Molecular profiling of human blastocysts reveals primitive endoderm defects among embryos of decreased implantation potential.

Human embryo implantation is remarkably inefficient, and implantation failure remains among the greatest obstacles in treating infertility. Gene expression data from human embryos have accumulated rapidly in recent years; however, identification of the subset of genes that determine successful implantation remains a challenge. We leverage clinical morphologic grading-known for decades to correlate with implantation potential-and transcriptome analyses of matched embryonic and abembryonic samples to identify factors and pathways enriched and depleted in human blastocysts of good and poor morphology. Unexpectedly, we discovered that the greatest difference was in the state of extraembryonic primitive endoderm (PrE) development, with relative deficiencies in poor morphology blastocysts. Our results suggest that implantation success is most strongly influenced by the embryonic compartment and that deficient PrE development is common among embryos with decreased implantation potential. Our study provides a valuable resource for those investigating the markers and mechanisms of human embryo implantation.

Ibuprofen inhibits key genes involved in androgen production in theca-interstitial cells.

OBJECTIVE: To study the effects of ibuprofen on androgen production, gene expression, and cell viability in rat theca-interstitial cells exposed to the proinflammatory stimuli interleukin-1ß (IL-1ß) and lipopolysaccharide (LPS). DESIGN: Animal study. SETTING: University-based research laboratory. PATIENTS/ANIMALS: Theca-interstitial cells were isolated from 30 day old female Sprague Dawley rats. INTERVENTIONS: Theca cells were cultured with pro-inflammatory media containing IL-1ß and LPS and compared with cells cultured in control media. MAIN OUTCOME MEASURES: Androstenedione quantification was performed on conditioned cell culture medium using liquid chromatography-mass spectrometry. Theca cell viability was assessed using PrestoBlue cell viability assay. The gene expression of Cyp17a1, Cyp11a1, and Hsd3b was analyzed using quantitative polymerase chain reaction. RESULTS: Both proinflammatory stimuli IL-1ß and LPS increased androstenedione concentration in cell culture medium, and these effects were mitigated with ibuprofen. Both inflammatory agents in addition increased the expression of key genes involved in androgen synthesis: Cyp17a1, Cyp11a1, and Hsd3b; the addition of ibuprofen to the culture medium inhibited these effects. Theca cell viability increased with IL-1ß and LPS. Ibuprofen inhibited the IL-1ß-mediated increase in cell viability but did not reverse the effects of LPS. CONCLUSIONS: In conclusion, our findings support the hypothesis that many of the alterations induced by inflammatory stimuli in theca-interstitial cells are abrogated by the addition of ibuprofen.

Equivalency of In vitro fertilization Success Rates in Elective Single Blastocyst Transfer and Elective Double Blastocyst Transfer: An Example of Equivalence Methodology in Clinical Reproductive Health.

CONTEXT: When comparing success rates between treatments, it is more appropriate to structure analyses in terms of equivalence rather than traditional analyses that assess differences. Unfortunately, no studies of elective single blastocyst transfer (eSBT) have been conducted in this manner. AIMS: The objective of this study was to assess clinical equivalence of in vitro fertilization success rates among patients undergoing eSBT. SETTINGS AND DESIGN: A historical prospective study was conducted at a private fertility center. METHODS: Medical records were reviewed to identify patients eligible for eSBT. Equivalency of success rates, defined as no more than a 10% difference based on 95% confidence intervals (CIs), was compared between eSBT (n = 125) and eDBT (n = 213) groups. RESULTS: Using traditional analysis techniques, no differences in pregnancy or live-birth rates were seen (eSBT: 84.6% vs. eDBT: 84.5%, P = 0.99; eSBT: 65.3% vs. eDBT: 72.3%, P = 0.23). The 95% CI around the difference in pregnancy rates ranged from -7.9 to 8.1, suggesting clinically equivalent pregnancy rates. Clinical equivalence was not established for live-births (95% CI = -18.5-4.5). CONCLUSIONS: Findings suggest comparable pregnancy rates can be achieved in a clinical setting when utilizing eSBT in good-prognosis patients. Although live-birth rate equivalence was not demonstrated, it is thought the additional complications associated with multiple gestations outweigh the potentially higher live-birth rate. The present study highlights the importance of utilizing equivalence analyses when making statements regarding the similarity of two treatments in reproductive health, rather than relying on superiority analyses alone.

Predictors of treatment failure in young patients undergoing in vitro fertilization.

PURPOSE: The purpose of the study was to evaluate whether routinely collected clinical factors can predict in vitro fertilization (IVF) failure among young, "good prognosis" patients predominantly with secondary infertility who are less than 35 years of age. METHODS: Using de-identified clinic records, 414 women <35 years undergoing their first autologous IVF cycle were identified. Logistic regression was used to identify patient-driven clinical factors routinely collected during fertility treatment that could be used to model predicted probability of cycle failure. RESULTS: One hundred ninety-seven patients with both primary and secondary infertility had a failed IVF cycle, and 217 with secondary infertility had a successful live birth. None of the women with primary infertility had a successful live birth. The significant predictors for IVF cycle failure among young patients were fewer previous live births, history of biochemical pregnancies or spontaneous abortions, lower baseline antral follicle count, higher total gonadotropin dose, unknown infertility diagnosis, and lack of at least one fair to good quality embryo. The full model showed good predictive value (c = 0.885) for estimating risk of cycle failure; at ≥80 % predicted probability of failure, sensitivity = 55.4 %, specificity = 97.5 %, positive predictive value = 95.4 %, and negative predictive value = 69.8 %. CONCLUSION: If this predictive model is validated in future studies, it could be beneficial for predicting IVF failure in good prognosis women under the age of 35 years.

Segregation by thermal diffusion in moderately dense granular mixtures.

A theory based on a solution of the inelastic Enskog equation that goes beyond the weak dissipation limit is used to determine the thermal diffusion factor of a binary granular mixture under gravity. The Enskog equation that aims to describe moderate densities neglects velocity correlations but retains spatial correlations arising from volume exclusion effects. As expected, the thermal diffusion factor provides a segregation criterion that shows the transition between the Brazil-nut effect (BNE) and the reverse Brazil-nut effect (RBNE) by varying the parameters of the system (masses, sizes, composition, density and coefficients of restitution). The form of the phase diagrams for the BNE/RBNE transition is illustrated in detail in the tracer limit case, showing that the phase diagrams depend sensitively on the value of gravity relative to the thermal gradient. Two specific situations are considered: i) absence of gravity, and ii) homogeneous temperature. In the latter case, after some approximations, our results are consistent with previous theoretical results derived from the Enskog equation. Our results also indicate that the influence of dissipation on thermal diffusion is more important in the absence of gravity than in the opposite limit. The present analysis, which is based on a preliminary short report of the author (Phys. Rev. E 78, 020301(R) (2008)), extends previous theoretical results derived in the dilute limit case.

Dense fluid transport for inelastic hard spheres.

The revised Enskog theory for inelastic hard spheres is considered as a model for rapid flow granular media at finite densities. A normal solution is obtained via the Chapman-Enskog method for states near the local homogeneous cooling state. The analysis is performed to first order in the spatial gradients, allowing identification of the Navier-Stokes order transport coefficients associated with the heat and momentum fluxes. In addition, the cooling rate is calculated to first order in the gradients and expressed in terms of the transport coefficients. The transport coefficients are determined from linear integral equations analogous to those for elastic collisions. The solubility conditions for these equations are confirmed and the transport coefficients are calculated as explicit functions of the density and restitution coefficient using a Sonine polynomial expansion. The results are not limited to small dissipation. Finally, the analysis is repeated using a simpler kinetic model. Excellent agreement is obtained with the results from the revised Enskog equation.

Homogeneous cooling state for a granular mixture.

The homogeneous cooling state for a binary mixture of inelastic hard spheres is studied using the Enskog kinetic theory. In the same way as for the one-component fluid, we propose a scaling solution in which the time dependence of the distribution functions occurs entirely through the temperature of the mixture. A surprising result is that the (partial) temperatures of each species are different, although their cooling rates are the same. Approximate forms for the distribution functions are constructed to leading order in a Sonine polynomial expansion showing a small deviation from Maxwellian, similar to that for the one-component case. The temperatures and overall cooling rate are calculated in terms of the restitution coefficients, the reduced density, and the ratios of mass, concentration, and sizes.

Simple and accurate theory for strong shock waves in a dense hard-sphere fluid.

Following an earlier work by Holian et al. [Phys. Rev. E 47, R24 (1993)] for a dilute gas, we present a theory for strong shock waves in a hard-sphere fluid described by the Enskog equation. The idea is to use the Navier-Stokes hydrodynamic equations but taking the temperature in the direction of shock propagation rather than the actual temperature in the computation of the transport coefficients. In general, for finite densities, this theory agrees much better with Monte Carlo simulations than the Navier-Stokes and (linear) Burnett theories, in contrast to the well-known superiority of the Burnett theory for dilute gases.