrees C. These results suggest a moderate increase in the rotational mobility of structured water molecules in the serum and the heart, and a pronounced decrease in the liver. Likewise, the modification of the Tlsvv temperature dependence curve's shape tends to confirm the existence of important conformational changes in the macromolecular assemblies, which markedly affect the properties of structured water, especially in the earliest stage of cancer development.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2000

Pregnancy induces a modulation of the cAMP phosphodiesterase 4-conformers ratio in human myometrium: consequences for the utero-relaxant effect of PDE4-selective inhibitors.

The inhibitory impacts of RP 73401, a phosphodiesterase type 4 (PDE4) selective inhibitor of the second generation, versus rolipram, the prototypal PDE4 inhibitor, were evaluated and compared on cAMP phosphodiesterase (PDE) activity and contractility of the myometrium in nonpregnant and pregnant women. In enzymatic studies, RP 73401 and rolipram inhibited the cAMP PDE activity with significantly greater maximal efficiency in the myometrium of pregnant compared with nonpregnant women (75 versus 55%; P <.05). Although myometrial PDE4 presented a single class of interaction with RP 73401 [pD(2) (-log [IC(50)]) = -8.2], it exhibited at least two classes of interaction with rolipram (pD(2) = -8.2 and -5.6). In the myometrium of pregnant versus nonpregnant women, rolipram is significantly more efficacious in the concentration range >0.01 to 100 microM (P <.01), whereas no difference was observed for the concentration range <0.01 microM. In contractility studies, RP 73401 was equally effective in relaxing myometrial strips from both nonpregnant and pregnant women (pD(2) = -8.8). Conversely, the ability of rolipram to inhibit contractions of the myometrium in pregnant women was significantly lower (pD(2) = -7.2) compared with that in nonpregnant women (pD(2) = -8.2; P <.01). Concomitantly, in the myometrium of pregnant women, a rise in immunoreactive PDE4B2 signal was detected, whereas the PDE4D3 signal was less intense. These results demonstrate that parallel to an accumulation of PDE4B2 isoform, a modification in the ratio of PDE4 conformers HPDE4 and LPDE4 (conformer that binds rolipram with high and low affinity, respectively) occurs in the myometrium of near-term pregnant women with an increase of LPDE4 functionally implicated in the contractile process. Such modifications provide a strong rationale to propose LPDE4 as potential pharmacologic targets for the design of new tocolytic treatments.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1999

Synthesis of Iron Oxide Nanoparticles Used as MRI Contrast Agents: A Parametric Study.

Colloidal iron oxides play an important role as magnetic resonance imaging (MRI) contrast agents. The superparamagnetic particles actually used are constituted by solid cores (diameter of 5-15 nm), generally coated by a thick polysaccharidic layer (hydrodynamic radii of 30-100 nm), and formulated by direct coprecipitation of iron salts in the presence of polymeric material. To better control the synthesis, we attempted to formulate new stable uncoated superparamagnetic nanoparticles. Colloids were generated by coprecipitation of an aqueous solution of iron salts and tetramethylammonium hydroxide (TMAOH) solution. The influence of parameters such as media composition, iron media, injection fluxes, Fe and TMAOH concentrations, temperature, and oxygen on size, magnetic and magnetic resonance relaxometric properties, and colloidal stability of particles were evaluated. We have determined the relative importance of these parameters as well as the optimal conditions for obtaining uncoated stable particles with an average size of 5 nm and interesting relaxivities. The interpretation of the observed limits takes into account diffusibilities of reactants and product, feeding rates of reactants, and surface properties of nanoparticles. A model of synthesis, related to spontaneous emulsification of suspensions, is proposed. Copyright 1999 Academic Press.

Journal Article↗
PubMed1999

Phosphorylcholine Coating of Iron Oxide Nanoparticles.

In order to develop thin-walled superparamagnetic nanoparticle suspensions as a contrast agent for magnetic resonance imaging, phosphorylcholine PC was used to coat iron oxide cores of 5 nm. Weak stable positively charged suspensions can be obtained at concentration greater than 3 mmol.l-1 (corresponding to about 3.2 molecules per nm2), while the addition of phosphorylglycerol PG decreases the electrophoretic mobility. Raising the pH over 6 leads to flocculation: the binding of PC on iron oxides as a function of pH appears to be reversible. By Langmuir analysis, two adsorption domains may be observed with a maximal density of 3.48 and 6.55 mol.nm-2, interpreted as a multilayer formation. Copyright 1999 Academic Press.

Journal Article↗
PubMed1999

Effect of pregnancy on PDE4 cAMP-specific phosphodiesterase messenger ribonucleic acid expression in human myometrium.

In light of the important role of the second messengers cAMP and cGMP in the mechanism of relaxation in the human myometrium, specific regulation of the phosphodiesterase (PDE) enzymatic system responsible for cyclic nucleotide inactivation is essential. We previously identified in the human myometrium PDE4 cAMP-specific PDE as by far the most abundant isoform. Here we have studied the expression patterns of mRNAs for the four cloned human PDE4 genes in the myometria of pregnant and non-pregnant women. Concurrent expression of the PDE4A, 4B, 4C and 4D genes is demonstrated. We found that the PDE4D transcripts are the most prominently expressed. PDE4A and PDE4B mRNAs also are markedly abundant, whereas lower expression is observed for PDE4C mRNAs. Interestingly, we showed that transcripts of PDE4B2 are more abundant in the myometria of pregnant women than in non-pregnant women, whereas no difference between the two tissues was detected for PDE4A, 4C and 4D mRNAs. Cultured human myometrial cells, which present a high level of PDE4 activity and express the four PDE4 mRNA subtypes, provide us with an appropriate model to further evaluate whether the level of expression of the PDE 4B2 mRNA subtype is under hormonal regulation.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1999

Identification and expression of Go1 and Go2 alpha-subunit transcripts in human myometrium in relation to pregnancy.

The 39-kDa Goalpha protein, the alpha subunit of a major heterotrimeric G protein of brain and neuroendocrine cells, was found to be present in human myometrium. Using three different antisera, we showed its strong expression in myometrium from pregnant patients as compared to nonpregnant ones. This is in agreement with the high expression level of its two isoforms (alphao1 and alphao2), previously described in late pregnancy. To better ascertain the nature of these immunoreactive isoforms, we investigated transcripts of the Goalpha gene in myometrium from pregnant and nonpregnant patients by reverse transcription-polymerase chain reaction (RT-PCR). In this tissue, the amplified cDNA product of a region common to both Go1alpha and Go2alpha mRNA variants was recognized as the Goalpha nucleotide sequence. Transcripts of Go1alpha and Go2alpha were identified by sequencing. A partial cDNA Go2alpha sequence was described, which differed from the Goalpha gene by two nucleotides in exon 8B. Levels of Go1alpha and Go2alpha transcripts analyzed by semi-quantitative RT-PCR were significantly higher in myometrium from pregnant than from nonpregnant patients. It is suggested that Goalpha gene expression in this tissue may contribute to modifications seen in the signaling pathways observed at the end of pregnancy.

Amino Acid Sequence↗
PubMed1999

Selective up-regulation of phosphodiesterase-4 cyclic adenosine 3',5'-monophosphate (cAMP)-specific phosphodiesterase variants by elevated cAMP content in human myometrial cells in culture.

In human myometrium, the modulation of intracellular cAMP content resulting from agonist-mediated stimulation of the receptor-adenylyl cyclase complex is largely influenced by the rate of cAMP hydrolysis by phosphodiesterase (PDE) isoenzymes. We have previously shown that the PDE4 family contributes to the predominant cAMP-hydrolyzing activity in human myometrium and that elevation of the PDE4B2 messenger RNA steady state level occurs in pregnant myometrial tissue. In the present study, we used a model of human myometrial cells in culture to determine whether an elevated cAMP concentration could influence PDE expression. As in myometrial tissue, high levels of PDE4 activity were detected in these smooth muscle cells. Long term treatment with 8-bromo-cAMP or forskolin resulted in a selective induction of PDE4B and of PDE4D short form messenger RNA variants. Concurrently, an increased immunoreactive signal for the PDE4B- and PDE4D-related isoenzymes was detected. This induction was consistent with an observed significant up-regulation of PDE4 activity. Accordingly, our results demonstrate that in human cultured myometrial cells, cAMP-elevating agents manipulate PDE4 activity through selective induction of synthesis of PDE4B and PDE4D short forms. Such a mechanism might have physiological importance during pregnancy by dampening hormonal stimulation and could thereby be involved in tolerance to the tocolytic effect of beta-adrenoceptor agonists.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1999

[Measurement of the quality of life in chronic hepatitis C: validation of a general index and specific index. First French results].

OBJECTIVES: To report the validation of 2 questionnaires of quality of life in chronic hepatitis C and the first results in 100 patients. METHODS: The questionnaire included 118 items and took 30 to 45 minutes to answer. It included a general index, the Nottingham Health Profile, with 38 items in 6 themes (physical mobility, social isolation, emotional reactions, pain, sleep and energy) and a specific index, the Montpellier Specific Index, with 80 items in 7 themes: symptoms, food, alcohol and tobacco, work, relations with other people, perception of disease. RESULTS: The questionnaires were self-administered to the 100 first patients with chronic hepatitis C without cirrhosis before treatment; 55 men, 45 women, average age 40 year-old, median Knodell's score 8 and median METAVIR score A2 F1. Reduction in the quality of life was frequent and was not highly correlated with biological, virological and histological parameters; it was associated with psychological disorders, reduced sexuality and apprehension of the future. CONCLUSION: This study showed the feasibility, validation, sensitivity and agreement of a quality of life questionnaire, which included a general index and a specific index of chronic hepatitis C in France. These initial results must be confirmed in studies during antiviral treatment of patients.

Adult↗
PubMed1994

Isolation and characterization of the rolipram-sensitive cyclic AMP-specific phosphodiesterase (type IV PDE) in human term myometrium.

On the basis of the potencies of classical selective modulators of cyclic nucleotide phosphodiesterase (PDE) activities, five cyclic nucleotide PDE isoforms have been isolated and characterized in the cytosolic fraction of human term myometrium. By means of successive ion-exchange chromatographies, a calcium-calmodulin sensitive isoform, a cyclic GMP-stimulated isoform, a cyclic GMP-inhibited isoform, a rolipram-sensitive cyclic AMP-specific isoform and a cyclic GMP-specific isoform, corresponding to PDE I, PDE II, PDE III, PDE IV and PDE V, respectively, have been identified. We found that near term, human myometrium contains a higher proportion of the rolipram-sensitive type IV PDE isoform (about 50% of total cyclic AMP hydrolytic activity) than the type III cyclic GMP-inhibited PDE isoform (only 10%). Type IV PDE displays simple Michaelis-Menten kinetics with a high affinity for cyclic AMP (Km approximately 4.4 microM) and is selectively and competitively inhibited by rolipram (K(i) approximately 0.9 microM) and Ro 20-1724 (K(i) approximately 2.6 microM). The predominance of type IV PDE at the end of pregnancy suggests that this isoform contributes, via a modulation of the intracellular cyclic AMP level, to local control of uterine motility and thus could help the myometrium prepare for pronounced contractile activity at the time of parturition.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1993

Biochemical characterization and autoradiographic localization of [125I]endothelin-1 binding sites on trophoblast and blood vessels of human placenta.

The presence of endothelin binding sites in the human placenta raises the question of the precise localization of these receptors on well defined placental constituents. In order to find an answer to this problem various approaches were used. Specific binding sites for [125I] endothelin-1 (ET-1) were identified on human term placenta, not only on membranes of smooth muscles stem villi vessels, but also on trophoblastic plasma membranes prepared from trophoblast in culture. Scatchard analysis of binding data revealed a single class of high affinity binding sites with Kd values of 26 +/- 4 pmol/L for stem villi vessels and 126 +/- 4 pmol/L for trophoblast in culture, with maximum binding capacities of 681 +/- 61 and 224 +/- 53 fmol/mg protein, respectively. The anatomical localization of these binding sites was determined by in vitro autoradiography. Autoradiograms obtained from placental sections incubated with [125I]ET-1 indicate that [125I]ET-1 high affinity binding sites exist on placental stem villi vessels and on the trophoblastic layer of the villi. The latter localization was also found on autoradiograms of trophoblast in culture. The human placental syncytiotrophoblast is a polarized epithelium with the microvillous membrane, facing maternal blood space and the basal plasma membrane, facing fetal circulation. [125I]ET-1 high affinity binding sites are present on both membranes but the number of binding sites is higher on the basal plasma membrane. These findings lead to the suggestion that ET-1 may be involved in the regulation of the feto-placental circulation and may subserve specific trophoblastic functions.

Arteries↗
PubMed1991

The effect of vasoactive intestinal peptide (VIP) on the contractile activity of human uterine smooth muscle.

1. In the present study we examined the in vitro effect of vasoactive intestinal peptide (VIP) on spontaneous contractions in both inner and outer layers of non-pregnant human myometrium. A dose-dependent relaxation was observed, but with a marked difference in sensitivity to VIP between the two layers, with an IC50 value of 1 x 10(-8) and 1 x 10(-5) mol L in the outer and inner layers, respectively. 2. We also established that VIP did not directly stimulate the adenylate cyclase activity. The only slight stimulations were observed in non-initial rate conditions. The maximal response of this indirect effect was obtained for VIP concentrations between 1 x 10(-9) and 1 x 10(-8) mol/L and this occurred to the same extent (an approximately 1.4-fold increase) in both layers. However this response is specific, since structurally related peptides such as glucagon, gastric inhibitory polypeptide (GIP), secretin, or human growth hormone-releasing factor (hGRF) had no effect in our preparations. 3. Autoradiographic studies revealed that specific VIP binding sites were located on the vascularization of the intermediate vascular layer and on arterioles and venules distributed in the inner and outer myometrial layers. They were also present in the endometrium, but not on smooth muscle cells of either layer. 4. Such observations could provide evidence for another signal transduction pathway to mediate the biological effect of VIP. An additional intermediate step on the vascularization distributed in all of the muscle cannot be excluded.

Adenylyl Cyclases↗
PubMed1989

Salivary oestradiol in spontaneous and stimulated menstrual cycles.

The determination of steroids in saliva provides useful information in the clinical study of various endocrine functions, and salivary progesterone concentration has been widely used for assessing corpus luteum function during the spontaneous menstrual cycle and early pregnancy. However, the determination of oestradiol in saliva (SE2) has previously been found unsatisfactory. SE2 profiles and saliva/plasma E2 ratios were established (during the different periods of the menstrual cycle) by a highly sensitive radioimmunoassay method during normal menstrual cycle. During cycles hyperstimulated for in-vitro fertilization and embryo transfer, the SE2 pattern is similar to the corresponding profile in plasma with a peri-ovulatory oestradiol peak. There is a significant difference between fertile and non-fertile cycles with a higher saliva/plasma ratio in conception cycles.

Adult↗
PubMed1988

Evolution of tissue levels of steroids: oestradiol-17 beta, oestrone and progesterone in the macaque myometrium during gestation.

In 15 cynomolgus monkeys between days 30-160 of gestation, tissue levels of oestrone (E1), oestradiol 17 beta (E2) and progesterone (P4) were assayed by RIA in the myometrium and the placenta. Myometrial samples were subdivided as follows: inner and outer layers adjacent to the placental area (IMP and OMP) and inner and outer layers from antiplacental areas (IMAP and OMAP). Steroid levels (ng/g wet wt) were in the range of known plasma values (ng/ml) and there was no asymmetric distribution of steroids between the various locations. When the results obtained in all the layers were pooled the gestational profiles indicated a decrease of E1 between days 80-130, whereas at the same time E2 and P4 increased. The ratio P4/E2 was 8 on day 40, 17 on day 80 and 9 on day 160. In the placenta, levels of E2 and P4 were 4 times higher, levels of E1 10 times higher than in the myometrium. Gestational profiles of the three steroids in the placenta increased from day 30 to day 160. Myometrium steroid content therefore does not appear to be a simple reflection of steroid diffusion from the site of production.

Animals↗