Value Analysis of Four-Dimensional Color Ultrasound Combined with Maternal Serological Index in Prenatal Screening for Fetal Anomalies.

Objective: This study aimed to assess the efficacy of combining four-dimensional (4D) color ultrasound with maternal serological index testing in prenatal screening for fetal anomalies. Methods: A retrospective analysis was conducted on data from 864 pregnant women who underwent prenatal checkups at the hospital between January 2020 and January 2021. During the mid-pregnancy period, serological tests were performed to determine levels of alpha-fetoprotein (AFP), free ß-subunit of human chorionic gonadotropin (Free-HCG ß), pregnancy-associated plasma protein A (PAPP-A), and vitamin B12 (VitB12). Additionally, 4D color ultrasound examinations were conducted. The gold standard for evaluation was the results of delivery or labor induction. AFP, Free-HCG ß, PAPP-A, and VitB12 levels were compared between the anomaly group and the normal group. The diagnostic efficacy of single and combined detection of serological indexes and 4D color ultrasound was analyzed, with the calculation of the areas under the curve (AUC) for different detection methods. Results: Among the 864 pregnant women, 44 cases (5.09%) exhibited fetal anomalies, while 820 cases (94.91%) did not. The anomaly group showed significantly higher multiples of the median (MOM) values for AFP and Free-HCG ß (P < .001) and significantly lower PAPP-A MOM and VitB12 levels (P < .001) compared to the normal group. The sensitivity of single detections for AFP MOM, Free-HCG ß MOM, PAPP-A MOM, VitB12, 4D color ultrasound, and combined detection were 63.64%, 68.18%, 65.91%, 54.55%, 77.27%, and 97.93%, respectively. The corresponding AUC values were 0.805, 0.829, 0.818, 0.761, 0.885, and 0.974. Conclusions: The combination of 4D color ultrasound with maternal serological index testing demonstrated high sensitivity in prenatal screening for fetal anomalies.

Clinical Value of Serum miR-124 and miR-200C Combined with Ultrasound NT in Screening Down Syndrome in Elderly Puerperae in the Second Trimester.

Objective: To evaluate the clinical value of serum miR-124 and miR-200C combined with ultrasound NT in screening Down syndrome (DS) in elderly puerperae during the second trimester. Methods: 84 elderly pregnant women at high risk of DS were included (DS group: 58, non-DS group: 26). Serum markers (uE3, ß-hCG, AFP, miR-124, and miR-200C) were measured. Differences in markers between groups were analyzed, and a prediction model was used for DS evaluation. Results: The DS group showed higher smoking, drinking, and radiation exposure rates (P < .05). MOM values of ß-hCG and AFP were higher, while MOM value of uE3 was lower in the DS group (P < .05). MiR-124 and miR-200C were up-regulated in the DS group (P < .05). The prediction model and ROC curve analysis indicated the diagnostic value of the markers for DS (AUC = 0.779, 0.817, 0.780, 0.884, 0.887, P < .05). MiR-124 had the highest diagnostic specificity. Conclusion: MiR-124 and miR-200C can serve as auxiliary serum markers for early screening of DS in elderly puerperae during the second trimester.

Successful laparoscopic surgical removal of a caesarean scar pregnancy (CSP) using temporary uterine artery ligation.

STUDY OBJECTIVE: To demonstrate a laparoscopic technique to remove a scar pregnancy. DESIGN: Stepwise demonstration of the surgical technique. SETTING: Santa Croce and Carle Hospital, Cuneo. INTERVENTION: Patient B.B. is a woman referred to our center for a suspected cesarean scar pregnancy (CSP) at 9 weeks gestation. CSP occurs approximately in 6% of all ectopic pregnancies. The estimated incidence is reported to be 1:1800 to 1:2500 in cesarean deliveries. Depending on its location, CSP can be categorized as either type 1, if the growth is in the uterine cavity, or type 2, if it expands toward the bladder and the abdominal cavity. If inadequately managed, it can lead to severe complications; most of them are hemorrhagic and can threaten the woman's life. There are several therapeutic approaches: local excision seems to be the most effective choice in type 2 CSP. In expert hands, the laparoscopic approach is perhaps the best surgical choice as tissue dissection, electrosurgical hemostasis, and vascular control can be effectively managed with minimal invasive access. Because severe intraoperative bleeding can occur, retroperitoneal vascular control is mandatory in this surgery. In type 1 CSP curettage, aspiration or hysteroscopic approach can be considered if the CSP is of small dimensions. A hysteroscopic approach can also be helpful in type 2 CSP during the laparoscopic removal, as intrauterine guidance. A potassium chloride local injection can be considered in a preoperative stage in the presence of a fetal heart rate. The systemic administration of methotrexate is usually ineffective as single agent, but it can be useful if administered as adjuvant therapy. Uterine artery embolization can be useful in an emergency setting to manage severe bleeding, but it can lead to complications in subsequent pregnancies and, more rarely, to premature ovarian failure. Considering poor bleeding at presentation, feasible dimensions, and the woman's desire for future pregnancy, ultrasound-guided aspiration and curettage was attempted. Because endouterine removal was incomplete, methotrexate injection was proposed as adjuvant therapy, but the administration was postponed as the patient tested positive for coronavirus disease 2019. A month later, beta-human chorionic gonadotropin level dropped from over 16 000 to 271 mU/mL, so an ultrasound and biochemical follow-up was performed. A month later, despite a low beta-human chorionic gonadotropin value, an increase in dimensions was observed at ultrasound, so surgical laparoscopic removal was offered. In this video article, laparoscopic removal of scar pregnancy is discussed in the following surgical steps: (1) Temporary closure of uterine arteries at the origin, using removable clips. (2) Retroperitoneal dissection to safely manage the scar pregnancy. (3) Dissection of the myometrial-pregnancy interface. (4) Double layer suture on the anterior uterine wall. CONCLUSION: Laparoscopic surgical management is a very effective surgical approach to remove CSP. Knowledge of retroperitoneal dissection and vascular control is necessary to carry out this surgical intervention safely and effectively.

A randomized, controlled, first-in-patient trial of choriogonadotropin beta added to follitropin delta in women undergoing ovarian stimulation in a long GnRH agonist protocol.

STUDY QUESTION: Does addition of choriogonadotropin beta (recombinant CG beta) to follitropin delta increase the number of good-quality blastocysts following ovarian stimulation in a long GnRH agonist protocol? SUMMARY ANSWER: At the doses investigated, the addition of CG beta reduced the number of intermediate follicles and related down-stream parameters including the number of oocytes and blastocysts. WHAT IS KNOWN ALREADY: CG beta is a novel recombinant hCG (rhCG) molecule expressed by a human cell line (PER.C6®) and has a different glycosylation profile compared to urinary hCG or rhCG derived from a Chinese Hamster Ovary (CHO) cell line. In the first-in-human trial, the CG beta pharmacokinetics were similar between men and women. In women, the AUC and the peak serum concentration (Cmax) increased approximately dose proportionally following single and multiple daily doses. In men, a single dose of CG beta provided higher exposure with a longer half-life and proportionately higher testosterone production than CHO cell-derived rhCG. STUDY DESIGN, SIZE, DURATION: This placebo-controlled, double-blind, randomized trial (RAINBOW) was conducted in five European countries to explore the efficacy and safety of CG beta as add-on treatment to follitropin delta in women undergoing ovarian stimulation in a long GnRH agonist protocol. Randomization was stratified by centre and age (30-37 and 38-42 years). The primary endpoint was the number of good-quality blastocysts (Grade 3 BB or higher). Subjects were randomized to receive either placebo or 1, 2, 4, 8 or 12 µg CG beta added to the daily individualized follitropin delta dose during ovarian stimulation. PARTICIPANTS/MATERIALS, SETTING, METHODS: In total, 620 women (30-42 years) with anti-Müllerian hormone (AMH) levels between 5 and 35 pmol/l were randomized in equal proportions to the six treatment groups and 619 subjects started treatment. All 619 subjects were treated with an individualized dose of follitropin delta determined based on AMH (Elecsys AMH Plus Immunoassay) and body weight. Triggering with rhCG was performed when 3 follicles were ≥17 mm but no more than 25 follicles ≥12 mm were reached. MAIN RESULTS AND THE ROLE OF CHANCE: The demographic characteristics were comparable between the six treatment groups and the overall mean age, body weight and AMH were 35.6 ± 3.3 years, 65.3 ± 10.7 kg and 15.3 ± 7.0 pmol/l, respectively. The incidence of cycle cancellation (range 0-2.9%), total follitropin delta dose (mean 112 µg) and duration of stimulation (mean 10 days) were similar across the groups. At stimulation Day 6, the number and size of follicles was similar between the treatment groups, whereas at the end-of-stimulation dose-related decrease of the intermediate follicles between 12 and 17 mm was observed in comparison to the placebo group. In contrast, the number of follicles ≥17 mm was similar between the CG beta dose groups and the placebo group. A reduced number of intermediate follicles (12 to 17 mm) and fewer oocytes (mean range 9.7 to 11.2) were observed for all doses of CG beta compared to the follitropin delta only group (mean 12.5). The mean number of good-quality blastocysts was 3.3 in the follitropin delta group and ranged between 2.1 and 3.0 across the CG beta groups. The incidence of transfer cancellation was higher in the 4, 8 and 12 µg group, mostly as no blastocyst was available for transfer. In the group receiving only follitropin delta, the ongoing pregnancy rate (10-11 weeks after transfer) was 43% per started cycle versus 28-39% in CG beta groups and 49% per transfer versus 38-50% in the CG beta groups. There was no apparent effect of CG beta on the incidence of adverse events, which was 48.1% in the placebo group and 39.6-52.3% in the CG beta dose groups. In line with the number of collected oocytes, the overall ovarian hyperstimulation syndrome incidence remained lower following follitropin delta with CG beta (2.0-10.3%) compared with follitropin delta only treatment (11.5%). Regardless of the dose, CG beta was safe and well-tolerated with low risk of immunogenicity. LIMITATIONS, REASONS FOR CAUTION: The effect of the unique glycosylation of CG beta and its associated potency implications in women were not known prior to this trial. Further studies will be needed to evaluate optimal doses of CG beta for this and/or different indications. WIDER IMPLICATIONS OF THE FINDINGS: The high ongoing pregnancy rate in the follitropin delta group supports the use of individualized follitropin delta dosing in a long GnRH agonist protocol. The addition of CG beta reduced the presence of intermediate follicles with the investigated doses and negatively affected all down-stream parameters. Further clinical research will be needed to assess the optimal dose of CG beta in the optimal ratio to follitropin delta to develop this novel combination product containing both FSH and LH activity for ovarian stimulation. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by Ferring Pharmaceuticals, Copenhagen, Denmark. B.M. and P.L. are employees of Ferring Pharmaceuticals. M.F.S., H.V., C.Y.A., M.F., C.B., A.P. and Y.K. have received institutional clinical trial fees from Ferring Pharmaceuticals. C.B. has received payments for lectures from Organon, Ferring Pharmaceuticals, Merck A/S and Abbott. M.F.S. has received payment for lectures from Ferring Pharmaceuticals. Y.K. has received payment for lectures from Merck and travel support from Gedeon Richter. H.V. has received consulting fees from Oxo and Obseva and travel support from Gedeon Richter, Ferring Pharmaceuticals and Merck. C.Y.A. has received payment for lectures from IBSA, Switzerland. M.F and C.Y.A. were reimbursed as members of the Data Monitoring Board in this trial. M.F. has an issued patent about unitary combination of FSH and hCG (EP1633389). TRIAL REGISTRATION NUMBER: 2017-003810-13 (EudraCT Number). TRIAL REGISTRATION DATE: 21 May 2018. DATE OF FIRST PATIENT'S ENROLMENT: 13 June 2018.

Successful conservative treatment of placenta accreta with traditional Chinese medicine: A case report.

RATIONALE: Currently, placenta accreta treatment mainly includes nonconservative surgical and conservative treatments such as Traditional Chinese medicine (TCM). This report describes the case of a 37-year-old woman who suffered incomplete placenta accreta after vaginal delivery and was cured by TCM. TCM treatment of placenta accreta has its own unique advantages, including low toxicity and few side effects, unaffected breastfeeding, and retention of the uterus, which can ensure the expulsion of residual placenta and be beneficial to patients' physical and mental health. PATIENT CONCERNS: Symptoms included a small amount of vaginal bleeding and occasional lesser abdominal pain. The patient showed lesser abdominal tenderness, a red tongue moss with petechial hemorrhage, and a hesitant pulse. The reproductive history was G3P2L2A1. In addition, the patient was afraid of having her uterus removed due to incomplete placental separation. DIAGNOSES: The case was diagnosed as placental accreta. Ultrasound is the preferred method of diagnosis, and biomarkers, such as beta hCG, assist in screening for placental accreta. Doppler ultrasonography showed that in the bottom of the right uterine cavity, there was an uneven echo group of 7.6 × 4.6 cm, which was not clearly demarcated from the posterior wall; the muscle layer became thinner, with a thinnest part of 0.19 cm, and abundant blood flow signals were observed (Fig. 1JOURNAL/medi/04.03/00005792-202102190-00086/figure1/v/2021-02-16T234818Z/r/image-tiff). The beta hCG was 580.92 mIu/ml. INTERVENTIONS: The patient initially underwent curettage therapy 9 days after delivery, but it failed due to excessive intraoperative bleeding. The patient then turned to TCM treatment. The doctor prescribed a multi-herbal formula. OUTCOMES: After 4 months, the residual placenta was expelled, and the patient's symptoms disappeared completely. No adverse and unexpected events occurred during treatment. During 3 months of follow-up, the patient had no abdominal pain, abnormal vaginal bleeding, or other complications. LESSONS: This study shows that TCM is safe and effective for treating placenta accreta, and it is worth recommending TCM as a conservative treatment along with other treatments. In practice, however, we find that the earlier TCM treatment is applied, the better the effect; therefore, early intervention with TCM is particularly important.

Efficacy of Oral Vitamin A in Reducing ß-hCG Levels in Low-Risk Gestational Trophoblastic Neoplasia Patients.

OBJECTIVE: Low-risk gestational trophoblastic neoplasia (GTN) is generally treated with single agent chemotherapy and methotrexate (MTX) as a first-line therapy. Vitamin A helps to increase trophoblast cell regression, as well as to decrease ß-hCG levels. Vitamin A also increases the effectiveness of MTX by inducing more malignant cell death than MTX alone. Therefore, the aim of the current study was to analyze the changes in ß-hCG levels in low-risk GTN patients following vitamin A administration. METHODS: This study was a randomized clinical trial, which examined initial serum vitamin A and ß-hCG levels in GTN patients before and after three cycles of MTX therapy. Patients were given vitamin A supplementation of 6,000 IU (1.8 mg RAEs) per day, and the changes in serum ß-hCG were observed after three cycles. Patients were grouped by ß-hCG levels (decreased or stagnant). RESULTS: A total of 32 low-risks GTN patients were divided into the intervention group (16 patients who received vitamin A supplementation) and the control group (16 patients who did not receive vitamin A supplementation). In the intervention group, the average initial ß-hCG level was 170,949.3 ± 354,452.1 mIU/mL, and the average ß-hCG post-cycle level was 1,611.9 ± 3,652.5 mIU/mL. In the control group, the average initial ß-hCG level was 178,834.1 ± 2913844.6 mIU/mL, and the average ß-hCG post-cycle level was 25,388.5 ± 58,437.7 mIU/mL. CONCLUSION: In patients with low-risk GTN who underwent MTX chemotherapy, the levels of ß-hCG and the incidence of chemo resistance in the intervention group were lower than those in the control group. Older age may also influence the incidence of chemo resistance in GTN patients. Oral administration of 6,000 IU vitamin A could help to reduce ß-hCG levels in low-risk GTN patients who receive MTX chemotherapy.
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Association between 7-day serum ß-hCG levels after frozen-thawed embryo transfer and pregnancy outcomes: a single-centre retrospective study from China.

OBJECTIVE: Early monitoring of plasma human chorionic gonadotropin (ß-hCG) level is vital in predicting pregnancy outcome. This study investigated the predictive value of serum ß-hCG level on the seventh day after frozen-thawed embryo transfer (FET) for ongoing pregnancy (OP) and adverse pregnancy (AP). DESIGN: Retrospective study. SETTING: The Reproductive and Genetic Center of the Affiliated Hospital of Shandong University of Traditional Chinese Medicine, China. PARTICIPANTS: 1061 pregnant women who underwent FET between January 2014 and January 2017. PRIMARY AND SECONDARY OUTCOME MEASURES: Pregnancy outcome. RESULTS: Serum ß-hCG levels on the seventh day after FET were higher in the single OP group compared with the biochemical pregnancy group (p<0.001). Besides, the serum ß-hCG cut-off level at 4.34 mIU/mL on the seventh day showed high predictive value (area under the curve (AUC)=0.852). Serum ß-hCG levels on the seventh day after FET were higher in the twin OP group compared with the single OP group (p<0.001). Also, the serum ß-hCG cut-off level at 17.95 mIU/mL on the seventh day showed high predictive value (AUC=0.903). Serum ß-hCG levels on the seventh day after FET were lower in the ectopic pregnancy group compared with the single OP group (p<0.001) whereas, serum ß-hCG cut-off level at 4.53 mIU/mL on the seventh day exhibited a high predictive value (AUC=0.860). Further, the serum ß-hCG levels on the seventh day after FET were lower in the single early spontaneous abortion group compared with the single OP group (p<0.001) while the serum ß-hCG cut-off level at 5.34 mIU/mL on the seventh day exhibited high predictive value (AUC=0.738). CONCLUSION: Serum ß-hCG on the seventh day after FET has good clinical significance for the prediction of OP and AP.

Branch retinal artery occlusion in a patient undergoing Methotrexate therapy for ectopic pregnancy: A case report.

Methotrexate is a commonly used agent in the treatment of an un-ruptured ectopic pregnancy. Thromboembolic events are rarely seen side effects of such a medicine. We report the case of the 22-year-old woman who underwent Methotrexate therapy for an un-ruptured ectopic pregnancy without any history of thromboembolic risk factors. A second dose (50 mg/m2) was administered to the patient showing a nondecreasing pattern of ß-HCG levels after an initial standard dosage of Methotrexate (50 mg/m2). On the 12th day of the treatment, a sudden onset of painless vision loss was seen in the right eye. Fundal imaging and fluorescein angiography revealed an occlusion of the superior temporal branch of the right retinal artery. After a month of hyperbaric oxygen therapy, complete recovery without loss of vision was achieved.

Marijuana smoking and outcomes of infertility treatment with assisted reproductive technologies.

STUDY QUESTION: What is the association of female and male partner marijuana smoking with infertility treatment outcomes with ART? SUMMARY ANSWER: Women who were marijuana smokers at enrollment had a significantly higher adjusted probability of pregnancy loss during infertility treatment with ART whereas, unexpectedly, there was a suggestion of more favorable treatment outcomes in couples where the man was a marijuana smoker at enrollment. WHAT IS KNOWN ALREADY: Data on the relation of female and male partner marijuana use with outcomes of infertility treatment is scarce despite increased use and legalization worldwide. STUDY DESIGN, SIZE, DURATION: We followed 421 women who underwent 730 ART cycles while participating in a prospective cohort (the Environment and Reproductive Health Study) at a fertility center between 2004 and 2017. Among them, 200 women (368 cycles) were part of a couple in which their male partner also enrolled in the study. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants self-reported marijuana smoking at baseline. Clinical endpoints were abstracted from electronic medical records. We used generalized linear mixed models with empirical standard errors to evaluate the association of baseline marijuana smoking with ART outcomes adjusting for participants' age, race, BMI, tobacco smoking, coffee and alcohol consumption, and cocaine use. We estimated the adjusted probability of implantation, clinical pregnancy, and live birth per ART cycle, as well as the probability of pregnancy loss among those with a positive B-hCG. MAIN RESULTS AND THE ROLE OF CHANCE: The 44% of the women and 61% of the men had ever smoked marijuana; 3% and 12% were marijuana smokers at enrollment, respectively. Among 317 women (395 cycles) with a positive B-hCG, those who were marijuana smokers at enrollment (N = 9, cycles = 16) had more than double the adjusted probability of pregnancy loss than those who were past marijuana smokers or had never smoked marijuana (N = 308, 379 cycles) (54% vs 26%; P = 0.0003). This estimate was based on sparse data. However, couples in which the male partner was a marijuana smoker at enrollment (N = 23, 41 cycles) had a significantly higher adjusted probability of live birth than couples in which the male partner was a past marijuana smoker or had never smoked marijuana (N= 177, 327 cycles) (48% vs 29%; P = 0.04), independently of the women's marijuana smoking status. Treatment outcomes of past marijuana smokers, male and female, did not differ significantly from those who had never smoked marijuana. LIMITATIONS, REASONS FOR CAUTION: Marijuana smoking was self-reported with possible exposure misclassification. Chance findings cannot be excluded due to the small number of exposed cases. The results may not be generalizable to couples from the general population. WIDER IMPLICATIONS OF THE FINDINGS: Even though marijuana smoking has not been found in past studies to impact the ability to become pregnant among pregnancy planners in the general population, it may increase the risk of pregnancy loss among couples undergoing infertility treatment. Marijuana smoking by females and males may have opposing effects on outcomes of infertility treatment with ART. STUDY FUNDING/COMPETING INTEREST(S): The project was financed by grants R01ES009718, P30ES000002, and K99ES026648 from the National Institute of Environmental Health Sciences (NIEHS). None of the authors has any conflicts of interest to declare.

Molecular and cellular effects of vitamin B12 forms on human trophoblast cells in presence of excessive folate.

Folic acid (FA) and iron are essential supplements during pregnancy. Similarly effects of vitamin B12 (B12) inadequacy and high folate and low B12 status, on pregnancy outcome are available. However there are no mandatory recommendations for B12. There are many forms of B12 viz. Cyanocobalamin (Cbl), Methylcobalamin (MeCbl), Adenosylcobalamin (AdCbl), and Hydroxycobalamin (HCbl) though there is limited consensus on which form has better efficacy. In the present study we have determined effect of various forms of B12 in the presence of two FA concentrations namely normal physiological (20ng/mL; NPFA) and supra-physiological (2000ng/mL; SPFA) concentration to mimic real time situation where FA is in excess due to supplementation. We assessed trophoblastic proliferation, viability, TNFα and EGFr mRNA expression, homocysteine, ß-hCG and MDA levels. Trophoblastic viability was significantly suppressed at SPFA concentration and was restored by B12 treatment with Cbl, AdCbl and combination of MeCbl+AdCbl. The mRNA expressions of TNFα were up-regulated, while EGFr were down-regulated at SPFA concentrations, as validated by RT-PCR. Treatment with MeCbl+AdCbl significantly decreased homocysteine and MDA levels at SPFA concentrations. High levels of FA alone had a detrimental effect on placental health and functions as reflected by decreased viability, EGFr expression and increased TNFα expression, homocysteine and MDA levels. Combination of B12 active forms i.e. MeCbl+AdCbl was found to be most effective in neutralising excess folate effect in-vitro.

Effect of folic acid on human trophoblast health and function in vitro.

INTRODUCTION: The combined intake of folic acid (FA) from prenatal multivitamin supplements and fortified foods can result in FA intake values that exceed the tolerable upper intake level (UL). It is unclear what impact FA intake above the UL may have on the feto-placental unit. Our objective was to determine the effects of increasing concentrations of FA on trophoblast health and function in vitro. METHODS: Two human placental cell lines [HTR-8/SVneo (n = 5 experiments) and BeWo (n = 5 experiments)] and human placenta tissue explants (n = 6 experiments) were exposed to increasing concentrations of FA (2-2000 ng/mL) for 48-h. Intracellular total folate concentration, trophoblast proliferation, viability, apoptosis, placenta cell invasion and ß-hCG hormone release were assessed. RESULTS: Exposure to increasing FA concentrations resulted in higher intracellular total folate in placental cell lines and tissue explants (p < 0.05); yet, only minimal effects of excess folic acid were observed on the primary indicators of placental health and function studied. Specifically, treatment with excess folic acid (2000 ng/mL) resulted in reduced cellular viability in the villous trophoblast BeWo cell line and increased rates of proliferation in the HT8-8/SVneo extravillous trophoblast cell line (p < 0.05). Further, deficient concentrations of folic acid (2 ng/mL) resulted in decreased cell viability and invasive capabilities of the HTR-8/SVneo extravillous trophoblast cell line (p < 0.05). DISCUSSION: Our results demonstrate that placental health and function may be compromised in conditions of folate deficiency, and not necessarily in conditions of excess FA. This finding supports the recommendation of prenatal folic acid supplementation in the North American population. Further work aimed at clarifying the therapeutic window of FA intake in the obstetrical population is warranted.

Oligopeptides of Chorionic Gonadotropin ß-Subunit in Induction of T Cell Differentiation into Treg and Th17.

The role of oligopeptides of chorionic gonadotropin ß-subunit (LQGV, AQGV, and VLPALP) in induction of differentiation into T-regulatory lymphocytes (Treg) and IL-17-producing lymphocytes (Th17) was studied in an in vitro system. Chorionic gonadotropin and oligopeptides promoted CD4(+) cell differentiation into functionally active Treg (FOXP3(+)GITR(+) and FOXP3(+)CTLA-4(+)), while chorionic gonadotropin and AQGV additionally stimulated IL-10 production by these cells. In parallel, chorionic gonadotropin and oligopeptides prevented CD4(+) cell differentiation into Th17 lymphocytes (ROR-gt(+)IL-17A(+)) and suppressed IL-17A secretion. Hence, oligopeptides of chorionic gonadotropin ß-subunit promoted differentiation of CD4(+) cells into Treg and, in parallel, suppress Th17 induction, thus virtually completely reproducing the effects of the hormone, which opens new vista for their use in clinical practice.

Can serum ferritin, vitamin B(12) and folic acid levels affect serum screening tests during pregnancy?

OBJECTIVE: To examine the relation of serum folate, vitamin B(12) and ferritin levels to 1st and 2nd trimester serum screening markers. METHODS: Fetal crown-rump length (CRL), nuchal translucency (NT), and first and second trimester serum screening tests of 228 pregnant women were obtained. In all cases, serum vitamin B(12), folic acid and ferritin levels were analyzed during the 11-14 week period. Levels below <15 µg/L, 3 ng/mL and 211 pg/mL were accepted as nutrient deficiency for serum ferritin, folic acid and vitamin B(12), respectively. Results of serum screening markers of women below and above these values were compared with each other. RESULTS: Comparison of groups with ferritin levels <15 and >15 µg/L for 1st and 2nd trimester serum screening parameters revealed significant differences between groups in terms of pregnancy associated plasma protein-A (PAPP-A), free ß-human chorionic gonadotropin (fb-hCG), AFP and hCG. Comparison of women with low versus normal B(12) levels revealed significant differences in terms of NT, PAPP-A and fb-hCG. CONCLUSION: Although sufficient, number of cases is limited in this study so results cannot be generalized to all population. It could be advised that in addition to folic acid supplementation, deficiencies of ferritin and B(12) must be corrected in patients considering pregnancy or early 1st trimester pregnant women to obtain more accurate serum screening results.

[Reference values for thyroid hormones in the population of pregnant women in Jaen (Spain)]. / Valores de referencia de hormonas tiroideas en la población de mujeres gestantes de Jaén.

OBJECTIVE: To evaluate thyroid function in the three trimesters of pregnancy in healthy women taking iodine and to define the reference ranges of normality in this population. DESIGN: Descriptive study of pregnant women to define the ranges of normality of thyroid hormones in this population. SETTING: Jaen and Osuna (Spain). POPULATION: Healthy pregnant women. METHODS: Thyroid hormone determination in the three trimesters of pregnancy in healthy women taking iodine supplements. RESULTS: A total of 429 pregnant women taking iodine supplements to maintain urinary iodine levels within the normal range were included. T4-l levels were between 0.60 and 1.06 in the first trimester, between 0.43 and 0.85 ng/dl in the second and between 0.40 and 0.82 ng/dl in the third. Thyroid stimulating hormone (TSH) reference values were between 0.23 and 4.18µUI/ml in the first trimester, 1.78 and 3.89µUI/ml in the second and 2.01 and 4.30µUI/ml in the third. T3-l values were between 2.33 and 3.84 pg/ml in the first trimester, between 2.04 and 3.51 pg/ml in the second and between 1.99 and 3.46 pg/ml in the third. CONCLUSION: Bearing the 3rd and 97th percentiles in mind, the reference ranges in our population were far below those recommended by our reference laboratory. In view of these results, these values should be redefined to avoid incorrect diagnoses of hyperthyroxinemia in healthy pregnant women.

Supportive care for women with unexplained recurrent miscarriage: patients' perspectives.

BACKGROUND Supportive care is currently the only 'therapy' that can be offered to women with unexplained recurrent miscarriage (RM). What these women themselves prefer as supportive care in their next pregnancy has never been substantiated. Therefore the aim of this study was to explore what women with unexplained RM prefer as supportive care during their next pregnancy. METHODS We performed explorative, semi-structured, in-depth interviews. The interviews were performed with 15 women with unexplained RM who were actively seeking conception. All interviews were conducted by telephone. The interviews were fully transcribed and two researchers independently identified text segments from the transcribed interviews and categorized them in the appropriate domain. RESULTS Women identified 20 different supportive care options; 16 of these options were preferred for their next pregnancy. Examples of the preferred supportive care were early and frequently repeated ultrasounds, ßHCG monitoring, practical advice concerning life style and diet, emotional support in the form of counselling, a clear policy for the upcoming 12 weeks and medication. The four supportive care options that were not preferred by the women were admittance to a hospital ward at the same gestational age as previous miscarriages, Complementary Alternative Medicine, ultrasound every other day and receiving supportive care from their general practitioner. CONCLUSIONS Our study identified several relevant preferences for supportive care in women with unexplained RM. Many of these can be offered by the gynaecologist and will help in guaranteeing high-quality patient-centred care.

Valores de referencia de hormonas tiroideas en la población de mujeres gestantes de Jaén / Reference values for thyroid hormones in the population of pregnant women in jaen (Spain)

Objetivo Valorar la función tiroidea en los tres trimestres de gestación en mujeres sanas suplementadas con yodo y definir los límites de referencia de la normalidad de esta población. Diseño Estudio descriptivo sobre la mujer gestante para definir los límites de normalidad de hormonas tiroideas en esta población. Emplazamiento Jaén y Osuna. Población Gestantes sanas. Métodos Determinación de hormonas tiroideas en los tres trimestres de gestación en mujeres sanas suplementadas con yodo. Resultados Cuatrocientas veintinueve gestantes fueron suplementadas con yodo para mantener nivel de yoduria en los límites de normalidad. Las concentraciones de T4-l estuvieron entre 0,60 y 1,06 para el primer trimestre, entre 0,43 y 0,85 ng/dl en el segundo trimestre y entre 0,40 y 0,82 ng/dl en el tercer trimestre. Para la TSH los valores de referencia son: 0,23 y 4,18μUI/ml en el primer trimestre, 1,78 y 3,89μUI/ml en el segundo trimestre y 2,01 y 4,30μUI/ml en el tercer trimestre. Para T3-l los límites en el primer trimestre es de 2,33 a 3,84 pg/ml, entre 2,04 y 3,51 pg/ml en el segundo trimestre y entre 1,99 y 3,46 pg/ml en el tercer trimestre. ConclusiónLos límites de referencia para nuestra población teniendo en cuenta los percentiles 3 y 97 están muy por debajo del recomendado por nuestro laboratorio de referencia, lo que obliga a redefinir estas concentraciones para evitar diagnosticar de forma incorrecta de hipotiroxinemia a la mujer gestante sana (AU)

Objective: To evaluate thyroid function in the three trimesters of pregnancy in healthy women taking iodine and to define the reference ranges of normality in this population. Design: Descriptive study of pregnant women to define the ranges of normality of thyroid hormones in this population. Setting: Jaen and Osuna (Spain).Population: Healthy pregnant women. Methods: Thyroid hormone determination in the three trimesters of pregnancy in healthy women taking iodine supplements. Results: A total of 429 pregnant women taking iodine supplements to maintain urinary iodine levels within the normal range were included. T4-l levels were between 0.60 and 1.06 in the first trimester, between 0.43 and 0.85 ng/dl in the second and between 0.40 and 0.82 ng/dl in thethird. Thyroid stimulating hormone (TSH) reference values were between 0.23 and 4.18 UI/mlin the first trimester, 1.78 and 3.89 UI/ml in the second and 2.01 and 4.30 UI/ml in the third.T3-l values were between 2.33 and 3.84 pg/ml in the first trimester, between 2.04 and 3.51pg/ml in the second and between 1.99 and 3.46 pg/ml in the third. Conclusion: Bearing the 3rd and 97th percentiles in mind, the reference ranges in our population were far below those recommended by our reference laboratory. In view of these results, these values should be redefined to avoid incorrect diagnoses of hyperthyroxinemia in healthypregnant women (AU)

Endogenously elevated androgens alter the developmental programming of the hypothalamic-pituitary axis in male mice.

Transgenic male mice that express human chorionic gonadotropin (hCG) α and ß subunits constitutively hypersecrete hCG and produce elevated levels of androgens. The aim of this study was to characterize the hypothalamic-pituitary function of these transgenic (hCGαß+) males by focusing on FSH regulation. Serum FSH levels and pituitary mRNA expression of Fshb, Lhb, Cga, Gnrhr and Esr1 were reduced, whereas Fst expression was increased in prepubertal hCGαß+ males as compared with wild-type. In the hypothalamus, Cyp19a1 expression, GnRH concentration and ex-vivo GnRH pulsatility were elevated in prepubertal hCGαß+ mice, whereas Kiss1 expression was decreased prepubertally and Gad67 expression was elevated neonatally. The effect of androgens on the developmental programming of the hypothalamic-pituitary axis of hCGαß+ males was evaluated by perinatal and prepubertal antiandrogen (flutamide) administration. Our studies identified a critical window between gestational day 18 and postnatal day 14, during which chronically elevated androgens and/or their locally produced metabolites activate the hypothalamus and concomitantly shut-down the gonadotropin axis.

Impact of metronomic UFT/cyclophosphamide chemotherapy and antiangiogenic drug assessed in a new preclinical model of locally advanced orthotopic hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is an intrinsically chemotherapy refractory malignancy. Development of effective therapeutic regimens would be facilitated by improved preclinical HCC models. Currently, most models consist of subcutaneous human tumor transplants in immunodeficient mice; however, these do not reproduce the extensive liver disease associated with HCC or metastasize. To address this deficiency, we developed an orthotopic model. Human HCC cells were transfected with the gene encoding secretable beta-subunit human choriogonadotropin (beta-hCG), which was used as a surrogate marker of tumor burden. The HCC cells were implanted into the left liver lobe of severe combined immunodeficient (SCID) mice, after which the efficacy of different therapies was evaluated on established, but liver-confined human Hep3B cell line HCC. Treatments included sorafenib or metronomic chemotherapy using cyclophosphamide (CTX), UFT, an oral 5-fluorouracil prodrug, or doxorubicin either alone or in various combinations, with or without an antiangiogenic agent, DC101, an anti-vascular endothelial growth factor receptor-2 antibody. Sorafenib inhibited tumor growth in a dose-dependent manner but caused severe weight loss in SCID mice, thus necessitating use of DC101 in subsequent experiments. Although less toxicity was observed using either single or doublet metronomic chemotherapy without any added antiangiogenic agent, none, provided survival benefit. In contrast, significantly improved overall survival was observed using various combinations of metronomic chemotherapy regimens such as UFT + CTX with DC101. In conclusion, using this model of liver-confined but advanced HCC suggests that the efficacy of a targeted antiangiogenic drug or metronomic chemotherapy can be mutually enhanced by concurrent combination treatment.

Kinetic analysis of a human chorionic gonadotropin-beta epitope-paratope interaction.

Kinetics of protein-protein or ligand-ligate interaction has predominantly been studied by optical spectroscopy (particularly fluorescence) and surface plasmon resonance biosensors. Almost all such studies are based on association kinetics between ligand-ligate and suffer from certain methodological and interpretational limitations. Therefore, kinetic analyses of dissociation data of such interactions become indispensable. In the present investigation, the radiolabeled human chorionic gonadotropin-beta ((125)IhCGbeta) was employed as a probe and nitrocellulose (NC) as a solid support to immobilize monoclonal antibody (MAb) G(1)G(10).1. The NC-G(1)G(10).1-(125)IhCGbeta complex (NC(com)) was prepared and the dissociation of radiolabeled hCGbeta was carried out in the presence of excess unlabeled ligate. From the experimental dissociation data under varying ionic strength, dissociation constants (k(- 1)), association constants (k(+1)) and affinity constants (k(a)) were calculated. The values obtained were utilized in exploring the amino acid residues constituting an epitopic region of hCGbeta involved in interaction with the complementary paratope on MAb G(1)G(10).1. Kinetic data of the present study supported our recently published findings [using single step-solid phase radioimmunoassay (SS-SPRIA)] that the core region of hCGbeta epitope consists of Arg (94,95) and Asp (99) while a Lys (104) and a His (106) are in proximity to the core epitopic region. Based on the results of present investigation, we conclude that dissociation kinetics coupled with SS-SPRIA unequivocally provides considerable insight into the study of ligand-ligate interactions and epitope analysis.

Effect of Gutai Decoction on the abortion rate of in vitro fertilization and embryo transfer.

OBJECTIVE: To study the effect of Chinese herbal medicine Gutai Decoction (GTD) on the abortion rate of in vitro fertilization and embryo transfer (IVF-ET). METHODS: Observed were two hundred and forty-seven women having received IVF-ET and with beta-human chorionic gonadotropin (beta-HCG) > 25 IU/L on the 14th day after transferring. All were treated conventionally with progesterone 20 - 80 mg per day after transferring and if necessary the treatment was supplemented with Progynova 2 - 4 mg per day, with the medication withdrawn gradually from the 9th week of pregnancy till stopped completely. Among them 131 cases received GTD medication additionally, for 109 cases of whom the medication started from the 2nd day of transferring (taken as Group A) and for the other 22 cases from the 14th day after transferring (taken as Group B), the other 116 cases with no additional GTD treatment given were taken as the control group, with the medication lasting to the 12th week. The abortion rate in them was observed. RESULTS: The abortion rate in Group A, Group B and the control group was 12.84%, 13.64% and 23.28%, respectively, the difference between the GTD treated groups and the control group was significant (P < 0.05). CONCLUSION: Chinese medicine GTD could reduce abortion rate in women receiving IVF-ET.