Serum periostin levels in early in pregnancy are significantly altered in women with miscarriage

Background: Miscarriage is a common complication in pregnancy and there is still a lack of biomarkers usable in asymptomatic patients before the event occurs. Periostin (PER), whose levels rise particularly during injury or inflammation, has been shown to play an important local role in implantation and early embryonic development. As PER has been described as a biomarker in various medical conditions we intended to evaluate if changes in PER serum levels may help to identify women at risk for spontaneous abortion in the first trimester. Methods: Women between 18 and 42 years without confounding comorbidities who conceived by IVF/ICSI and ovarian hyperstimulation were analysed in the study after informed consent. Maternal serum samples from 41 patients were assessed at the time of pregnancy testing (PT) and the following first ultrasound checkup (US). Patients were subsequently divided in two groups: (1) patients with subsequent miscarriage in the first trimester (n = 18) and (2) patients with ongoing pregnancy (n = 23), allowing for statistical analysis and investigating the change of PER levels per individual. PER levels were measured using enzyme-linked immunosorbent assay. Statistical analysis was performed using the Fisher exact and Student’s t test. p ≤ 0.05 was considered to be significant. Results: There was no significant difference concerning possible confounders between the two groups. We did not find any significant difference in PER levels at the time point of PT or US. By investigating the interindividual changes of PER between the two time points however, we observed that patients with a following miscarriage showed increasing levels of PER at the time point of PT compared to US in contrast to patients with an ongoing pregnancy who demonstrated a decrease in PER levels. These alterations were significant in the absolute as well as in the relative comparison. Conclusion: The relative expression of PER between PT and US is significantly altered in asymptomatic women with subsequent miscarriage compared to women with ongoing pregnancy. Therefore systemic PER levels might represent a potential promising biomarker for the assessment of pregnancy outcome. Trial registration Not applicable

Cytokines in relation to hCG are significantly altered in asymptomatic women with miscarriage – a pilot study

Background: Spontaneous abortion is one of the most common complications in early pregnancy. A preventive test to identify women who will experience a miscarriage, even before first symptoms occur, is not established. Activation of maternal immunological tolerance seems to be essential for early fetal development and various cytokines have been described in different stages of pregnancy. Therefore, we aimed to investigate if chemokine levels at the time of pregnancy testing relative to human Choriogonadotropin (hCG) are altered in patients who will experience a miscarriage in this pregnancy. Methods: We obtained blood samples from 39 women. Dependent on the follow-up, patients with a positive pregnancy test were subsequently divided in two groups: ongoing pregnancy (n = 22) and miscarriage (n = 17) in this pregnancy. Immunological and endocrine profiling of maternal plasma at the time of pregnancy testing (5th week of gestation) was performed for each group at the time of pregnancy test using Multiplex and ELISA analysis. Results: hCG was significantly decreased in patients with abortion whereas levels of IL-1ra, MIP-1a and TNF-alpha were significantly increased. GCSF/ IL-1ra-ratio was 1.66-fold increased in patients with ongoing pregnancy. TGF-beta /MIP1a-ratio was significantly 3.45-times higher in patients with miscarriage. Comparing patients with ongoing pregnancy to patients experiencing a miscarriage, we could demonstrate significant alterations of the ratios MIP1a/hCG, IL-1ra/hCG, TNFalpha/hCG, MCP1/hCG, IL-6/hCG, TPO/hCG and TGF-beta1/hCG. The strongest effects were seen for the ratio MIP1a/hCG, IL-1ra/hCG and TNFalpha/hCG. Conclusions: We have shown that cytokines in relation to hCG after 4 weeks of gestation are significantly altered in women with miscarriage, promising potential as a prognostic biomarker

FMR1 and AKT/mTOR signaling in human granulosa cells : functional interaction and impact on ovarian response

We aimed to determine whether a functional link with impact on female ovarian reserve exists between FMR1 expression and expression ratios of AKT/mTOR signaling genes in human granulosa cells in vivo, as suggested from prior in vitro data. Three hundred and nine women, who were classified as normal (NOR; n = 225) and poor (POR; n = 84) responders based on their ovarian reserve, were recruited during stimulation for assisted reproductive techniques. Expressions of FMR1 and of key genes of the AKT/mTOR and AKT/FOXO1/3 signaling pathways were comparatively analyzed in their granulosa cells. FMR1 expression in granulosa cells of NOR and POR correlated significantly with AKT1, TSC2, mTOR, and S6K expression. No correlation was found between FMR1 and FOXO1 in all, and FOXO3 expression in POR, patients. AKT1 expression was significantly higher and FOXO1 expression lower in POR samples, whereas AKT1 expression was lower and FOXO1 expression was higher in NOR samples. In human native granulosa cells, FMR1 expression significantly correlated with the expression of key genes of the AKT/mTOR signaling pathway, but not with the FOXO1/3 signaling pathway. Our data point to a functional link between FMR1 expression and expression of the AKT/mTOR signaling pathway genes controlling human follicular maturation

FMR1 expression in human granulosa cells increases with exon 1 CGG repeat length depending on ovarian reserve

Background: Fragile-X-Mental-Retardation-1- (FMR1)-gene is supposed to be a key gene for ovarian reserve and folliculogenesis. It contains in its 5’-UTR a triplet-base-repeat (CGG), that varies between 26 and 34 in general population. CGG-repeat-lengths with 55–200 repeats (pre-mutation = PM) show instable heredity with a tendency to increase and are associated with premature-ovarian-insufficiency or failure (POI/POF) in about 20%. FMR1-mRNA-expression in leucocytes and granulosa cells (GCs) increases with CGG-repeat-length in PM-carriers, but variable FMR1-expression profiles were also described in women with POI without PM-FMR1 repeat-length. Additionally, associations between low numbers of retrieved oocytes and elevated FMR1-expression levels have been shown in GCs of females with mid-range PM-CGG-repeats without POI. Effects of FMR1-repeat-lengths-deviations (n < 26 or n > 34) below the PM range (n < 55) on ovarian reserve and response to ovarian stimulation remain controversial. Methods: We enrolled 229 women undergoing controlled ovarian hyperstimulation for IVF/ICSI-treatment and devided them in three ovarian-response-subgroups: Poor responder (POR) after Bologna Criteria, polycystic ovary syndrome (PCO) after Rotterdam Criteria, or normal responder (NOR, control group). Subjects were subdivided into six genotypes according to their be-allelic CGG-repeat length. FMR1-CGG-repeat-length was determined using ALF-express-DNA-sequencer or ABI 3100/3130 × 1-sequencer. mRNA was extracted from GCs after follicular aspiration and quantitative FMR1-expression was determined using specific TaqMan-Assay and applying the ΔΔCT method. Kruskall-Wallis-Test or ANOVA were used for simple comparison between ovarian reserve (NOR, POR or PCO) and CGG-subgroups or cohort demographic data. All statistical analysis were performed with SPSS and statistical significance was set at p ≤ 0.05. Results: A statistically significant increase in FMR1-mRNA-expression-levels was detected in GCs of PORs with heterozygous normal/low-CGG-repeat-length compared with other genotypes (p = 0.044). Conclusion: Female ovarian response may be negatively affected by low CGG-alleles during stimulation. In addition, due to a low-allele-effect, folliculogenesis may be impaired already prior to stimulation leading to diminished ovarian reserve and poor ovarian response. A better understanding of FMR1 expression-regulation in GCs may help to elucidate pathomechanisms of folliculogenesis disorders and to develop risk-adjusted treatments for IVF/ICSI-therapy. Herewith FMR1-genotyping potentially provides a better estimatation of treatment outcome and allows the optimal adaptation of stimulation protocols in future

Enhanced thermal stability of organic solar cells comprising ternary D-D-A bulk-heterojunctions

Organic solar cells: Polymer mixtures enhance the thermal stability Organic solar cells increase their lifetime by adding another polymer component, paving the way towards commercialization. A team led by Alexander Colsmann at Karlsruhe Institute of Technology, Germany conducted systematic spectroscopic investigations and device characterizations to demonstrate that the degradation of PTB7-Th: PC61BM solar cell can be efficiently suppressed by incorporating the near infrared-absorbing polymer PDTP-DFBT. Upon harsh thermal stress at 120 °C for 2 h, the ternary solar cells show only a minor relative deterioration of 10% with a high power conversion efficiency of 6%. This work reveals the importance of a third component to lock the phase conformation of the polymer and fullerene domains. This is a key step for the thermally stable power output thus the commercialization of the organic solar cells

Exam preparatory course for the 2nd part of the German medical examination in obstetrics and gynecology – a potential tool for the recruitment of new residents during the occupational decision process before the practical year?

Background: The “Second Stage of the Physician Exam” at the end of the 5th year of medical school in Germany is the final step before the “Practical Year.” An exam preparatory class can cover the complete content of Obstetrics and Gynecology (OB/GYN) in two days. We raise the question of whether such training might promote students’ interest in the given specialty during occupational decision making and whether it could even be used by hospitals as a recruitment tool. This investigation is even more important in the context of fierce competition among young professionals at clinics and in different specialties. Methods: We conducted a multimodal course evaluation for four exam preparatory courses (each of which lasted two days and involved 8.5 h of teaching), including pre- and post-course tests with 20 multiple-choice questions to quantify the level of skill gain. Additionally, a standardized evaluation of course satisfaction was performed, followed by a post-exam questionnaire that dealt with studying activities and individual professional objectives. Results: Overall, n = 197 students took part in four identical courses. Among them, n = 121 completed the pre−/post-course tests, n = 170 completed the evaluation, and n = 110 completed the post-exam questionnaire. An average improvement from 13.9 to 17.2 correct answers was observed (max. 20; pre−/post-difference 95%-CI: [2.77; 3.86], t-test: p < 0.0001). By trend, the students noted that course participation positively influenced their later choice of specialty training (m = 3.63; scale 1 = “strongly disagree,” 5 = “strongly agree”). Conclusions: In addition to self-studying, condensed classroom training is effective and reasonable and might also increase the attractivity of OB/GYN among students and have a positive effect on recruitment

GRN, NOTCH3, FN1, and PINK1 expression in eutopic endometrium – potential biomarkers in the detection of endometriosis – a pilot study

Purpose!#!Endometriosis (EM) is a common gynecological disease affecting 10-15% of women of reproductive age. However, molecular mechanisms and pathogenesis are still not completely understood. Furthermore, due to the absence of a reliable clinical biomarker, the only viable method for the often-delayed definitive diagnosis is laparoscopic surgery. Our objective was to analyze molecular differences of selected endometrial proteins and genes of women suffering from different stages of EM compared with healthy women to evaluate potential clinical biomarkers.!##!Methods!#!We analyzed eutopic endometrial tissue samples from women undergoing a laparoscopic surgery (n = 58). mRNA gene expression of progranulin (GRN), neurogenic locus notch homolog protein (NOTCH3), fibronectin (FN1), and PTEN-induced kinase 1 (PINK1) was analyzed using qRT-PCR. Protein expression was determined using ELISA and immunohistochemistry.!##!Results!#!Significant differences in gene expression between the different stages of the disease were noted for GRN, NOTCH3, FN1, and PINK1 (p < 0.05). The endometrium of women with minimal EM (ASRM I) showed the highest mRNA expression. Protein levels of GRN and FN1 on the other hand were significantly decreased in the endometrium of women with EM compared with those of healthy controls. Furthermore, for GRN and FN1, we could detect a correlation of protein expression with the severity of the disease.!##!Conclusion!#!Our findings suggest a potential use of GRN and FN1 as clinical biomarkers to detect endometriosis. In addition, GRN, NOTCH3, FN1, and PINK1 could potentially be useful to differentiate between the underlying stages of the disease. However, a validation with a larger study population is needed

Plausibility of Menstrual Cycle Apps Claiming to Support Conception

The interval of peak fertility during the menstrual cycle is of limited duration, and the day of ovulation varies, even in women with fairly regular cycles. Therefore, menstrual cycle apps identifying the “fertile window” for women trying to conceive must be quite precise. A deviation of a few days may lead the couple to focus on less- or non-fertile days for sexual intercourse and thus may be worse than random intercourse. The aim of the present investigation was to develop a scoring system for rating available apps for determining the fertile window and secondarily pilot test 12 apps currently available in both German and English (consisting of 6 calendar-based apps: Clue Menstruations- und Zykluskalender, Flo Menstruationskalender, Maya-Mein Periodentracker, Menstruationskalender Pro, Period Tracker Deluxe, and WomanLog-Pro-Kalender; 2 calculothermal apps: Ovy and Natural Cycles; and 4 symptothermal apps: myNFP, Lady Cycle, Lily, and OvuView). The calendar-based apps were investigated by entering several series of cycles with varying lengths, whereas the symptom-based apps were examined by entering data of cycles with known temperature rise, cervical mucus pattern, and clinical ovulation. The main criteria for evaluating the cycle apps were as follows: (1) What methods/parameters were used to determine the fertile window? (2) What study results exist concerning that underlying method/parameters? (3) What study results exist concerning the app itself? (4) Was there a qualified counseling service? The calendar-based apps predicted the fertile days based on data of previous cycles. They obtained zero points in our scoring system, as they did not comply with any of the evaluated criteria. Calculothermal apps had similar deficits for predicting the most fertile days and produced suboptimal results (Ovy 3/30 points and Natural Cycles 2/30 points). The symptothermal apps determined the fertile days based on parameters of the current cycle: Lady Cycle scored 20/30 points, myNFP 20/30 points, Lily 19/30 points, and OvuView 11/30 points. We concluded that the available cycle apps vary according to their underlying scientific quality and clear rating criteria have been suggested. Three of the tested apps were judged to be eligible for further study. The scientific evaluation of cycle apps depends on good prospective studies undertaken by independent investigators who are free of commercial bias