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Biomedical subjects

F Muller

Publications and source records attributed to F Muller.

At least 19 recordsLinked to original sources
PubMed2003

Hyperechogenic fetal bowel: a large French collaborative study of 682 cases.

Hyperechogenic fetal bowel is detected in 0.1-1.8% of pregnancies during the second or third trimester. This ultrasound sign is associated with cystic fibrosis or other conditions (e.g., chromosomal anomalies, viral infection) but no large-scale prospective studies have been conducted. This 1997-1998 multicenter study in 22 molecular biology laboratories identified 682 cases of hyperechogenic fetal bowel detected by routine ultrasound examination during the second (86%) or third trimester. The fetal bowel was considered hyperechogenic when its echogenicity was broadly similar to, or greater than, that of the surrounding bone. Karyotyping, screening for viral infection, and screening for cystic fibrosis mutations were performed in all cases. Pregnancy outcome and postnatal follow-up were obtained in 656 of the 682 cases (91%). In 447 cases (65.5%), a normal birth was observed. Multiple malformations were observed in 47 cases (6.9%), a significant chromosomal anomaly was noted in 24 (3.5%), cystic fibrosis in 20 (3%), and viral infection in 19 (2.8%). In utero unexplained fetal death occurred in 1.9% of cases, toxemia in 1.2%, IUGR in 4.1%, and premature birth in 6.2%. This study demonstrates that this ultrasound sign is potentially associated with medically significant outcomes. Having established that the bowel is hyperechogenic, recommended investigations should include a detailed scan with Doppler measurements, fetal karyotyping, cystic fibrosis screening, and infectious disease screening. After birth, newborns require pediatric examination because a surgical treatment may be necessary. This should be combined with clear counseling of the parents.

Chromosome Aberrations↗
PubMed2003

Congenital erythropoietic porphyria (Günther's disease): two cases with very early prenatal manifestation and cystic hygroma.

Congenital erythropoietic porphyria (CEP) or Günther's disease is the rarest form of the porphyrias. The disease is usually diagnosed at birth or during early infancy, but rarely in utero. We describe here the first two cases of very early prenatal expression of CEP with cystic hygroma diagnosed at 14 weeks in the first fetus and at 19 weeks in the second. Both fetuses presented with severe nonimmune hydrops fetalis as early as 19 and 22 weeks, associated with intrauterine growth retardation, hyperechogenic kidneys and bones. Amniotic fluid was dark brown and uro- and coproporphyrin I was dramatically increased. Molecular screening of the CEP gene detected heterozygous C73R mutation in both fetuses, the other parental mutation being as yet unknown.

Abortion, Eugenic↗
PubMed2003

Frequency and clinical consequences of extremely high maternal serum PAPP-A levels.

A multicentre study was carried out to determine the frequency and clinical consequences of extremely high maternal serum pregnancy-associated plasma protein (PAPP)-A. There was a total of 79 pregnancies with PAPP-A exceeding 5.0 multiples of the gestation-specific median in a series of 46 776 pregnancies tested (0.2%) at the 7 collaborating centres. Five pregnancies were lost to follow-up, one miscarried and one with Noonan's syndrome was terminated. Of the remaining 72 that ended in a live birth, one infant had gastroschisis and five pregnancies had obstetric complications: pre-eclampsia, pregnancy-induced hypertension, gestational diabetes and two with growth retardation. Among women with high PAPP-A and no complications or adverse outcomes, there was no evidence of a substantial change in the levels of other Down syndrome markers or the extent of nuchal translucency. Three analytical methods were used to assay PAPP-A and yielded different frequencies of extremely high levels (0.05%, 0.4% and 0.6%) possibly owing to cross-reaction with another substance. We conclude that women with high PAPP-A can be reassured that there is no reason to suppose that the outcome of pregnancy will differ from those with normal levels, provided other markers are normal. If, as more centres move their Down syndrome screening practice to the first trimester, additional cases emerge with Noonan's syndrome or gastroschisis and raised PAPP-A, this advice will need to be modified.

Adult↗
PubMed2003

Expression of pregnancy-associated plasma protein-A (PAPP-A) during human villous trophoblast differentiation in vitro.

Pregnancy-associated placental protein-A (PAPP-A), first isolated from maternal serum, has been identified as a metalloprotease cleaving insulin-like growth factor binding protein-4 (IGFBP-4). The source of PAPP-A during pregnancy is unclear. We therefore investigated PAPP-A expression during in vitro human villous cytotrophoblast cell (CT) differentiation into syncytiotrophoblast (ST). CT were isolated from normal first trimester, second trimester and term placentae (n=10) and cultured to form ST. PAPP-A mRNA was quantified by real-time PCR, and PAPP-A protein expression was studied by immunocytochemistry and TRACE technology with specific monoclonal antibodies. PAPP-A mRNA expression in total placental extracts increased during the course of pregnancy. PAPP-A protein was detected in the cytoplasm of both CT and ST. ST formation in vitro was associated with a 19-fold increase in PAPP-A mRNA expression and an 8-fold increase in PAPP-A secretion into the culture medium. No significant difference in PAPP-A production was observed between cultured cells isolated from early and term placentae. In conclusion, PAPP-A production in vitro, is associated to the differentiation of villous cytotrophoblast cells into syncytiotrophoblast, independently of the age of gestation.

Adult↗
PubMed2003

[Towards an improved antenatal screening for cystic fibrosis].

BACKGROUND: Cystic Fibrosis is an autosomal and recessive lethal disease which affects in France one newborn in 3.000. New technologies may afford quite a cheap and efficient screening for a large set of mutations within the same assay in order to test their presence or absence. These procedures are very valuable for prenatal diagnosis for further pregnancies when couples at risk have been identified through a first affected newborn. But, for carriers or couples at risk before the birth of a first child, these antenatal screening methods remain of limited efficacy. However carrier screening would be the only way, on a public health standpoint, to decrease the disease frequency as no therapy seems to emerge till now. Recently hyperechogenic fetal bowel at routine ultrasound in the second trimester has been recognized to be associated with various deleterious conditions, especially cystic fibrosis. These observations lead praticians to investigate for parent CFTRmutations screening and subsequent prenatal diagnosis if the two parents are carriers. METHODS: Through data issued from two prospective investigations, our study aimed at the estimation of both the sensibility and efficiency of the screening for cystic fibrosis using ultrasound foetal bowel examination. RESULTS: Using the frequency of the disease in the population and the number of affected fetuses within the hyperechoic sample (20 in 641 in a recent study), our analysis may lead to the conclusion that fetal echogenic bowel may concern about 0.75% of fetuses. CONCLUSION: Orders of magnitude of the sensibility and efficiency of cystic fibrosis screening through fetal echogenic bowel are calculated and lead to the conclusion that sonographic screening might decrease the number of affected newborn more than two time less.

Cystic Fibrosis↗
PubMed2003

[Hyperechogenic fetal bowel: collaborative study of 682 cases].

OBJECTIVES: Hyperechogenic fetal bowel is detected in 0.1-1.8% of pregnancies during the second or third trimester. This ultrasound sign is associated with severe pathologies but no large-scale prospective studies have been conducted. MATERIALS AND METHODS: A multicenter study identified 682 cases of hyperechogenic fetal bowel detected by routine ultrasound examination. RESULTS: Pregnancy outcome and postnatal follow-up were obtained in 657 of the 682 cases (96%). In 447 cases (65.5%), a normal birth was observed. Severe multiple malformations were observed in 47 cases (7.1%), a severe chromosomal anomaly in 24 (3.5%), cystic fibrosis in 20 (3%), and viral infection in 19 (2.9%). In utero fetal death occurred in 13 cases (1.9%), a placental and/or maternal pathology in 23 cases (3.5%), IUGR in 28 cases (4.1%) and premature birth in 42 cases (6.2%). CONCLUSION: This study demonstrates the potential severity of this ultrasound sign. Recommended investigations include a detailed scan, fetal karyotyping, cystic fibrosis screening, infectious disease screening. After birth, newborns require pediatric examination because a surgical treatment may be necessary. This should be combined with clear counseling of the parents.

Chromosome Aberrations↗
PubMed2002

Predicting the risk of cystic fibrosis with abnormal ultrasound signs of fetal bowel: results of a French molecular collaborative study based on 641 prospective cases.

Hyperechogenic fetal bowel is prenatally detected by ultrasound during the second trimester of pregnancy in 0.1-1.8% of fetuses. It has been described as a normal variant but has often been associated with severe diseases, notably cystic fibrosis (CF). The aim of our study was to determine the risk of CF in a prospective study of 641 fetuses with ultrasonographically abnormal fetal bowel and the residual risk when only one mutation is detected in the fetus. Fetal cells and/or parental blood cells were screened for CFTR mutations. Two screening steps were used, the first covering the mutations most frequently observed in French CF patients (mutation detection rate of 70-90%) and, when a CF mutation was detected, a DGGE-sequencing strategy. We observed a 3.1% risk of CF when a digestive tract anomaly was prenatally observed at routine ultrasound examination. The risk was higher when hyperechogenicity was associated with bowel dilatation (5/29; 17%) or with the absence of gall bladder (2/8; 25%). The residual risk of CF was 11% when only one CF mutation was detected by the first screening step, thereby justifying in-depth screening. Mutations associated with severe CF (DeltaF508 mutation) were more frequently observed in these ultrasonographically and prenatally detected CF cases. However, the frequency of heterozygous cases was that observed in the normal population, which demonstrates that heterozygous carriers of CF mutations are not at increased risk for hyperechogenic bowel. In conclusion, fetal bowel anomalies indicate a risk of severe cystic fibrosis and justify careful CFTR molecular analysis.

Cystic Fibrosis↗
PubMed2002

Human placental growth hormone--a review.

Placental growth hormone (PGH) is the product of the GH-V gene, predominantly expressed in the syncytiotrophoblast layer of the human placenta. PGH differs from pituitary growth hormone by 13 amino acids and possesses one glycosylation site. It has high somatogenic and low lactogenic activities. In the maternal circulation from 12-20 weeks up to term, PGH gradually replaces pituitary growth hormone, which becomes undetectable. PGH is secreted by the placenta in a non-pulsatile manner. This continuous secretion appears to have important implications for physiological adjustment to gestation and especially in the control of maternal IGF1 levels. PGH secretion is regulated in vitro and in vivo by glucose. Lower maternal levels of PGH are observed in pregnancies with fetal growth retardation. PGH is one example of a trophoblast hormone, which allows maternal metabolic adaptation to pregnancy. In addition, our recent data on its expression in invasive extravillous trophoblasts suggest that the physiological role of PGH might also include a direct influence of this hormone on placental development via an autocrine or paracrine mechanism.

Adult↗
PubMed2001

Capillary electrophoresis of associative diblock copolymers.

Water soluble diblock copolymers composed of a long poly(styrene sulfonate) chain (between 200 and 400 monomers) and a short poly(ethylene propylene) or poly(tert.-butylstyrene) hydrophobic end (20-50 monomers) are highly associative and form micelles in aqueous solution. The micelles are composed of a small hydrophobic core and a polyelectrolyte corona, the dimensions of which can be estimated by neutron and light scattering. These physical techniques are, however, not amenable to discriminate easily between the free copolymer and the copolymer micelle. Capillary electrophoresis was implemented in this work as a new and effective tool to investigate the behaviour of such associative copolymer systems. Since the rate of exchange between the micellised and free states is very slow in comparison with the time scale of the electrophoretic process, the electropherograms of the diblock copolymers obtained in plain aqueous borate buffers exhibit two peaks assigned to the two states mentioned above. The identification of the two peaks was first made on the basis of the retention orders of the two peaks equally obtained in similar conditions by size-exclusion chromatography. The copolymer micelles appeared to have a smaller electrophoretic mobility than the free copolymers. This peak assignment is also consistent with the observed ratio of the time-corrected peak areas and peak dispersions. The effects of the copolymer concentration, electric field, temperature and hydroorganic composition of the medium was also studied. Such systems do not exhibit a defined concentration threshold equivalent to a classical critical micelle concentration. Adding methanol to the electrolyte resulted in the progressive loss of baseline return between the two peaks, which might be attributed to a slight increase in the rate of exchange between the two states. Finally, adding a neutral surfactant to the electrolyte at a concentration in excess of its critical micelle concentration resulted in a decrease in the electrophoretic mobility of the peak attributed to the free copoplymer, while the electrophoretic mobility of the copolymer micelle remained unperturbed.

Chromatography, Gel↗
PubMed2001

Twelve novel mutations in the tissue-nonspecific alkaline phosphatase gene (ALPL) in patients with various forms of hypophosphatasia.

Hypophosphatasia is a rare inherited disorder characterized by defective bone mineralization and deficiency of serum and tissue liver/bone/kidney tissue alkaline phosphatase (L/B/K ALP) activity. We report here the characterization of tissue-nonspecific alkaline phosphatase (TNSALP) gene mutations in a series of 11 families affected by various forms of hypophosphatasia. Nineteen distinct mutations were found, 7 of which were previously reported. Eleven of the 12 new mutations were missense mutations (Y11C, A34V, R54H, R135H, N194D, G203V, E218G, D277Y, F310G, A382S, V406A), the last one (998-1G>T) was a mutation affecting acceptor splice site.

Adult↗
PubMed2001

A molecular approach to dominance in hypophosphatasia.

Hypophosphatasia is an inherited disorder characterized by defective bone mineralization and a deficiency of tissue-nonspecific alkaline phosphatase (TNSALP) activity. The disease is highly variable in its clinical expression, because of various mutations in the TNSALP gene. In approximately 14% of the patients tested in our laboratory, only one TNSALP gene mutation was found, despite exhaustive sequencing of the gene, suggesting that missing mutations are harbored in intron or regulatory sequences or that the disease is dominantly transmitted. The distinction between these two situations is of importance, especially in terms of genetic counseling, but dominance is sometimes difficult to conclusively determine by using familial analysis since expression of the disease may be highly variable, with parents of even severely affected children showing no or extremely mild symptoms of the disease. We report here the study of eight point mutations (G46 V, A99T, S164L, R167 W, R206 W, G232 V, N461I, I473F) found in patients with no other detectable mutation. Three of these mutations, G46 V, S164L, and I473F, have not previously been described. Pedigree and/or serum alkaline phosphatase data suggested possible dominant transmission in families with A99T, R167 W, and G232 V. By means of site-directed mutagenesis, transfections in COS-1 cells, and three-dimensional (3D) modeling, we evaluated the possible dominant effect of these eight mutations. The results showed that four of these mutations (G46 V, A99T, R167 W, and N461I) exhibited a negative dominant effect by inhibiting the enzymatic activity of the heterodimer, whereas the four others did not show such inhibition. Strong inhibition resulted in severe hypophosphatasia, whereas partial inhibition resulted in milder forms of the disease. Analysis of the 3D model of the enzyme showed that mutations exhibiting a dominant effect were clustered in two regions, viz., the active site and an area probably interacting with a region having a particular biological function such as dimerization, tetramerization, or membrane anchoring.

Adolescent↗
PubMed2001

Defect of syncytiotrophoblast formation and human chorionic gonadotropin expression in Down's syndrome.

The syncytiotrophoblast (ST) is a major component of the human placenta as it is involved in feto-maternal exchanges and the secretion of pregnancy-specific hormones. We have studied the formation and function of the ST in normal and trisomy 21 (T21)-affected placenta using the in vitro model of cytotrophoblast differentiation into ST. Cytotrophoblast cells were isolated from first trimester, second trimester and term placentae. In vitro cytotrophoblast cells isolated from normal placenta fused to form the ST. This was associated with an increase in the transcript levels and the secretion of human chorionic gonadotropin (hCG). However, the secretion of hCG decreased through pregnancy. In T21-affected placentae, we observed a defect (or a delay) in ST formation and a dramatic decrease in the synthesis and secretion of this hormone compared with cultured cells isolated from control age-matched placentae. These results were confirmed by a significant (P < 0.05) decrease in transcript levels of alpha and beta subunits of hCG in total homogenates of T21-affected placentae compared with controls. These results suggest a decrease in functional mass of ST in T21 placenta, and therefore a decrease in production of placental pregnancy-specific polypeptide hormones.

Adult↗
PubMed2001

Anatomical and sonographical studies on the development of fecal continence and sphincter development in human fetuses.

The aim of this study was to specify the sonographic, anatomical and morphological aspects of the fetal anal sphincter and to compare them with pathological and physiological findings. The sphincter was examined by serial sectioning and staining of embryo and fetal tissue and by real-time ultrasound. Its function was analysed using amniotic fluid digestive enzyme assays in cases of anorectal atresia and cystic fibrosis. Morphological findings indicate that the functional components of the anal sphincter do not differentiate before 30 weeks and therefore do not account for the observed anal continence at 22 weeks. Ultrasound measurements of the sphincter indicate three developmental phases: 1) slow growth from 14 to 19 weeks; 2) rapid growth from 19 to 30 weeks; 3) subsequently, no further increase, but contractions indicative of peristaltism. Amniotic fluid digestive enzyme assays indicate that anal sphincter maturation begins with perforation of the anal membrane at 12 weeks. Comparison of pathological cases (anorectal atresia and cystic fibrosis) suggests two possible explanations of fetal anal obstruction: increasing viscosity of digestive secretion or the presence of the three anal sphincter muscles, even if still immature. Our results clarify the evacuation and retention of meconium during fetal life and the role of the terminal part of the digestive tract, notably the anal sphincter. Prenatal diagnosis of anorectal atresia is therefore possible before 20 weeks of gestation by measurement of amniotic fluid digestive enzymes and ultrasonography, thus enabling better neonatal management.

Amniotic Fluid↗
PubMed2001

Overexpression of copper zinc superoxide dismutase impairs human trophoblast cell fusion and differentiation.

The syncytiotrophoblast is the major component of the human placenta, involved in feto-maternal exchanges and secretion of pregnancy-specific hormones. Multinucleated syncytiotrophoblast arises from fusion of mononuclear cytotrophoblast cells. In trisomy 21-affected placentas, we recently have shown that there is a defect in syncytiotrophoblast formation and a decrease in the production of pregnancy-specific hormones. Due to the role of oxygen free radicals in trophoblast cell differentiation, we investigated the role of the key antioxidant enzyme, copper/zinc superoxide dismutase, encoded by chromosome 21 in in vitro trophoblast differentiation. We first observed that overexpression of superoxide dismutase in normal cytotrophoblasts impaired syncytiotrophoblast formation. This was associated with a significant decrease in mRNA transcript levels and secretion of hCG and other hormonal markers of syncytiotrophoblast. We confirmed abnormal cell fusion by overexpression of green fluorescence protein-tagged superoxide dismutase in cytotrophoblasts. In addition, a significant decrease in syncytin transcript levels was observed in superoxide dismutase-transfected cells. We then examined superoxide dismutase expression and activity in isolated trophoblast cells from trisomy 21-affected placentas. Superoxide dismutase mRNA expression (P < 0.05), protein levels (P < 0.01), and activity (P < 0.05) were significantly higher in trophoblast cells isolated from trisomy 21-affected placentas than in those from normal placentas. These results suggest that superoxide dismutase overexpression may directly impair trophoblast cell differentiation and fusion, and superoxide dismutase overexpression in Down's syndrome may be responsible at least in part for the failure of syncytiotrophoblast formation observed in trisomy 21-affected placentas.

Cell Differentiation↗
PubMed2000

Molecular cloning and characterization of the human protein kinase D2. A novel member of the protein kinase D family of serine threonine kinases.

We have isolated the full-length cDNA of a novel human serine threonine protein kinase gene. The deduced protein sequence contains two cysteine-rich motifs at the N terminus, a pleckstrin homology domain, and a catalytic domain containing all the characteristic sequence motifs of serine protein kinases. It exhibits the strongest homology to the serine threonine protein kinases PKD/PKCmicro and PKCnu, particularly in the duplex zinc finger-like cysteine-rich motif, in the pleckstrin homology domain and in the protein kinase domain. In contrast, it shows only a low degree of sequence similarity to other members of the PKC family. Therefore, the new protein has been termed protein kinase D2 (PKD2). The mRNA of PKD2 is widely expressed in human and murine tissues. It encodes a protein with a molecular mass of 105 kDa in SDS-polyacrylamide gel electrophoresis, which is expressed in various human cell lines, including HL60 cells, which do not express PKCmicro. In vivo phorbol ester binding studies demonstrated a concentration-dependent binding of [(3)H]phorbol 12,13-dibutyrate to PKD2. The addition of phorbol 12,13-dibutyrate in the presence of dioleoylphosphatidylserine stimulated the autophosphorylation of PKD2 in a synergistic fashion. Phorbol esters also stimulated autophosphorylation of PKD2 in intact cells. PKD2 activated by phorbol esters efficiently phosphorylated the exogenous substrate histone H1. In addition, we could identify the C-terminal Ser(876) residue as an in vivo phosphorylation site within PKD2. Phosphorylation of Ser(876) of PKD2 correlated with the activation status of the kinase. Finally, gastrin was found to be a physiological activator of PKD2 in human AGS-B cells stably transfected with the CCK(B)/gastrin receptor. Thus, PKD2 is a novel phorbol ester- and growth factor-stimulated protein kinase.

Amino Acid Sequence↗
PubMed2000

A cGMP-signaling pathway in a subset of olfactory sensory neurons.

It is well established that signal transduction in sensory neurons of the rat olfactory epithelium involves a cAMP-signaling pathway. However, a small number of olfactory neurons specifically express cGMP-signaling components, namely a guanylyl cyclase (GC-D) and a cGMP-stimulated phosphodiesterase (PDE2). Here, we show that this subset of olfactory neurons expressing GC-D and PDE2 does also express the subunit of a cGMP-selective cyclic nucleotide-gated (CNG) channel that has been previously identified in cone photoreceptors. Further, components of the prototypical cAMP-signaling pathway could not be detected in this subpopulation of cells. These results imply that these neurons use an alternative signaling pathway, with cGMP as the intracellular messenger, and that, in these cells, the receptor current is initiated by the opening of cGMP-gated channels.

Amino Acid Sequence↗
PubMed2000

[Fetal pain].

IN UTERO CARE: The definition of pain proposed by the International Association for the Study of Pain is not adapted to the newborn or to the fetus because it assumes recognition and verbal expression of an unpleasant experience. Neonatologists have however demonstrated that full term and highly premature infants experience pain. In addition, the health of these infants improves with proper management. Such an approach is indispensable, not only from an obvious humane point of view, but also because treatment of pain in utero could have a beneficial effect for the fetus. PRENATAL PAIN AND ITS CONSEQUENCES: As it is impossible to resolve the question of conscious perception of pain by the fetus, we use experimental or clinical arguments favoring sensitivity to pain to assess pain during fetal life. We have also investigated the deleterious consequences of antenatal pain and how to evaluate them clinically in order to propose therapeutic care. It can be accepted that the fetus is able to perceive pain as early as 26 weeks gestation, possibly from 20 weeks. In the short-term, fetal pain causes changes in behavior, hemodynamics and hormonal functions but the long-term consequences remain unknown. ANTENATAL ANALGESIA: As no validated data on assessment of pain in the fetus are available, prevention becomes primordial in all at risk situations (pregnancy termination beyond 24 weeks gestation, in utero interventions). Morphine derivatives (sufentanil) would be the analgesic of choice for antenatal pain.

Animals↗