"Jack-of-all-trades" is parthenogenetic.

Sex is evolutionarily more costly than parthenogenesis, evolutionary ecologists therefore wonder why sex is much more frequent than parthenogenesis in the majority of animal lineages. Intriguingly, parthenogenetic individuals and species are as common as or even more common than sexuals in some major and putative ancient animal lineages such as oribatid mites and rotifers. Here, we analyzed oribatid mites (Acari: Oribatida) as a model group because these mites are ancient (early Paleozoic), widely distributed around the globe, and include a high number of parthenogenetic species, which often co-exist with sexual oribatid mite species. There is evidence that the reproductive mode is phylogenetically conserved in oribatid mites, which makes them an ideal model to test hypotheses on the relationship between reproductive mode and species' ecological strategies. We used oribatid mites to test the frozen niche variation hypothesis; we hypothesized that parthenogenetic oribatid mites occupy narrow specialized ecological niches. We used the geographic range of species as a proxy for specialization as specialized species typically do have narrower geographic ranges than generalistic species. After correcting for phylogenetic signal in reproductive mode and demonstrating that geographic range size has no phylogenetic signal, we found that parthenogenetic lineages have a higher probability to have broader geographic ranges than sexual species arguing against the frozen niche variation hypothesis. Rather, the results suggest that parthenogenetic oribatid mite species are more generalistic than sexual species supporting the general-purpose genotype hypothesis. The reason why parthenogenetic oribatid mite species are generalists with wide geographic range sizes might be that they are of ancient origin reflecting that they adapted to varying environmental conditions during evolutionary history. Overall, our findings indicate that parthenogenetic oribatid mite species possess a widely adapted general-purpose genotype and therefore might be viewed as "Jack-of-all-trades."

Self-Observation and Peer Feedback as a Faculty Development Approach for Problem-Based Learning Tutors: A Program Evaluation.

PROBLEM: Good teaching requires spontaneous, immediate, and appropriate action in response to various situations. It is even more crucial in problem-based learning (PBL) tutorials, as the tutors, while directing students toward the identification and attainment of learning objectives, must stimulate them to contribute to the process and provide them with constructive feedback. PBL tutors in medicine lack opportunities to receive feedback from their peers on their teaching strategies. Moreover, as tutorials provide little or no time to stop and think, more could be learned by reflecting on the experience than from the experience itself. We designed and evaluated a faculty development approach to developing PBL tutors that combined self-reflection and peer feedback processes, both powerful techniques for improving performance in education. INTERVENTION: We developed an observation instrument for PBL facilitation to be used both by tutors to self-observe and reflect on own teaching strategies and by peers to observe and provide feedback to tutors. Twenty PBL sessions were video-recorded. Tutors completed the instrument immediately after their PBL session and again while watching their video-recorded session (self-observation). A group of three observers completed the instrument while watching each recorded session and provided feedback to each tutor (peer observation and feedback). We investigated tutors' perceptions of the feasibility and acceptability of the approach and gathered data on its effectiveness in enhancing tutors' facilitation skills. CONTEXT: The preclinical medical curriculum at the University of Geneva is essentially taught by PBL. A new program of faculty development based on self-observation and peer feedback was offered to voluntary tutors and evaluated. OUTCOME: Our results suggest that self-observation and peer feedback, supported by an instrument, can be effective in enhancing tutors' facilitation skills. Reflection on self-observation raised teachers' awareness of the effectiveness of the strategies they used to foster student learning. This motivated a need to change their teaching practice. However, for the changes to become operative, peer feedback was required, providing the cues and strategies needed to improve the facilitation skills. LESSONS LEARNED: Peer coaching was considered feasible and useful to improve tutors' facilitation skills. Evaluating the program made it possible to assess tutors' needs and the reasons underlying their difficulties, and this in turn provided the basis for advanced workshops. Nonetheless, aspects related to logistics and the time constraints of such an individualized approach, as well as the cultural appropriation of peer coaching, might be obstacles that need to be addressed.

Effect of Growth Hormone on Endometrial Thickness and Fertility Outcome in the Treatment of Women with Panhypopituitarism: A Case Report.

BACKGROUND: The role of growth hormone (GH) in female reproduction has become a topic of increasing interest over the last decade. The replacement of GH for ovulation induction in women with hypopituitarism remains controversial. The role of GH in the human endometrium is still largely unknown. To the best of our knowledge, this study represents the first case report showing evidence that GH might play a role not only for ovulation induction, but also for the development of endometrial thickness in women with hypopituitarism. CASE: A 32-year-old hypophysectomized. woman, known for primary infertility, experienced multiple IVF/embryo transfer failures with inadequate endometrial development. The use of GH replacement therapy followed by conventional controlled ovarian hyperstimulation enabled endometrial development and better ovarian response to gonadotropins, leading to a successful ongoing pregnancy. CONCLUSION: The substitution with GH resulted in fewer days of ovarian stimulation, an acceptable endometrium, and a twin pregnancy delivered at 38 weeks' gestation.

Hemispheric specialization varies with EEG brain resting states and phase of menstrual cycle.

A growing body of behavioral studies has demonstrated that women's hemispheric specialization varies as a function of their menstrual cycle, with hemispheric specialization enhanced during their menstruation period. Our recent high-density electroencephalogram (EEG) study with lateralized emotional versus neutral words extended these behavioral results by showing that hemispheric specialization in men, but not in women under birth-control, depends upon specific EEG resting brain states at stimulus arrival, suggesting that hemispheric specialization may be pre-determined at the moment of the stimulus onset. To investigate whether EEG brain resting state for hemispheric specialization could vary as a function of the menstrual phase, we tested 12 right-handed healthy women over different phases of their menstrual cycle combining high-density EEG recordings and the same lateralized lexical decision paradigm with emotional versus neutral words. Results showed the presence of specific EEG resting brain states, associated with hemispheric specialization for emotional words, at the moment of the stimulus onset during the menstruation period only. These results suggest that the pre-stimulus EEG pattern influencing hemispheric specialization is modulated by the hormonal state.

Role of decidua in trophoblastic invasion.

OBJECTIVE: Proliferation, migration and invasion of trophoblastic cells into the maternal endometrium are essential steps in human embryo implantation and placentation. Trophoblast invasion is normally limited in time, only during first and early second trimester of pregnancy, and in space, limited to the endometrium and the proximal third of myometrium. This process requires among other factors: the metalloproteinases (MMP) 2 and 9. Shallow trophoblast invasion is associated with pathologies including preeclampsia and fetal growth restriction whereas unlimited invasion is associated with hydatidiform moles and choriocarcinomas. METHODS: In order to understand the role of decidua in this endometrial invasion by trophoblastic cells, we have developed a model of coculture of decidual and cytotrophoblastic cells in which we can evaluate the effect of each partner on the proliferative and invasive properties of the other. RESULTS: Surprisingly, decidual cells secrete highest levels of MMPs, and their invasive potential seems to be increased in presence of cytotrophoblast (CTB). In contrast, invasive properties of CTB are not modified by decidual cells. CONCLUSION: CTB secrete factors that favour invasion whereas decidua seems not to play a major role in regulating CTB invasion in vitro. Moreover, it is interesting to note that decidual cells could have potent invasive capacity which could explain, at least in part, endometriosis.

Alteration of circulating Placental Leucine Aminopeptidase (P-LAP) activity in preeclampsia.

OBJECTIVE: Placental Leucine Aminopeptiadse (P-LAP) also known as oxytocinase, is secreted by syncytiotrophoblast and increases gradually during pregnancy until delivery. It is a regulator of uterine contractions, of vascular resistance and of volume of the retroplacental blood pool. Recently, it was shown that it could also regulate metalloproteinase 9 activity and thus, invasiveness of trophoblastic cells. Since development of preeclampsia could be initiated by decreased cytotrophoblastic invasion of spiral arterioles and a reduced uteroplacental perfusion, we speculate that circulating P-LAP activity could be decreased during preeclampsia. MATERIALS AND METHODS: Case-control study was evaluated in 84 women. P-LAP activity was measured in n=51 healthy pregnant women at term, and compared with n=16 normotensive women delivering preterm and n=17 women diagnosed with pre-eclampsia. P-LAP activity was determined by colorimetry in plasma samples using L-Leucine-p-nitroanilide as substrate. RESULTS: P-LAP activity was significantly lower in sera of preeclamptic women (0.91+/-0.122 mDO/min) as compared to normotensive controls (1.41+/-0.103 mDO/min; p=0.003) irrespective of time of delivery. CONCLUSIONS: These findings confirm the probable involvement of P-LAP in trophoblast invasion and development of preeclampsia.

Glucose-regulated protein 78: a new partner of p53 in trophoblast.

Although wild-type p53 protein is overexpressed in first trimester trophoblast, it is inactive towards its target genes Metalloproteinase 2 and 9. This seems to be due to a complex mechanism of inactivation and stabilization of p53 relying on the formation of protein complexes involving the N-terminus of p53. To detect the proteins associated with this sequence, we incubated biotinylated p53 N-terminal peptide in cytotrophoblastic cell medium 24 h before lysis of cells. We purified the proteins retained on biotinylated peptide using a neutravidin affinity column. Proteins were then identified by peptide mass finger printing followed or not by peptide fragmentation sequencing. Among these proteins, we identified glucose-regulated protein 78 (GRP78) and verified its interaction with p53 in trophoblastic cells by immunoprecipitation and Western blot analysis. Moreover, the decreased expression of GRP78 induced by GRP78siRNA or versipelostatin decreased the formation of high molecular weight p53 complexes and p53 monomer and increased trophoblastic invasion. These results suggest that GRP78 is involved in inactivation and stabilization of p53 and in the regulation of trophoblastic invasion.

Coculture of decidua and trophoblast to study proliferation and invasion.

Proliferation, migration, and invasion of trophoblastic cells into the maternal endometrium are essential steps of human embryo implantation and placentation. Trophoblast invasion is normally limited in time (first trimester) and space (to the endometrium and to the proximal third of myometrium). Temporal and spatial regulation of trophoblast invasion is mediated in an autocrine way by trophoblastic factors and in a paracrine way by uterine factors. Shallow trophoblast invasion is associated with pathologies including preeclampsia and fetal growth restriction whereas unlimited invasion is associated with hydatidiform moles and choriocarcinomas. In order to understand this important biological process and to characterize some of its regulatory factors, we have developed a model of coculture of decidual and cytotrophoblastic cells in which we can evaluate the effect of each partner on the proliferative and invasive properties of the other.

Clinical uses of anti-Müllerian hormone assays: pitfalls and promises.

OBJECTIVE: To investigate whether the controversy about fluctuations of anti-Müllerian hormone (AMH) levels during the menstrual cycle results from differences between the immunoassays currently available: the Beckman Coulter Immunotech kit (Fullerton, CA) and the Diagnostic Systems Laboratories kit (Webster, TX). DESIGN: Prospective trial. SETTING: Fertility clinics of two tertiary university hospitals. PATIENT(S): One hundred sixty-eight blood samples from three different populations. Serial samples at set intervals from the LH surge were taken in a fourth population of 10 volunteers. INTERVENTION(S): We remeasured AMH levels by using the Diagnostic Systems Laboratories kit in 168 blood samples in which AMH initially had been measured by using the Beckman Coulter assay. We also conducted serial AMH measurements (n = 7) during the menstrual cycle of 10 women. MAIN OUTCOME MEASURE(S): Linear regression of AMH levels determined by using 2 different assays and analysis of variance of serial measurements in the menstrual cycle. RESULT(S): We found a linear relationship between the 2 methods, with a correlation coefficient of 0.88. When repeated individual AMH measures were longitudinally analyzed in relation to the LH surge, a slight but significant decrease was observed after ovulation. CONCLUSION(S): Differences in AMH fluctuations during the menstrual cycle reported in recent publications do not result from the use of different AMH assays. The changes in AMH levels after ovulation are slight, yet statistically significant. However, the fluctuations observed are smaller than intercycle variability and therefore are not clinically relevant as far as AMH measurements for clinical purposes are concerned. In daily practice, AMH therefore can be measured anytime during the menstrual cycle.

Is screening for fetal anomalies reliable in HIV-infected pregnant women? A multicentre study.

OBJECTIVE: To assess the impact of HIV infection on the reliability of the first-trimester screening for Down syndrome, using free beta-human chorionic gonadotrophin, pregnancy-associated plasma protein-A and fetal nuchal translucency, and of the second-trimester screening for neural tube defects, using alpha-fetoprotein. PATIENTS AND METHODS: Multicentre study comparing the multiples of the median of markers for Down syndrome and neural tube defect screening among 214 HIV-infected pregnant women and 856 HIV-negative controls undergoing a first-trimester Down syndrome screening test, and 209 HIV-positive women and 836 HIV-negative controls with a risk evaluation for neural tube defect. The influence of treatment, chronic hepatitis and HIV disease characteristics were also evaluated. RESULTS: Multiples of the median medians for pregnancy-associated plasma protein-A and beta-human chorionic gonadotrophin were lower in HIV-positive women than controls (0.88 vs. 1.05 and 0.84 vs. 1.09, respectively; P < 0.005), but these differences had no impact on risk estimation; no differences were observed for the other markers. No association was found between HIV disease characteristics, antiretroviral treatment use at the time of screening or chronic hepatitis and marker levels. CONCLUSION: Screening for Down syndrome during the first trimester and for neural tube defect during the second trimester is accurate for HIV-infected women and should be offered, similar to HIV-negative women.

Effects of ligands or substrate of insulin-regulated aminopeptidase (IRAP) on trophoblast invasion.

Insulin-regulated aminopeptidase (IRAP) activity increases during placentation and in the invasive tumor cell of trophoblast suggesting a role for this peptidase in the invasiveness of normal and malignant trophoblast. To investigate this hypothesis, we studied the effects of substrate (OT) and inhibitors (angiotensin peptides and LVV-H7) of IRAP on the first trimester trophoblast proliferation and invasion. Addition of these peptides in the culture medium of trophoblastic cells significantly decreased metalloproteinase-9 activity and cellular invasiveness while no effect was observed on cell proliferation. The peptide IRAP inhibitors could exert their effect on cytotrophoblastic cell invasiveness by inhibition of its enzymatic activity, and thus increasing half life of the known placental peptide substrate of IRAP, OT.

Human chorionic gonadotropin stimulates matrix metalloproteinases-2 and -9 in cytotrophoblastic cells and decreases tissue inhibitor of metalloproteinases-1, -2, and -3 in decidualized endometrial stromal cells.

OBJECTIVE: To investigate the influence of hCG on trophoblastic matrix metalloproteinases (MMPs) -2 and -9 as well as endometrial tissue inhibitor of metalloproteinases (TIMPs) -1, -2, and -3. DESIGN: In vitro experiment. SETTING: Research laboratory at a university medical center. PATIENT(S): Women undergoing legal abortions and premenopausal women undergoing hysterectomy for benign reasons. INTERVENTION(S): Human first trimester cytotrophoblasts and decidualized endometrial stromal cells were incubated with recombinant hCG. MAIN OUTCOME MEASURE(S): Trophoblastic MMP-2 and -9 were analyzed by enzyme-linked immunosorbent assay (ELISA) and zymography, and endometrial TIMP-1, -2, and -3 were measured by real time reverse transcriptase-polymerase chain reaction and ELISA. RESULT(S): HCG increases the secretion of MMP-2 and -9 in cytotrophoblasts dose dependently. This effect occurs after 4 hours of incubation and becomes less pronounced after 24 hours. In contrast, TIMP-1, -2, and -3 are significantly reduced by hCG in endometrial stromal cells in a time- and dose-dependent manner. CONCLUSION(S): These results suggest a regulatory role of hCG on the MMP/TIMP system at the implantation site. By increasing trophoblastic MMP secretion and reducing endometrial TIMP expression, hCG may be an important tool for the invading embryo to regulate the depth of its implantation.

Hemodynamic effect of angiotensin II receptor blockade in postmenopausal women on a high-sodium diet: A double-blind, randomized, placebo-controlled study.

BACKGROUND: Hypertension becomes increasingly prevalent after menopause. Postmenopausal women are more responsive to salt than premenopausal women, and they have been reported to develop marked renal vasoconstriction on a high-sodium diet. OBJECTIVE: The aim of this study was to assess whether angiotensin II receptor blockade can restore a normal pattern of renal response to salt in postmenopausal women on a high-sodium diet. We also assessed segmental renal sodium handling in that population. METHODS: Normotensive and hypertensive postmenopausal women not receiving hormone replacement therapy were enrolled in this prospective, double-blind, placebo-controlled, crossover study. They were assigned to receive irbesartan 150 mg or placebo for 6 weeks; the sequence in which they received irbesartan or placebo was randomized. During the last week of treatment, they received a high-sodium diet (250 mmol/d). Ambulatory blood pressure (ABP), glomerular filtration rate (GFR), and effective renal plasma flow (ERPF) were measured using sinistrin and para-amino-hippurate clearances. Renal sodium handling was assessed by measuring endogenous lithium clearance on day 7 of the high-salt diet. RESULTS: Nineteen women (mean age, 54.7 years; range, 43-72 years; 7 normotensive subjects [mean age, 53.4 years; range, 47-61 years] and 12 hypertensive subjects [mean age, 55.4 years; range, 43-72 years]) were included in the study. When the data for all 19 subjects were pooled, ABP was significantly lower with irbesartan than placebo both during the day (120 [3]/79 [2] vs 127 [3]/85 [2] mm Hg; both, P < 0.01) and at night (systolic BP, 107 [4] vs 111 [4] mm Hg [P < 0.01] and diastolic BP, 71 [2] vs 75 [2] mm Hg [P < 0.05]). Compared with placebo, irbesartan was not associated with a significant change in GFR in either the normotensive or the hypertensive women. When the data for all 19 subjects were pooled, irbesartan was associated with a significant increase in ERPF compared with placebo (372 [21] vs324 [18] mL/min · 1.73 m(2); P < 0.05). When the hypertensive and normotensive women were considered separately, the effect was more pronounced in the hypertensive women than in the normotensive women, but the changes did not reach statistical significance. When the data for all subjects were pooled, irbesartan was associated with a significant increase in daytime urinary sodium excretion compared with placebo (135 [13] vs 106 [13] µmol/min; P < 0.05) and a significant decrease at night (109 [13] vs 136 [19] µmol/min; P < 0.05). Fractional excretion of lithium (FELi), an inverse marker of proximal sodium reabsorption, increased significantly during the daytime with irbesartan compared with placebo (47% [6.5%] vs 35% [4.7%]; P < 0.05). At nighttime, FELi was significantly higher in the hypertensive subjects receiving irbesartan compared with placebo (43% [7.2%] vs 29% [6.5%]; P < 0.05). The fractional distal reabsorption of sodium did not change significantly with irbesartan compared with placebo. CONCLUSIONS: The results from this study suggest that angiotensin II receptor blockade had a favorable impact on BP, renal hemodynamics, and renal sodium handling in these salt-replete postmenopausal women. Blockade of the renin-angiotensin system restored the normal pattern of renal response to high sodium intake in these women.

Undetectable serum anti-Müllerian hormone levels and occurrence of ongoing pregnancy.

OBJECTIVE: To discuss, on the basis of the experience of two clinical cases and extensive literature review, the significance of extremely low levels of anti-Müllerian hormone (AMH), also known as Müllerian-inhibiting substance, in infertile women. DESIGN: Case report. SETTING: University-based infertility clinic at a medical center in Switzerland. PATIENT(S): Two women, 29 and 41 years of age and with a 2- and 4-year history of secondary infertility, respectively. INTERVENTION(S): Clinical, radiological, and biological investigation of infertility, including repeated measurements of the serum AMH with serial ELISA assays. MAIN OUTCOME MEASURE(S): Levels of AMH and development of ongoing pregnancy. RESULT(S): Both women had a spontaneous ongoing pregnancy despite undetectable AMH levels. CONCLUSION(S): Although it is helpful for day-to-day management of infertile patients, the predictive value of AMH for the occurrence of a spontaneous ongoing pregnancy has limits.

Serum antimüllerian hormone levels remain stable throughout the menstrual cycle and after oral or vaginal administration of synthetic sex steroids.

OBJECTIVE: To investigate whether oral or vaginal administration of contraceptive hormones might affect antimüllerian hormone (AMH) levels. DESIGN: Prospective trial with women recruited by advertisement. Women who wished contraception were randomized between oral or vaginal estroprogestative contraception, and those who did not choose contraception were included in the control group. SETTING: Fertility clinic of a tertiary university hospital. PATIENT(S): Twenty-four young, healthy volunteer women with regular cycles who had received no hormonal contraception for at least 3 months before the study. INTERVENTION(S): Oral or vaginal estroprogestative contraception from day 5 to 25 of a menstrual cycle versus no contraception. MAIN OUTCOME MEASURE(S): Intercycle and intracycle variations of serum AMH levels in normally ovulating volunteers and following the initiation of oral or vaginal estroprogestative contraception. RESULT(S): Fluctuations of AMH levels observed during the menstrual cycle remained within cycle-to-cycle variability in cycling controls and in women receiving oral or vaginal contraception. CONCLUSION(S): Our findings confirm that AMH levels remain steady during the menstrual cycle and indicate that they are unaffected by exogenous sex steroids used for contraception whether administered orally or vaginally.

Factors regulating trophoblast invasion.

Implantation in the human is unique. This uniqueness is characterized on the maternal side by a spontaneous and massive decidualization of the endometrium and on the embryonic side by an almost unlimited invasive potential. Human embryos express an intrinsic invasive potential, which allows them to implant almost anywhere except in the endometrium because it protects itself from implantation. Human implantation is thus only possible during a limited period of time known as the implantation window. This mini review stresses the importance of studying trophoblast invasion into the endometrium as a model for human implantation. Cytotrophoblastic cells (CTB) can easily be isolated from first-trimester legal abortions and retain their invasive behavior when cultured in vitro. This model shows that matrix metalloproteinases (MMPs) are produced by CTB and are instrumental to their invasive behavior. Embryo implantation and tumor invasion use these same biochemical mediators for invasion. However, in contrast to tumor invasion, trophoblast invasion is limited both in time and space: it occurs during the first trimester of pregnancy and invasion does not go beyond the proximal third of the myometrium. Factors regulating MMP expression are of maternal and fetal origin.

Identification of BARD1 splice-isoforms involved in human trophoblast invasion.

The tumor suppressor protein BARD1, originally discovered as BRCA1-binding protein, acts in conjunction with BRCA1 as ubiquitin ligase. BARD1 and BRCA1 form a stable heterodimer and dimerization, which is required for most tumor suppressor functions attributed to BRCA1. In addition, BARD1 has BRCA1-independent functions in apoptosis, and a role in control of tissue homeostasis was suggested. However, cancer-associated mutations of BARD1 are rare; on the contrary, overexpression of truncated BARD1 was found in breast and ovarian cancer and correlated with poor prognosis. Here we report that human cytotrophoblasts, which show a strong similarity with cancer cells in respect of their invasive behavior and capacity of matrix metalloprotease production, overexpress isoforms of BARD1 derived from differential splicing. We demonstrate that expression of BARD1 and its isoforms is temporally and spatially regulated by human chorionic gonadotropin and by hypoxia, both factors known to regulate the invasive phase and proliferation of cytotrophoblasts. Interestingly, we found a subset of BARD1 isoforms secreted by cytotrophoblasts. BARD1 repression by siRNAs, mitigates the interference of cytotrophoblasts with cell adhesion of collagen matrix-dependent epithelial cells, suggesting a role of BARD1 isoforms in extracellular matrix remodelling and in cytotrophoblasts invasion.

Establishment of detailed reference values for luteinizing hormone, follicle stimulating hormone, estradiol, and progesterone during different phases of the menstrual cycle on the Abbott ARCHITECT analyzer.

During a normal menstrual cycle, serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, and progesterone can vary widely between cycles for the same woman, as well as between different woman. Reliable reference values based on the local population are important for correct interpretation of laboratory results. The purpose of our study was to determine detailed reference values for these hormones throughout the menstrual cycle using the Abbott ARCHITECT system. From 20 volunteers (age 20-36 years) with normal cycles and no use of oral contraceptives, samples were taken every day during their cycle. Volunteers received three vaginal ultrasound examinations (days 10 and 13, and 1 or 2 days after ovulation) to measure follicular and corpus luteum development. Hormone levels were measured using the corresponding ARCHITECT assay and were synchronized to the LH peak. Median, and 5th and 95th percentile values were determined for each day of the cycle, as well as for early follicular (days -15 to -6), late follicular (days -5 to -1), LH peak (day 0), early luteal (+1 to +4), mid-luteal (days +5 to +9), and late luteal (days +10 to +14) phases of the cycle. Based on our data, we were able to establish detailed reference values for LH, FSH, estradiol, and progesterone, which should aid in the interpretation of results for these reproductive hormones in a variety of circumstances.