Ronit Haimov-Kochman

Endometrial NK Cells Are Special Immature Cells That Await Pregnancy

NK cells populate the human endometrium before pregnancy. Unlike decidual NK cells that populate the decidua during pregnancy, the NK cells present in the human endometrium, before pregnancy, have not been fully characterized. In this study, we provide a detailed analysis of the origin, phenotype, and function of endometrial NK cells (eNK). We show that eNK cells have a unique receptor repertoire. In particular, they are negative for NKp30 and chemokine receptor expression, which distinguishes them from any other NK subset described so far. We further show that eNK cells lack NK-specific functional phenotype and activity such as cytokine secretion and cytotoxicity, before IL-15 stimulation. Following such stimulation, endometrial NK cells acquire phenotype and function that are similar to those of decidual NK cells. We therefore suggest that eNK cells are inactive cells (before IL-15 activation and in relation to the known NK activity) that are present in the endometrium before conception, waiting for pregnancy.

Gradual discontinuation of hormone therapy does not prevent the reappearance of climacteric symptoms: a randomized prospective study.

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Modeling of Human Cytomegalovirus Maternal-Fetal Transmission in a Novel Decidual Organ Culture

ABSTRACT Human cytomegalovirus (HCMV) is the leading cause of congenital infection, associated with severe birth defects and intrauterine growth retardation. The mechanism of HCMV transmission via the maternal-fetal interface is largely unknown, and there are no animal models for HCMV. The initial stages of infection are believed to occur in the maternal decidua. Here we employed a novel decidual organ culture, using both clinically derived and laboratory-derived viral strains, for the ex vivo modeling of HCMV transmission in the maternal-fetal interface. Viral spread in the tissue was demonstrated by the progression of infected-cell foci, with a 1.3- to 2-log increase in HCMV DNA and RNA levels between days 2 and 9 postinfection, the expression of immediate-early and late proteins, the appearance of typical histopathological features of natural infection, and dose-dependent inhibition of infection by ganciclovir and acyclovir. HCMV infected a wide range of cells in the decidua, including invasive cytotrophoblasts, macrophages, and endothelial, decidual, and dendritic cells. Cell-to-cell viral spread was revealed by focal extension of infected-cell clusters, inability to recover infectious extracellular virus, and high relative proportions (88 to 93%) of cell-associated viral DNA. Intriguingly, neutralizing HCMV hyperimmune globulins exhibited inhibitory activity against viral spread in the decidua even when added at 24 h postinfection—providing a mechanistic basis for their clinical use in prenatal prevention. The ex vivo-infected decidual cultures offer unique insight into patterns of viral tropism and spread, defining initial stages of congenital HCMV transmission, and can facilitate evaluation of the effects of new antiviral interventions within the maternal-fetal interface milieu.

Reproductive outcome of fresh or frozen–thawed embryo transfer is similar in high-risk patients for ovarian hyperstimulation syndrome using GnRH agonist for final oocyte maturation and intensive luteal support

BACKGROUND Triggering ovulation by GnRH agonist (GnRHa) in GnRH antagonist IVF protocols coupled with adequate luteal phase support has recently been suggested as a means to prevent ovarian hyperstimulation syndrome (OHSS). Our objective was to examine the outcome of fresh embryo transfer (f-ET) after triggering ovulation by GnRHa and providing intensive luteal phase supplementation, compared with that of the next first frozen-thawed embryo transfer (ft-ET) after cycles with the same protocol and cryopreservation of all the embryos. METHODS We performed a cohort study at a university-based IVF clinic. The study population was patients at high risk for OHSS. A daily dose of 50 mg i.m. progesterone in oil and 6 mg of oral 17-β-estradiol initiated on oocyte retrieval day in the f-ET group (n= 70). In the ft-ET group (n= 40) the embryos were cryopreserved and transferred in the next cycle. RESULTS The live birth rate per f-ET was 27.1 versus 20% in the ft-ET groups [P = 0.4; rate ratio = 1.36 (0.65-2.81)]. The implantation, pregnancy and spontaneous abortion rates were comparable in both groups. None of the patients developed OHSS. CONCLUSIONS In this observational cohort study, we showed that triggering ovulation with GnRHa and intensive luteal phase support is a promising new modality to prevent OHSS without the cost of cycle cancellation, ET deferral and reduced clinical pregnancy rates. Confirmation of these findings by RCTs is now required.

The natural course of endometrial polyps: Could they vanish when left untreated?

OBJECTIVE To report the occurrence of spontaneous regression of three endometrial polyps detected by hysteroscopy. DESIGN Case series. SETTING A uterine imaging unit in an academic medical center. PATIENT(S) Three patients diagnosed as having an endometrial polyp of 5-8 mm on hysteroscopy. INTERVENTION(S) Patient deferral of the surgical procedure for several months. MAIN OUTCOME MEASURE(S) Presence of a uterine polyp in the next hysteroscopy. RESULT(S) The polyps disappeared spontaneously. CONCLUSION(S) Deferral of hysteroscopic polypectomy for a few months in asymptomatic women in the hope of spontaneous regression of the polyps may be justified.

Zika Virus Infects Early- and Midgestation Human Maternal Decidual Tissues, Inducing Distinct Innate Tissue Responses in the Maternal-Fetal Interface

ABSTRACT Zika virus (ZIKV) has emerged as a cause of congenital brain anomalies and a range of placenta-related abnormalities, highlighting the need to unveil the modes of maternal-fetal transmission. The most likely route of vertical ZIKV transmission is via the placenta. The earliest events of ZIKV transmission in the maternal decidua, representing the maternal uterine aspect of the chimeric placenta, have remained unexplored. Here, we show that ZIKV replicates in first-trimester human maternal-decidual tissues grown ex vivo as three-dimensional (3D) organ cultures. An efficient viral spread in the decidual tissues was demonstrated by the rapid upsurge and continued increase of tissue-associated ZIKV load and titers of infectious cell-free virus progeny, released from the infected tissues. Notably, maternal decidual tissues obtained at midgestation remained similarly susceptible to ZIKV, whereas fetus-derived chorionic villi demonstrated reduced ZIKV replication with increasing gestational age. A genome-wide transcriptome analysis revealed that ZIKV substantially upregulated the decidual tissue innate immune responses. Further comparison of the innate tissue response patterns following parallel infections with ZIKV and human cytomegalovirus (HCMV) revealed that unlike HCMV, ZIKV did not induce immune cell activation or trafficking responses in the maternal-fetal interface but rather upregulated placental apoptosis and cell death molecular functions. The data identify the maternal uterine aspect of the human placenta as a likely site of ZIKV transmission to the fetus and further reveal distinct patterns of innate tissue responses to ZIKV. Our unique experimental model and findings could further serve to study the initial stages of congenital ZIKV transmission and pathogenesis and evaluate the effect of new therapeutic interventions. IMPORTANCE In view of the rapid spread of the current ZIKV epidemic and the severe manifestations of congenital ZIKV infection, it is crucial to learn the fundamental mechanisms of viral transmission from the mother to the fetus. Our studies of ZIKV infection in the authentic tissues of the human maternal-fetal interface unveil a route of transmission whereby virus originating from the mother could reach the fetal compartment via efficient replication within the maternal decidual aspect of the placenta, coinhabited by maternal and fetal cells. The identified distinct placental tissue innate immune responses and damage pathways could provide a mechanistic basis for some of the placental developmental abnormalities associated with ZIKV infection. The findings in the unique model of the human decidua should pave the way to future studies examining the interaction of ZIKV with decidual immune cells and to evaluation of therapeutic interventions aimed at the earliest stages of transmission.

Hot flashes revisited: Pharmacological and herbal options for hot flashes management. What does the evidence tell us?

Background.  Hot flashes are the most frequent symptoms of menopause and the most common reason for climacteric women seeking medical advice. Estrogen therapy is by far the most effective therapy. However, fears of side‐effect of estrogen therapy urged many patients to seek alternative modalities for symptomatic relief.

Models of vertical cytomegalovirus (CMV) transmission and pathogenesis

Despite the considerable clinical impact of congenital human cytomegalovirus (HCMV) infection, the mechanisms of maternal–fetal transmission and the resultant placental and fetal damage are largely unknown. Here, we discuss animal models for the evaluation of CMV vaccines and virus-induced pathology and particularly explore surrogate human models for HCMV transmission and pathogenesis in the maternal–fetal interface. Studies in floating and anchoring placental villi and more recently, ex vivo modeling of HCMV infection in integral human decidual tissues, provide unique insights into patterns of viral tropism, spread, and injury, defining the outcome of congenital infection, and the effect of potential antiviral interventions.

Regular exercise is the most significant lifestyle parameter associated with the severity of climacteric symptoms: a cross sectional study

OBJECTIVE To assess the association between demographic and lifestyle parameters and perceived severity of the climacteric syndrome in perimenopausal women. STUDY DESIGN A cross-sectional study of 151 healthy women aged 45-55 years who attended the University Medical Center affiliated menopause clinics. The analysis was based on self completion of the Greene climacteric score, consisting of psychological, somatic/physical, sexual and vasomotor subscores. The Greene total score and subscores were the main outcomes of the study. RESULTS Of all demographic, anthropometric and lifestyle parameters recorded, the correlates with reduced total Greene score were high-order maternity and regular physical exercise. Mothers of 3 or more children reported significantly lower total Greene score (18±12.8 vs. 22.1±8.1) (p=0.01) as well as lower psychological subscore (8.7±6.8 vs. 11.5±5.4) (p=0.01). Regular physical activity was also associated with significantly lower total Greene score (17.0±11.0 vs. 22.6±11.3) (p=0.01) and specifically lower psychological subscore (9.5±6.6 vs. 12.8±7.7) (p=0.03) and sexual subscore (1.1±0.99 vs. 1.61±1.05) (p=0.03). Linear regression models showed that regular exercise was the lifestyle parameter most significantly correlated with a lower total Greene score (p=0.006) independent of menopausal status. Of particular note, regular exercise was significantly correlated with lower psychological (p=0.006) and physical subscores (p=0.06). Moreover, the higher the frequency of exercise (both aerobic and non aerobic), the lower the severity of the climacteric symptoms reported, yet the vasomotor and sexual subscores remained unchanged. CONCLUSIONS Regular exercise of at least 3 times a week was the most significant lifestyle parameter to be associated with the severity of climacteric symptoms.

Sex ratio is remarkably constant

OBJECTIVE To study whether the sex of the offspring is related to increasing parental age, gravidity, and parity, hypothesizing an altered male-to-female sex ratio with the advancing parental age. DESIGN A large retrospective cohort study. SETTING The study analyzed birth records of Hadassah Hebrew University Medical Center in Jerusalem from June 2003 to December 2006. PATIENT(S) 35,837 birth records were analyzed including 941 multifetal deliveries, excluding foreign inhabitants (n = 744), missing data for the main study outcome (n = 2) and parturients over 50 years to control for egg donation (n = 26). INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Male-to-female sex ratio. RESULT(S) The male-to-female sex ratio of all the newborns was 1.05. This ratio did not change significantly with either maternal or paternal age. Neither gravidity nor parity affected the male-to-female ratio. The only factor that affected the regression of sex ratio was the length of gestation. CONCLUSION(S) Sex ratio at birth is remarkably constant. No association was found between parental age or birth order and neonatal sex ratio.