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Objective: To measure the expression of adiponectin, leptin, and their respective receptors in the human endometria of fertile women compared with women with unexplained recurrent implantation failure (IF) during the window of implantation.Design: Controlled, prospective, clinical study.Setting: Teaching hospital and university research laboratory.Patient(s): Thirty-one endometrial biopsies from women with IF and 19 fertile controls.Intervention(s): Human endometrial biopsies.Main Outcome Measure(s): Gene and protein expression of endometrial biopsies.Result(s): Endometrial leptin expression was significantly lower in the IF group compared with fertile women. In contrast, leptin receptor (Ob-R) expression was higher in endometria of women with IF. Concerning the adiponectin system, adiponectin was expressed to the same extent in both groups. Conversely, the expression of its two receptors, AdipoR1 and AdipoR2, was reduced in endometria of women with IF compared with fertile women.Conclusion(s): Although progesterone resistance seems to be a common state of the endometrium in some human reproductive disorders, such as endometriosis or polycystic ovary syndrome, modification in leptin endometrial expression seems to be specific to IF. These results strongly suggest that changes in Ob-R and AdipoR expression profiles [1] should be implicated in the development of uterine receptivity, and [2] may therefore be potential new targets for prediction of IF. [ABSTRACT FROM AUTHOR]

Granulocyte colony stimulating factor (G-CSF or CSF-3) in individual follicular fluids (FF) appears to correlate with the birth potential of the corresponding embryo in two opposite models of ovarian monitoring, standard ovarian hyperstimulation and modified natural IVF/ICSI cycles. A selection of individual follicular fluids over thousand was performed to select the ones corresponding to an embryo successfully transferred with the traceability of each sample until birth. Each fluid was analysed through multiplex bead based technology. In both, FF G-CSF appears as an excellent non invasive biomarker of oocyte competence in regard to its very significant power to discriminate potentiality of birth, independently-so adding value- to our embryo morphology based-selection. Such result may have tremendous consequences on the overall mortality and morbidity related to reproductive medicine. To evaluate the requirements for routine FF G-CSF quantification, we compared FF G-CSF measurements with two multiplexed bead-based assay purchased from Bio-Rad and R&D Laboratories and a commercial (R&D) standard G-CSF ELISA kit. 139 individual FF related to transferred embryo were analyzed for their cytokine profile while the fate of each transferred embryo was recorded. Effect of dilution, of multiplexing versus single-plexing the bead-based detection as well as comparison with other methods as flow-cytometry will be described. The correlation from a data collected in the follicular fluid to the event BIRTH clearly suggests an underlying dialogue toward a genetically programmed local state of immune tolerance. Preliminary results show that on the uterine side the CSF- related pathway is related to the overall local equilibrium suitable for a normal angiogenesis and adequate immunotrophicity of the conceptus. [ABSTRACT FROM AUTHOR]

Background: Despite recent advances in prenatal genetic diagnosis, medical geneticists still face considerable difficulty in interpreting the clinical outcome of copy-number-variant duplications and defining the mechanisms underlying the formation of certain chromosomal rearrangements. Optical genome mapping (OGM) is an emerging cytogenomic tool with proved ability to identify the full spectrum of cytogenetic aberrations., Methods: Here, we report on the use of OGM in a prenatal diagnosis setting. Detailed breakpoint mapping was used to determine the relative orientations of triplicated and duplicated segments in two unrelated foetuses harbouring chromosomal aberrations: a de novo 15q23q24.2 triplication and a paternally inherited 13q14.2 duplication that overlapped partially with the RB1 gene., Results: OGM enabled us to suggest a plausible mechanism for the triplication and confirmed that the RB1 duplication was direct oriented and in tandem. This enabled us to predict the pathogenic consequences, refine the prognosis and adapt the follow-up and familial screening appropriately., Conclusion: Along with an increase in diagnostic rates, OGM can rapidly highlight genotype-phenotype correlations, improve genetic counselling and significantly influence prenatal management., (© 2024 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Importance: Bacterial vaginosis (BV) is a well-known risk factor for preterm birth. Molecular diagnosis of BV is now available. Its impact in the screening and treatment of BV during pregnancy on preterm births has not been evaluated to date., Objective: To evaluate the clinical and economic effects of point-of-care quantitative real-time polymerase chain reaction screen and treat for BV in low-risk pregnant women on preterm birth., Design, Setting, and Participants: The AuTop trial was a prospective, multicenter, parallel, individually randomized, open-label, superiority trial conducted in 19 French perinatal centers between March 9, 2015, and December 18, 2017. Low-risk pregnant women before 20 weeks' gestation without previous preterm births or late miscarriages were enrolled. Data were analyzed from October 2021 to November 2022., Interventions: Participants were randomized 1:1 to BV screen and treat using self-collected vaginal swabs (n = 3333) or usual care (n = 3338). BV was defined as Atopobium vaginae (Fannyhessea vaginae) load of 108 copies/mL or greater and/or Gardnerella vaginalis load of 109 copies/mL or greater, using point-of-care quantitative real-time polymerase chain reaction assays. The control group received usual care with no screening of BV., Main Outcomes and Measures: Overall rate of preterm birth before 37 weeks' gestation and total costs were calculated in both groups. Secondary outcomes were related to treatment success as well as maternal and neonate health. Post hoc subgroup analyses were conducted., Results: Among 6671 randomized women (mean [SD] age, 30.6 [5.0] years; mean [SD] gestational age, 15.5 [2.8] weeks), the intention-to-treat analysis of the primary clinical and economic outcomes showed no evidence of a reduction in the rate of preterm birth and total costs with the screen and treat strategy compared with usual care. The rate of preterm birth was 3.8% (127 of 3333) in the screen and treat group and 4.6% (153 of 3338) in the control group (risk ratio [RR], 0.83; 95% CI, 0.66-1.05; P = .12). On average, the cost of the intervention was €203.6 (US $218.0) per participant, and the total average cost was €3344.3 (US $3580.5) in the screen and treat group vs €3272.9 (US $3504.1) in the control group, with no significant differences being observed. In the subgroup of nulliparous women (n = 3438), screen and treat was significantly more effective than usual care (RR, 0.62; 95% CI, 0.45-0.84; P for interaction = .003), whereas no statistical difference was found in multiparous (RR, 1.30; 95% CI, 0.90-1.87)., Conclusion and Relevance: In this clinical trial of pregnant women at low risk of preterm birth, molecular screening and treatment for BV based on A vaginae (F vaginae) and/or G vaginalis quantification did not significantly reduce preterm birth rates. Post hoc analysis suggests a benefit of screen and treat in low-risk nulliparous women, warranting further evaluation in this group., Trial Registration: ClinicalTrials.gov Identifier: NCT02288832.

Repeated embryo implantation failures (RIF) is a source of distress and frustration for patients and clinicians alike. Today's approaches for treating RIF are largely empirical and have limited effectiveness. The main causes of RIF are poor endometrial receptivity and poor-quality embryos. Recent studies have suggested the involvement of immune dysregulation due to an imbalance between T-helper (Th) 1 and Th2 cytokines; this opens up perspectives for treating women with RIF and increasing the implantation rate. We conducted an interventional, longitudinal, prospective cohort study of the impact of correcting the cytokine imbalance on the clinical pregnancy rate in women with RIF. Seventy-seven women with RIF underwent an endometrial biopsy during the implantation window. The cytokine profile was evaluated by studying the activation and maturation of uterine natural killer (uNK) cells, the IL-15/Fn-14 mRNA ratio (a biomarker of uNK activation/maturation), and the IL-18/TWEAK mRNA ratio (a marker of angiogenesis and the Th1/Th2 balance). Personalized treatment was initiated for women with an abnormal endometrial cytokine profile (hyper-activation or hypo-activation). We documented the clinical pregnancy rate after subsequent embryo transfers. In total, 72.7% (56/77) of patients had an abnormal endometrial cytokine profile (hyper-activation in 68.8% (n = 53) and hypo-activation in 3.9% (n = 3). After treatment (or not) as a function of the endometrial profile, the overall clinical pregnancy rate was 30.2%. Our results indicated a potential positive effect of appropriate treatment on the ongoing pregnancy rate in women with RIF, despite the small number of cases analyzed. The results must now be validated in randomized studies with larger numbers of well-characterized patients. By applying a previously published decision tree, this treatment approach could be implemented in clinics worldwide.

Introduction: Acute kidney injury (AKI) is frequently observed in patients with COVID-19 admitted to intensive care units (ICUs). Observational studies suggest that cardiovascular comorbidities and mechanical ventilation (MV) are the most important risk factors for AKI. However, no studies have investigated the renal impact of longitudinal covariates such as drug treatments, biological variations, and/or MV parameters., Methods: We performed a monocentric, prospective, longitudinal analysis to identify the dynamic risk factors for AKI in ICU patients with severe COVID-19., Results: Seventy-seven patients were included in our study (median age: 63 [interquartile range, IQR: 53-73] years; 58 (75%) men). Acute kidney injury was detected in 28 (36.3%) patients and occurred at a median time of 3 [IQR: 2-6] days after ICU admission. Multivariate Cox cause-specific time-dependent analysis identified a history of hypertension (cause-specific hazard (CSH) = 2.46 [95% confidence interval, CI: 1.04-5.84]; P = .04), a high hemodynamic Sequential Organ Failure Assessment score (CSH = 1.63 [95% CI: 1.23-2.16]; P < .001), and elevated Paco 2 (CSH = 1.2 [95%CI: 1.04-1.39] per 5 mm Hg increase in Pco 2 ; P = .02) as independent risk factors for AKI. Concerning the MV parameters, positive end-expiratory pressure (CSH = 1.11 [95% CI: 1.01-1.23] per 1 cm H 2 O increase; P = .04) and the use of neuromuscular blockade (CSH = 2.96 [95% CI: 1.22-7.18]; P = .02) were associated with renal outcome only in univariate analysis but not after adjustment., Conclusion: Acute kidney injury is frequent in patients with severe COVID-19 and is associated with a history of hypertension, the presence of hemodynamic failure, and increased Pco 2 . Further studies are necessary to evaluate the impact of hypercapnia on increasing the effects of ischemia, particularly in the most at-risk vascular situations., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Down syndrome (DS) is the most common chromosomal disorder. It is responsible for intellectual disability (ID) and several medical conditions. Although men with DS are thought to be infertile, some spontaneous paternities have been reported. The few studies of the mechanism of infertility in men with DS are now dated. Recent research in zebrafish has indicated that overexpression of DYRK1A (the protein primarily responsible for ID in DS) impairs gonadogenesis at the embryonic stage. To better ascertain DYRK1A's role in infertility in DS, we investigated the effect of DYRK1A overexpression in a transgenic mouse model. We found that overexpression of DYRK1A impairs fertility in transgenic male mice. Interestingly, the mechanism in mice differs slightly from that observed in zebrafish but, with disruption of the early stages of spermatogenesis, is similar to that seen in humans. Unexpectedly, we observed hypogonadotropic hypogonadism in the transgenic mice.

Background: Although chromosome rearrangements are responsible for spermatogenesis failure, their impact depends greatly on the chromosomes involved. At present, karyotyping and Y chromosome microdeletion screening are the first-line genetic tests for patients with non-obstructive azoospermia. Although it is generally acknowledged that X or Y chromosome rearrangements lead to meiotic arrest and thus rule out any chance of sperm retrieval after a testicular biopsy, we currently lack markers for the likelihood of testicular sperm extraction (TESE) in patients with other chromosome rearrangements., Results: We investigated the use of a single nucleotide polymorphism comparative genome hybridization array (SNP-CGH) and whole-exome sequencing (WES) for two patients with non-obstructive azoospermia and testicular meiotic arrest, a reciprocal translocation: t(X;21) and t(20;22), and an unsuccessful TESE. No additional gene defects were identified for the t(X;21) carrier - suggesting that t(X;21) alone damages spermatogenesis. In contrast, the highly consanguineous t(20;22) carrier had two deleterious homozygous variants in the TMPRSS9 gene; these might have contributed to testicular meiotic arrest. Genetic defect was confirmed with Sanger sequencing and immunohistochemical assessments on testicular tissue sections., Conclusions: Firstly, TMPRSS9 gene defects might impact spermatogenesis. Secondly, as a function of the chromosome breakpoints for azoospermic patients with chromosome rearrangements, provision of the best possible genetic counselling means that genetic testing should not be limited to karyotyping. Given the risks associated with TESE, it is essential to perform WES - especially for consanguineous patients., (© 2021. The Author(s).)

Throughout the entire first trimester of pregnancy, fetal growth is sustained by endometrial secretions, i.e. histiotrophic nutrition. Endometrial stromal cells (EnSCs) accumulate and secrete a variety of nutritive molecules that are absorbed by trophoblastic cells and transmitted to the fetus. Glycogen appears to have a critical role in the early stages of fetal development, since infertile women have low endometrial glycogen levels. However, the molecular mechanisms underlying glycogen metabolism and trafficking at the fetal–maternal interface have not yet been characterized. Among the various factors acting at the fetal–maternal interface, we focused on adiponectin – an adipocyte-secreted cytokine involved in the control of carbohydrate and lipid homeostasis. Our results clearly demonstrated that adiponectin controls glycogen metabolism in EnSCs by (i) increasing glucose transporter 1 expression, (ii) inhibiting glucose catabolism via a decrease in lactate and ATP productions, (iii) increasing glycogen synthesis, (iv) promoting glycogen accumulation via phosphoinositide-3 kinase activation and (v) enhancing glycogen secretion. Furthermore, our results revealed that adiponectin significantly limits glycogen endocytosis by human villous trophoblasts. Lastly, we demonstrated that once glycogen has been endocytosed into placental cells, it is degraded into glucose molecules in lysosomes. Taken as a whole, the present results demonstrate that adiponectin exerts a dual role at the fetal–maternal interface by promoting glycogen synthesis in the endometrium and conversely reducing trophoblastic glycogen uptake. We conclude that adiponectin may be involved in feeding the conceptus during the first trimester of pregnancy by controlling glycogen metabolism in both the uterus and the placenta., Competing Interests: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported., (© 2018 Society for Endocrinology)

Aim: The aim of this study was to investigate whether recurrent pregnancy loss (RPL) is associated with adipokine gene polymorphisms (namely the leptin -2548 (G/A), adiponectin 276 (G/T), and adiponectin 45 (T/G) polymorphisms) and/or adipokine serum levels., Methods: A total of 145 women participated in the study. For the analysis of serum adipokine levels, 19 healthy fertile women (control group) and 60 women suffering from RPL were included. For the polymorphism analysis, 126 women suffering from RPL were included. Serum adipokine levels were determined using a commercial radioimmunoassay kit. Adipokine polymorphisms were analyzed using an allele-specific polymerase chain reaction (PCR)., Results: Our immunoassays revealed that serum leptin levels were similar in control and RPL groups (17.34 and 20.16 ng/mL, respectively). In contrast, serum adiponectin levels were significantly higher in women with RPL than in controls (9.83 and 6.89 μg/mL, respectively; P < 0.05). Unfortunately, our allele-specific PCR experiments did not reveal any significant differences in allele frequency between women with RPL and NCBI allele frequencies., Conclusion: This study demonstrates that adiponectinemia is increased in patients suffering from RPL. However, association of adiponectin with adverse pregnancy outcomes remains to be elucidated., (© 2018 Japan Society of Obstetrics and Gynecology.)

Successful human embryo implantation requires a proper differentiation of endometrial stromal cells (ESCs) into decidual cells, during a process called decidualization. ESCs express specific molecules, such as prolactin, insulin-like growth factor-binding protein-1 (IGFBP-1) and connexin-43. Decidual cells are also involved in the control of trophoblast invasion, by secreting various factors, such as matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). Adiponectin is an adipokine with insulin-sensitizing, anti-inflammatory and anti-proliferative effects. At the embryo-maternal interface, adiponectin promotes differentiation and invasion of human trophoblastic cells. We hypothesize that the effects of adiponectin on endometrium could counteract its pro-invasive effects previously described in the human trophoblast. In this context, we have firstly demonstrated that adiponectin downregulates IGFBP-1 and connexin-43 mRNA expressions, as well as prolactin secretion in ESCs, suggesting an anti-differentiative effect of adiponectin. Secondly, we found that invasive capacities of trophoblastic cell line HTR-8/SVneo are reduced in the presence of conditioned media from ESC cultured in the presence of adiponectin. Adiponectin's anti-invasive action is associated with a decreased activity of MMP-2 and MMP-9, and an increased TIMP-3 mRNA expression in ESCs. Finally, adiponectin receptors ( ADIPOR1 and ADIPOR2 ) knockdown abolishes the anti-differentiative and anti-invasive effects of adiponectin in human ESCs. Altogether, our results suggest that adiponectin reduces the decidualization process and inversely induces the production of endometrial factors that limit trophoblast invasion. Thus, through a dual control in trophoblast and endometrial cells, adiponectin appears as a pivotal actor of the embryo implantation process., (© 2017 The authors.)

From the earliest stages of gestation, embryonic-maternal interaction has a key role in a successful pregnancy. Various factors present during gestation may significantly influence this type of juxta/paracrine interaction. PreImplantation Factor (PIF) is a recently identified factor with activity at the fetomaternal interface. PIF is secreted by viable embryos and directly controls placental development by increasing the invasive capacity of human extravillous trophoblasts (EVTs). To further specify PIF's role in the human placenta, we analyzed the genome-wide expression profile of the EVT in the presence of a synthetic PIF analog (sPIF). We found that sPIF exposure altered several pathways related to p53 signaling, survival and the immune response. Functional assays revealed that sPIF acts through the p53 pathway to reduce both early and late trophoblast apoptosis. More precisely, sPIF (i) decreases the phosphorylation of p53 at Ser-15, (ii) enhances the B-cell lymphoma-2 (BCL2) expression and (iii) reduces the BCL2-associated X protein (BAX) and BCL2 homologous antagonist killer (BAK) mRNA expression levels. Furthermore, invalidation experiments of TP53 allowed us to demonstrate that PIF's effects on placental apoptosis seemed to be essentially mediated by this gene. We have clearly shown that p53 and sPIF pathways could interact in human trophoblast and thus promotes cell survival. Furthermore, sPIF was found to regulate a gene network related to immune tolerance in the EVT, which emphasizes the beneficial effect of this peptide on the human placenta. Finally, the PIF protein levels in placentas from pregnancies affected by preeclampsia or intra-uterine growth restriction were significantly lower than in gestational age-matched control placentas. Taken as a whole, our results suggest that sPIF protects the EVT's functional status through a variety of mechanisms. Clinical application of sPIF in the treatment of disorders of early pregnancy can be envisioned.

Background: International recommendations in favor of screening for vaginal infection in pregnancy are based on heterogeneous criteria. In most developed countries, the diagnosis of bacterial vaginosis is only recommended for women with high-risk of preterm birth. The Nugent score is currently used, but molecular quantification tools have recently been reported with a high sensitivity and specificity. Their value for reducing preterm birth rates and related complications remains unexplored. This trial was designed to assess the cost-effectiveness of a systematic screen-and-treat program based on a point-of-care technique for rapid molecular diagnosis, immediately followed by an appropriate antibiotic treatment, to detect the presence of abnormal vaginal flora (specifically, Atopobium vaginae and Gardnerella vaginalis) before 20 weeks of gestation in pregnant women in France. We hypothesized that this program would translate into significant reductions in both the rate of preterm births and the medical costs associated with preterm birth., Methods/design: A multicenter, open-label randomized controlled trial (RCT) will be conducted in which 20 French obstetrics and gynecology centers will recruit eligible pregnant women at less than 20 weeks gestation with singleton pregnancy and with a low-risk factor for preterm birth. Interventions will include a) an experimental group that will receive a systematic rapid screen-and-treat program from a point-of-care analysis using a molecular quantification method and b) a control group that will receive usual care management. Randomization will be in a 1:1 allocation ratio. The primary endpoint that will be assessed over a period of 12 months will be the incremental cost-effectiveness ratio (ICER) expressed as cost per avoided preterm birth before 37 weeks. Secondary endpoints will include ICER per avoided preterm birth before 24, 28 and 32 weeks, obstetrical outcomes, neonatal outcomes, rates of treatment failure and recurrence episodes for positive women. Uncertainty surrounding these estimates will be addressed using nonparametric bootstrapping and represented using cost-effectiveness acceptability curves. A total of 6,800 pregnant women will be included., Discussion: This appropriate randomized controlled design will provide insight into the cost-effectiveness and therefore the potential cost savings of a rapid screen-and-treat strategy for molecular abnormal vaginal flora in pregnant women. National and international recommendations could be updated based on the findings of this study., Trial Registration: ClinicalTrials.gov: NCT02288832 (registration date: 30 October 2014); Eudract: 2014-001559-22.

Objective: To measure mitochondrial content and the expression of estrogen-related receptor-γ (ERRγ, a major inducer of mitochondrial biogenesis) in placentas from women with intrauterine growth restriction (IUGR) associated or not with pre-eclampsia (PE), relative to control placentas., Design: Case-control study., Setting: Teaching hospital and university research laboratory., Patient(s): Thirty-nine placentas from women with IUGR, 8 IUGR+PE, and 30 controls., Intervention(s): None., Main Outcome Measure(s): Mitochondrial DNA and protein content, gene and protein expression., Result(s): We observed significantly lower placental mitochondrial DNA and protein contents (associated with down-regulation of ERRγ expression) in IUGR and IUGR+PE placentas, relative to control placentas. Our results also revealed that the placental mitochondrial DNA content was directly correlated with fetal weight. Moreover, we observed significantly lower peroxisome proliferator-activated receptor-γ coactivator-1α and sirtuin 1 messenger RNA expression levels in IUGR+PE placentas, relative to control placentas., Conclusion(s): The low mitochondrial DNA and protein contents observed in IUGR placentas are probably due to down-regulation of ERRγ expression. This finding suggests that ERRγ has a major role in the control of placental development., (Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Different studies performed in rodents revealed that bisphenol-A (BPA), an environmental compound, altered early embryonic development. However, little is known concerning the direct effects of BPA on human implantation process. Thus, we decided to study in vitro BPA's effects on proliferative capacities of the human trophoblastic cell line, JEG-3. For this purpose, we first have shown that JEG-3 cells express the specific BPA receptor, namely estrogen-related receptor γ1 (ERRγ1). Secondly, we demonstrated that BPA did not exert any cytotoxic action in JEG-3 cells up to 10(-6)M. Moreover [(3)H]-thymidine incorporation experiments revealed that BPA significantly reduced cell proliferation. The results also showed that BPA induced JEG-3 apoptosis capacity as reflected by DNA fragmentation experiments. In conclusion, we describe here the direct impact of BPA on trophoblastic cell number mediated through both anti-proliferative and pro-apoptotic effects., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) could play a role in the regulation of interleukin (IL)-15 and IL-18, cytokines crucial for angiogenesis and uterine natural killer (uNK) cell recruitment during embryo implantation. We therefore confirmed the endometrial presence of TWEAK/fibroblast growth factor inducible-14 (Fn-14) and documented simultaneously the cytotoxic KIR receptor (NKp46) of uNK cells in the human endometrium while TWEAK, Fn-14, IL-15, and IL-18 mRNA were quantified by real-time polymerase chain reaction in relation to the recruitment of CD56+ cells among fertile control women and patients who had failed to implant after assisted reproduction treatment., (Copyright (c) 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Numerous epidemiological studies have documented that obesity is a risk factor for breast cancer especially in post-menopausal women. However, the molecular basis of this association is not well known. In contrast to leptin, plasma levels of adiponectin, another major adipokine, are decreased in obese subjects. Therefore, we and others hypothesized that adiponectin may be a paracrine factor negatively controlling mammary tumor development. We recently demonstrated growth inhibition of the estrogen-sensitive breast cancer MCF-7 cell line by adiponectin. The purpose of the present study was to determine whether this anti-proliferative effect of adiponectin also applies to the MDA-MB 231 estrogen-insensitive breast epithelial cancer cell line. Our results demonstrate that i) the adiponectin-specific receptors AdipoR1 and R2 are expressed in these cells, and ii) the subphysiological concentrations of recombinant adiponectin inhibit MDA-MB 231 cell growth and concomitantly enhance the expression of Bax and p53, two pro-apoptotic genes. Moreover, the invalidation of AdipoR1 and R2 mRNA experiments demonstrated that the anti-proliferative and pro-apoptotic effects of adiponectin were partially mediated via AdipoR1 and R2. We describe, for the first time, that AdipoR mRNA expression was down-regulated by adiponectin and leptin in MDA-MB 231 cells. Taken altogether, these results strongly suggest that the two adipokines should be considered as i) additional factors of breast cancer risk, and ii) may therefore be potential targets in breast cancer therapy.

Objective: To evaluate the influence of aging on the achondroplasia mutation rate in the male germline., Design: Studies in sperm and testis biopsy DNA according to donor's age., Setting: University teaching hospital., Patient(s): Seventeen donors aged 30 to 65 years for sperm collection and 14 deceased donors aged 53 to 95 years for testis biopsies, all with normal stature., Intervention(s): Testes were obtained from 14 deceased donors, and sperm was obtained from 17 patients who requested ART., Main Outcome Measure(s): Real-time polymerase chain reaction quantification of the G1138A mutation in sperm and testis biopsies., Result(s): The rate of G1138A mutation did not significantly vary with age in sperm, whereas in testis biopsies it increased markedly past the age of 70 years. Moreover, and for the first time, a mosaic for this mutation was detected in the testis of three subjects who were >80 years of age., Conclusion(s): These findings could contribute to providing a molecular explanation for the increased incidence of achondroplastic offspring with advanced paternal age.

Introduction: Uterine receptivity was assessed simultaneously by measurement of vasoactive cytokines possibly involved in development of spiral arteries and by assessment of endometrial and uterine arterial blood flow. The objective was to explore the relationship between cytokine-related dysregulation and endometrial vascularisation in women with repeated implantation failures after in vitro fertilisation embryo transfer (IVF-ET)., Materials and Methods: We studied 40 women with recurrent IVF/ICSI-ET failures, despite replacement of more than 10 embryos of 'good quality', and 8 fertile controls. Three-dimensional ultrasound with power angiography was performed to record the sub-endometrial vascular flow index (VFI) and uterine artery pulsatility index prior to endometrial biopsy at day 21-23 of a monitored natural cycle. Endometrial IL-18, IL-18BP and IL-15 mRNA expression was assessed by real-time PCR, and the number of CD56(+) cells determined by immunochemistry., Results: IL-18 and IL-15 mRNA expression was significantly different between the two groups. The range of variation in vascular imaging data was increased in the implantation failure (IF) group. The mRNA ratio for IL-15, but not the other cytokines, correlated with sub-endometrial vascular flow (r=0.65; p<0.001). This ratio correlated also with the mean number of CD56(+) cells per high-power field (r=0.41; p=0.005). Both IL-18 and IL-18BP mRNA expression was significantly negatively correlated with mean uterine artery pulsatility index (r=-0.37 and -0.43; p=0.02 and 0.01, respectively)., Conclusion: Comprehensive ultrasonographic indicators appear to be related to various mechanisms, including insufficient or excessive uterine NK cell recruitment and inadequate endothelial vascular remodelling. New molecular tools may be useful in providing greater precision of uterine receptivity than ultrasonic indicators alone.

It is well known that pregnancy is associated with fat weight gain. However, the mechanisms whereby fat mass accumulation is controlled during this period are poorly understood. Therefore, we attempted to determine whether human chorionic gonadotropin (HCG), in vitro, influences human adipose tissue development and/or metabolism. For the first time, HCG/LH receptor was characterized in human adipose cells. We also demonstrated that physiological concentrations of HCG, while unaltering both lipolysis and expression of two markers of lipogenesis (FAS and ADD1) in human mature adipocytes, stimulate human preadipocyte growth via the activation of a protein kinase A-independent mitogen-activated protein kinase/c-fos signaling pathway. HCG also moderately increases the preadipocyte differentiation capacity as reflected by enhanced glycerophosphate dehydrogenase activity and expression of key adipogenic transcriptional factors (C/enhancer-binding protein alpha and peroxisome proliferator-activated receptor gamma 2). Finally, HCG significantly stimulates the secretion of the pro-adipogenic factor, leptin, from human adipose tissue. Taken altogether, these data suggest that the pro-adipogenic effect of HCG in human preadipocytes contributes to explain why increased fat storage occurs during the first trimester of pregnancy.

Objective: To assess the impact of antibiotic prophylaxis on the emergence of vancomycin-resistant strains of Enterococcus faecium, Enterococcus faecalis, and Staphylococcus aureus and the incidence of surgical site infection (SSI) after vancomycin or cefazolin prophylaxis for femoral neck fracture surgery., Design: Prospective cohort study., Setting: A hospital with a high prevalence of methicillin-resistant S. aureus (MRSA) carriage., Patients: All patients admitted with a femoral neck fracture from March 1, 2004 through February 28, 2005 were prospectively identified and screened for MRSA and vancomycin-resistant (VRE) carriage at admission and at day 7. Deep incisional and organ/space SSIs were also recorded., Results: Of 263 patients included in the study, 152 (58%) received cefazolin and 106 (40%) received vancomycin. At admission, the prevalence of MRSA carriage was 6.8%; it was 12% among patients with risk factors and 2.2% among patients with no risk factors (P=.002). At day 7 after surgery, there were 6 patients (2%) who had hospital-acquired MRSA, corresponding to 0.7% in the cefazolin group and 5% in the vancomycin group (P=.04); none of the MRSA isolates were resistant to glycopeptides. The rate of VRE carriage at admission was 0.4%. Three patients (1%) had acquired carriage of VRE (1 had E. faecium and 2 had E. faecalis); all 3 were in the cefazolin group (2% of patients) and none in the vancomycin group (P=.27). Eight SSIs (3%) occurred, 4% in the cefazolin group and 2% in the vancomycin group (P=.47)., Conclusions: This preliminary study demonstrates that cefazolin and vancomycin prophylaxis have similar impacts on the emergence of glycopeptide-resistant pathogens. Neither MRSA infection nor increased rates of SSI with other bacteria were observed in the vancomycin group, suggesting that a larger multicenter study should be initiated.

Components of the adipose renin-angiotensin system (RAS) have been suggested as providing a potential path-way linking obesity to hypertension. In adipose cells, the biological responses to beta-adrenergic stimulation are mediated by an increase in intracellular cAMP. Because an association exists among body fat mass, hypertension, and increased sympathetic stimulation, we examined the influence of cAMP on angiotensinogen (ATG) expression and secretion in human adipose tissue and in parallel we studied the DNA binding activity of CRE transcriptional factors. A 24 h exposure to the cAMP analog 8Br-cAMP resulted in significant increases in ATG mRNA levels (+176+/-60%) and protein secretion (+40+/-27%). The ability of 8Br-cAMP to promote ATG gene expression was unaltered by H89, a protein kinase A inhibitor, because H89 per se was found to stimulate ATG mRNA levels and protein secretion. Moreover, 8Br-cAMP stimulated the specific CRE DNA binding activity (+115+/-14%) in human adipocyte nuclear extracts as assessed by electrophoretic mobility shift assays. These results indicate that cAMP upregulates in vitro ATG expression and secretion in human adipose tissue and that the induction in ATG mRNA levels appears to result, at least in part, from positive effects on the DNA binding activity of CRE transcription factors. Further studies are required to determine whether this regulatory pathway is activated in human obesity and to elucidate the importance of adipose ATG to the elevated blood pressure observed in this pathological state.

The adipose renin-angiotensin system (RAS) has been assigned to participate in the control of adipose tissue development and in the pathogenesis of obesity-related hypertension. In adipose cells, the biological responses to beta-adrenergic stimulation are mediated by an increase in intracellular cAMP. Because cAMP is known to promote adipogenesis and because an association exists between body fat mass, hypertension, and increased sympathetic stimulation, we examined the influence of cAMP on angiotensinogen (ATG) expression and secretion in rat adipose tissue. Exposure of primary cultured differentiated preadipocytes to the cAMP analog 8-bromoadenosine 3',5'-cyclic monophosphate (8-BrcAMP) or cAMP-stimulating agents (forskolin and IBMX) results in a significant increase in ATG mRNA levels. In adipose tissue fragments, 8-BrcAMP also increases ATG mRNA levels and protein secretion, but not in the presence of the protein kinase A inhibitor H89. The addition of isoproterenol, known to stimulate the synthesis of intracellular cAMP via beta-adrenoreceptors, had the same stimulatory effect on ATG expression and secretion. These results indicate that cAMP in vitro upregulates ATG expression and secretion in rat adipose tissue via the protein kinase A-dependent pathway. Further studies are required to determine whether this regulatory pathway is activated in human obesity, where increased sympathetic tone is frequently observed, and to elucidate the importance of adipose ATG to the elevated blood pressure observed in this pathological state.

By repeated and successive treatments of five strains of methicillin-resistant Staphylococcus aureus with sub-inhibitory concentrations of vancomycin and of teicoplanin, the authors have confirmed that selection of resistant strains could be obtained more easily with teicoplanin than with vancomycin. Moreover, we have shown that treatments with subinhibitory concentrations of teicoplanin could also influence the activity of vancomycin, although the strains have never been in contact with the latter antibiotic. This could account, at least in part, for the downhill evolution of the activity of glycopeptides against staphylococci, observed this last years. Indeed, the efficacy of these antibiotics upon which treatment of severe infections due to multiresistant staphylococci relies, is lowering. Considering the challenge, this risk is worth being not only evaluated by a reinforced epidemiologic surveillance, but also limited by more severe criteria for the prescription and the follow-up of treatments with glycopeptides.