Use of transgenic mice model for understanding the placentation: towards clinical applications in human obstetrical pathologies?

The mammalian embryo and fetus are unable to develop without a well-established, functional placenta. This transitory yet indispensable structure attaches the conceptus to the uterus and establishes the vascular connections necessary for nutrient and gaseous exchange between maternal and fetal compartments. Genetic targeting strategy allows the generation of mice lacking a specific gene. Such approaches reveal: (i) the high incidence of mutant embryonic or fetal death in utero, and (ii) the extraembryonic (placental) causes of these deaths. Due to the similarities presented between mouse and human placenta, we propose to use the potential of mouse targeting experiments as a model in order to understand human obstetrical pathologies. In this paper, we first review genes that have been demonstrated to be required in mice for implantation, choriovitelline and chorioallantoic placentation. Using examples (integrins, homeoboxs, hepatocyte growth factor or epidermal growth factor receptor...) we demonstrate the reality and efficiency of such an approach. Other candidate genes (receptor of leukemia inhibitory factor, Wnt2 or retinoic acid receptor alpha...) in order to understand, prevent and treat human obstetrical pathologies.

Increased serum levels of interleukin 10 in Sjögren's syndrome; correlation with increased IgG1.

OBJECTIVE: To determine levels of interleukin 10 (IL-10) and IgG subclasses in serum from 53 patients with primary Sjögren's syndrome (SS). METHODS: Serum levels of IL-10 were measured using specific sandwich ELISA in 25 patients with "definite" SS, 28 with "possible" SS, and 32 healthy controls. Interferon-gamma (IFN-gamma) and transforming growth factor-beta1 (TGF-beta1) were also measured by immunoassays. Immunoglobulin classes, IgG subclasses, and C-reactive protein were measured by nephelometry. RESULTS: Circulating IL-10 was elevated in 25 patients. The increase reached significance in the group with possible SS (p = 0.03) versus controls. In the group with definite SS, IL-10 level was correlated with IgG1 level (p = 0.01, r = 0.67) and with focus score (p = 0.01). IFN-gamma was undetectable in most patients. TGF-beta1 was higher (not significantly) in possible SS than in definite SS. CONCLUSION: IL-10 is increased in SS and may account for the overproduction of IgG1 in the syndrome. High IL-10 in the absence of increased IgG1 in possible SS suggests that IL-10 may be necessary but not sufficient for IgG1 overproduction and that other factors are involved. Whereas the correlation of IL-10 level with focus score was expected, it is intriguing that IL-10 was more frequently increased in the incomplete (possible) form of SS than the complete (definite) form. Elevated IL-10 may characterize the lower stage of eccrine dysfunction and perhaps contributes to limiting its severity.

Arterial obliteration in POEMS syndrome: possible role of vascular endothelial growth factor.

Acute arterial obliteration is a newly acknowledged manifestation of the POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes), in which overproduction of proinflammatory cytokines has been implicated. We describe a case in which serum levels of proinflammatory cytokines were normal or slightly raised. In contrast, vascular endothelial growth factor (VEGF) was greatly increased. This angiogenic and vascular permeability factor is involved in the development of atheromatous and thrombotic lesions and may be responsible for the arterial complications of the disorder.

Variations of cytokine levels and production in CAPD patients.

Macrophages, predominant cells in dialysates of patients on CAPD without peritonitis, produce a wide variety of substances including cytokines. The aim of this study was to examine the cytokine production in five uninfected patients. This work investigated the presence in dialysates of interleukin-1beta, interleukin-6, interleukin-8, tumor necrosis factor alpha and the ability of peritoneal macrophages to produce these cytokines. These results were compared with values obtained from control group in non-uremic conditions (peritoneal lavage with isotonic saline or dialysis fluid). All cytokines were detectable in dialysates. Interindividual variations in cytokine concentration in dialysates were wider than variations of production of cytokines ex vivo by stimulated and unstimulated cells. In control group, dialysis fluid inhibited the cytokine production and with isotonic saline, cells produced less cytokines than dialysis patients' cells. The highest levels of interleukin-1 and tumor necrosis factor in dialysates and the highest capacity to respond to LPS were observed in patients having the shortest duration of dialysis. The variability observed did not seem to be due to cells themselves but to their environment.

Fetal serum erythropoietin in twin pregnancies with discordant growth. A clue for the prenatal diagnosis of monochorionic twins with vascular communications.

Ten sets of diamniotic twins with discordant fetal growth (ultrasonographic estimated fetal weight difference > 25%) and abnormal amniotic fluid volume were assessed for fetal serum erythropoietin concentration (Epo). All 20 fetuses had a percutaneous umbilical blood sampling performed between 21 and 33 weeks gestation. Three sets of twins were dichorionic while 7 sets were monochorionic. In these 7 monochorionic sets a vascular communication between twins was demonstrated prenatally and postnatally. From 24 weeks gestation the smaller twin of the dichorionic group had a higher serum Epo than its larger cotwin; the larger cotwin's serum Epo was within normal limits for singleton controls. All fetuses with documented vascular communications had higher serum Epo concentration than singleton controls. These findings suggest that determination of fetal serum Epo in the large cotwin may be a clue to the diagnosis of vascular communications between twins with discordant growth.

Serum erythropoietin and reticulocyte counts in inflammatory process.

The role of erythropoietin in the pathogenesis of anaemia associated with inflammatory disorders is unclear. We studied serum erythropoietin levels in patients with inflammatory process of varying aetiologies. Serum erythropoietin levels and reticulocyte counts were prospectively measured in 40 patients with inflammatory syndromes and compared with values obtained in 20 patients with myelodysplastic syndromes. Significant inverse correlation between erythropoietin levels and haemoglobin concentration were noted in the 2 groups. The slope of the regression line for patients with inflammatory disorders was lower as compared with that for the myelodysplastic syndromes. In all cases, when the erythropoietin response in relation to degree of anaemia is compared with that which occurs in patients with myelodysplastic syndromes, the inadequate erythropoietin response in patients with chronic inflammatory process becomes evident. In patients with inflammatory process, a relationship between erythropoietin levels and reticulocyte counts were only noted in patients with mildly anaemia (haemoglobin concentration higher than 10.5 g/dl). This study suggests blunted erythropoietin production and impaired marrow response to this hormone in the anaemia which occurs in inflammatory syndromes and supports the hypothesis that these disorders may contribute to the development of the anaemia associated with inflammatory disorders.

Reticulocyte response to endogenous erythropoietin after renal transplantation.

We determined in a prospective study reticulocyte counts and serum erythropoietin concentrations after renal transplantation in 37 recipients of renal allografts. Erythropoietin decreased in 35 patients out of 37 during surgery. Results concerning reticulocyte counts allowed us to define two groups of patients. Group 1: 33 patients had a reticulocyte peak before d29. Among them the reticulocyte peak followed the first Epo peak in 22 patients (1a) and occurred after several Epo peaks in 11 patients (1b). Patients of groups 1b had a serum creatinine level above 300 mumol/l at the time of the first Epo peak. Group 2: 4 patients with acute tubular necrosis had no reticulocytes peak before d29 despite one or several erythropoietin peaks. Post-operative erythropoietin reduction was not entirely explained by hemodilution or by per-operative blood transfusions. The erythropoietin peak appeared to be efficient only when creatinine at the time of the peak was under 200 mumol/l according to the inhibition of erythropoiesis during renal failure.

Serum erythropoietin in small for gestational age fetuses.

Serum erythropoietin (Epo) concentration was compared prenatally in adequate (AGA) and small for gestational age (SGA) fetuses. Fifty-four percutaneous umbilical blood samplings were paired with maternal blood and assessed for Epo, hematocrit and reticulocyte count. Seventeen fetuses were growth-retarded (SGA) on the basis of ultrasonic biometry and birth weight. Controls (AGA; n = 37) underwent cordocentesis for risk of toxoplasmosis, maternal age or malformations (CNS, GI, heart). No cytogenetic abnormality or infections was found in the 54 fetuses. Linear and polynomial regressions were fitted to determine correlations between parameters. Nonparametric Mann-Whitney test was used for comparison between groups. Gestational age at sampling was similar in AGA and SGA. The SGA fetuses had a higher Epo concentration than controls (p < 0.001). Fetal AGA Epo increased significantly throughout pregnancy (p < 0.01) but did not correlate with maternal Epo (p > 0.05). An inverse correlation was found between fetal reticulocyte count and Epo concentration (p < 0.02). The mechanism of high Epo level in SGA fetuses may involve low pO2 and hemoconcentration.

[Kinetics of erythropoietin blood levels from D-1 to D-29 in kidney transplantation]. / Cinétique de l'érythropoïétinémie de J-1 à J29 en transplantation rénale.

This study of serum erythropoietin levels and reticulocytes counts in the first month after kidney transplantation shows that the erythropoietin peak is efficient only when serum creatinine level at the time of the peak is under 200 mumol/l.