Visfatin Affects the Transcriptome of Porcine Luteal Cells during Early Pregnancy.

Visfatin/NAMPT (VIS), the hormone exerting a pleiotropic effect, is also perceived as an important factor in the regulation of reproductive processes and pregnancy maintenance. Previous studies confirmed its involvement in the control of porcine pituitary and ovary function. In this study, we hypothesized that VIS may affect the global transcriptome of luteal cells and thus regulate the functioning of the ovaries. Illumina's NovaSeq 6000 RNA sequencing was performed to investigate the differentially expressed genes (DEGs) and long non-coding RNAs (DELs) as well as the occurrence of differential alternative splicing events (DASs) in the porcine luteal cells exposed to VIS (100 ng/mL) during the implantation period. The obtained results revealed 170 DEGs (99 up- and 71 downregulated) assigned to 45 functional annotations. Moreover, we revealed 40 DELs, of which 3 were known and 37 were described for the first time. We identified 169 DASs events. The obtained results confirmed a significant effect of VIS on the transcriptome and spliceosome of luteal cells, including the genes involved in the processes crucial for successful implantation and pregnancy maintenance as angiogenesis, steroidogenesis, inflammation, cell development, migration, and proliferation.

Epigenetic role of LINE-1 methylation and key genes in pregnancy maintenance.

Spontaneous abortion is a pregnancy complication characterized by complex and multifactorial etiology. About 5% of childbearing women are globally affected by early pregnancy loss (EPL) and most of them experience recurrence (RPL). Epigenetic mechanisms and controlled inflammation are crucial for pregnancy maintenance and genetic predispositions may increase the risk affecting the maternal-fetal crosstalk. Combined analyses of global methylation, inflammation and inherited predispositions may contribute to define pregnancy loss etiopathogenesis. LINE-1 epigenetic regulation plays crucial roles during embryo implantation, and its hypomethylation has been associated with senescence and several complex diseases. By analysing a group of 230 women who have gone through pregnancy interruption and comparing those experiencing spontaneous EPL (n = 123; RPL, 54.5%) with a group of normal pregnant who underwent to voluntary interruption (VPI, n = 107), the single statistical analysis revealed significant lower (P < 0.00001) LINE-1 methylation and higher (P < 0.0001) mean cytokine levels (CKs: IL6, IL10, IL17A, IL23) in EPL. Genotyping of the following SNPs accounted for different EPL/RPL risk odds ratio: F13A1 rs5985 (OR = 0.24; 0.06-0.90); F13B rs6003 (OR = 0.23; 0.047-1.1); FGA rs6050 (OR = 0.58; 0.33-1.0); CRP rs2808635/rs876538 (OR = 0.15; 0.014-0.81); ABO rs657152 (OR = 0.48; 0.22-1.08); TP53 rs1042522 (OR = 0.54; 0.32-0.92); MTHFR rs1801133/rs1801131 (OR = 2.03; 1.2-3.47) and FGB rs1800790 (OR = 1.97; 1.01-3.87), although Bonferroni correction did not reach significant outputs. Principal Component Analysis (PCA) and logistic regression disclosed further SNPs positive/negative associations (e.g. APOE rs7412/rs429358; FGB rs1800790; CFH rs1061170) differently arranged and sorted in four significant PCs: PC1 (F13A, methylation, CKs); PC3 (CRP, MTHFR, age, methylation); PC4 (F13B, FGA, FGB, APOE, TP53, age, methylation); PC6 (F13A, CFH, ABO, MTHFR, TP53, age), yielding further statistical power to the association models. In detail, positive EPL risk association was with PC1 (OR = 1.81; 1.33-2.45; P < 0.0001) and negative associations with PC3 (OR = 0.489; 0.37-0.66; P < 0.0001); PC4 (OR = 0.72; 0.55-0.94; P = 0.018) and PC6 (OR = 0.61; 0.46-0.81; P = 0.001). Moreover, significant inverse associations were detected between methylation and CKs levels in the whole group (rIL10 = - 0.22; rIL17A = - 0.25; rIL23 = - 0.19; rIL6 = - 0.22), and methylation with age in the whole group, EPL and RPL subgroups (r2TOT = 0.147; r2EPL = 0.136; r2 RPL = 0.248), while VPI controls lost significance (r2VPI = 0.011). This study provides a valuable multilayer approach for investigating epigenetic abnormalities in pregnancy loss suggesting genetic-driven dysregulations and anomalous epigenetic mechanisms potentially mediated by LINE-1 hypomethylation. Women with unexplained EPL might benefit of such investigations, providing new insights for predicting the pregnancy outcome and for treating at risk women with novel targeted epidrugs.

Effects of long-acting injectable progesterone supplementation at early dioestrus on pregnancy maintenance in beef and dairy recipient cattle.

We tested in the present study the hypothesis that supplementation with long-acting P4 (iP4) at different times of the initial dioestrus improves pregnancy rates in dairy and beef recipients submitted to fixed-time embryo transfer (FTET). Recipients from commercial farms had their oestrous cycle synchronized with an E2/P4-based protocol in three experiments (Exp. 1 to 3). In Exp. 1, dairy heifers (n = 76) and cows (n = 104) were randomly assigned to two experimental groups: the control group (n = 89) and the iP4D4 group (n = 91). For Exps. 2 and 3, suckled beef recipients were used. In Exp. 2, recipients were assigned to two experimental groups: Control group (n = 147) and iP4D7 group (n = 144); whereas in Exp. 3, recipients were randomly assigned to three experimental groups: Control group (n = 85), iP4-D4 group (n = 86) and iP4D7 group (n = 81). Recipients in the iP4D4 and iP4-D7 groups received an i.m. administration of 150 mg iP4, on D4 or D7 (D0 was the day of expected oestrus). On D7, all recipients were evaluated by transrectal ultrasonography and those that had a CL received a fresh or vitrified in vitro-produced embryo. In Exp. 2 and 3, the CL area was also determined by ultrasonography at the time of FTET. The pregnancy diagnosis was performed at 30 days in Exp. 1, 57 days in Exp. 2, and between 40 and 72 days of pregnancy in Exp. 3. In Exp. 1, the pregnancy rate did not differ (p > .1) between the Control group (38.2% [34/89]) and iP4D4 group (49.5% [45/91]); yet, a parity effect indicated a greater (p < .05) pregnancy rate in heifers (57.9% [44/76]) than cows (30.8% [32/104]). In Exp. 2, the pregnancy rate was greater (p < .05) in the iP4D7 group (45.0% [65/144]) than in the Control group (34.0% [50/147]). Also, a greater (p = .08) pregnancy rate was observed for recipients with a small CL (≤2.75 cm2 ) that were treated with iP4 on the day of FTET than the control recipients (46.4% [32/69] vs. 32.6% [28/86]). In Exp. 3, no significant effects (p > .1) of the treatment group or CL size were detected on pregnancy rates at days 30 and 60. In conclusion, the beneficial effects of iP4 supplementation at early dioestrus on pregnancy maintenance may vary according to the experimental conditions, but its use at the time of FTET can be used as an alternative to enhance the fertility of beef recipients in challenging conditions in commercial herds.

Descripción de las personas gestantes afiliadas a OSEP que solicitan una interrupción del embarazo / Description of pregnant people affiliated to osep who request a pregnancy interruption

En 2021 entró en vigencia en Argentina la Ley N.º 27.610. El objetivo es describir características de afiliadas a OSEP que solicitaron interrupción del embarazo (SIE).Trabajo observacional descriptivo. Se analizaron las variables del 0800 del Ministerio de Salud de la Nación de todas las personas que SIE con OSEP, entre el 24/01 y 31/12/2021. Los datos fueron analizados con SPSS Statistics. Se utilizaron moda, mediana, porcentaje, tasa y el chi2. Se recibieron 427 SIE, se concretaron 330 (77,3%). Solicitaron ive: media 28,59 años. Modo 19 y 33 años. Concretaron ive: modo 22 años. 84,5% se realizó ambulatorio con misoprostol. De las SIE, 50,4% eran solteras, 43,4% trabajaba, 59,1% tenía secundario completo. Se desconoce 32,8%. De las SIE, 52,7% refirió haber estado utilizando MAC (54,2% preservativo; 37,4% anticonceptivos orales; 2,8% métodos "naturales"; 2,2% DIU). La mayor cantidad fue de zonas urbanas del Gran Mendoza. Sin embargo, se observan tasas elevadas en zonas rurales respecto de algunas zonas urbanas y más pobladas. Se observó progresión de SIE a lo largo del año. Un 11% después de SIE decidió continuar con el embarazo. Aparentemente ninguna de las variables tuvo relación con esa decisión. El MAC utilizado fue mayormente preservativo y anticonceptivos orales. Esto podría indicar falta de educación y poco acceso a métodos de larga duración. La problemática de interrupción es transversal. En base a los resultados de este trabajo, las personas sin pareja conviviente, ante un embarazo no planificado serían las que SIE. Ninguna otra variable parece actuar como determinante. Tampoco del paso de la solicitud a la interrupción efectiva o a la continuación del embarazo. Hay que aumentar la accesibilidad a MAC en zonas rurales (AU)

In 2021, Law No. 27610 entered into force in Argentina. The objective is to describe characteristics of people with OSEP who requested termination of pregnancy (PWRTP). Descriptive observational work. The variables of the 0800 of the Ministry of Health of Argentina of all the PWRTP with OSEP, between 01/24 and 12/31/2021, were analyzed. Data were analyzed with SPSS Statistics. Mode, median, percentage, rate and chi2 were used. PWRTP: 427 requests were received, 330 (77.3%) were completed. PWRTP: mean 28.59 years. Mode 19 and 33 years. People who had an abortion: mode 22 years. 84.5% were performed on an outpatient basis with misoprostol. 50.4% of the PWRTP were single, 43.4% worked, 59.1% had completed high school, 32.8% unknown, 52.7% reported having been using contraceptive methods (CM): 54.2% condoms; 37.4% oral contraceptives; 2.8% "natural" methods; 2.2% IUDs. The largest amount was from urban areas of Mendoza. However, high rates are observed in rural areas. A progression of the amount of PWRTP was observed throughout the year. 11% after requesting an abortion decided to continue with the pregnancy. Apparently none of the variables was related to that decision. The CM used were mostly condoms and oral contraceptives. This may indicate a lack of education and poor access to long-acting CM. The problem of interruption is transversal. People without a cohabiting partner, faced with an unplanned pregnancy, are the ones who RTP. No other variable seems to act as a determinant. Nor from the transition from the request to the effective interruption or continuation of the pregnancy. We must increase the accessibility to CM in rural areas (AU)

Expression profile of genes related to pregnancy maintenance in Dromedary Camel during the first trimester.

So far, few signals involved in embryo-maternal dialogue have been identified in pregnant she-camel. Our objective was to investigate expression profiles of genes relevant to uterine extracellular matrix remodeling (ITGB4, SLCO2A1, FOS, and JUN), uterine tissue vascularization, and placental formation (VEGFA, PGF, and PDGFA), embryonic growth and development (IGF1 and PTEN), plus cell death of uterine tissue (BCL2) in early pregnant versus non-pregnant she-camels. Forty genital tracts (20 pregnant and 20 non-pregnant) and blood samples were collected from abattoirs. Total RNA was extracted from uterine tissues and qRT-PCR was conducted for candidate genes. Serum concentrations of progesterone (P4) and estradiol17-ß (E2) were measured. Expression of ITGB4, FOS, and PGF genes increased (P < 0.001) in the right uterine horn of pregnant versus non-pregnant she-camels. Moreover, JUN, SLCO2A1, VEGFA, and PTEN mRNAs were up-regulated (P < 0.001) in various segments of uterine tissues in pregnant groups. The PDGFA transcript was over-expressed (P < 0.001) in both uterine horns of pregnant groups. Additionally, IGF1 was higher (P < 0.001) in the right horn and the uterine body of pregnant groups, and expression of BCL2 was increased (P < 0.001) in the pregnant uterine body. Moreover, serum concentrations of P4 were higher (P < 0.001) and E2 lower (P < 0.05) in pregnant she-camels. Taken together, the fine-tuning of genes related to implantation, matrix formation, vascularization, and placental formation is highly required for successful pregnancy in she-camels.

Tim-3 Coordinates Macrophage-Trophoblast Crosstalk via Angiogenic Growth Factors to Promote Pregnancy Maintenance.

T-cell immunoglobulin mucin-3 (Tim-3) is an important checkpoint that induces maternal-fetal tolerance in pregnancy. Macrophages (Mφs) play essential roles in maintaining maternal-fetal tolerance, remodeling spiral arteries, and regulating trophoblast biological behaviors. In the present study, the formation of the labyrinth zone showed striking defects in pregnant mice treated with Tim-3 neutralizing antibodies. The adoptive transfer of Tim-3+Mφs, rather than Tim-3-Mφs, reversed the murine placental dysplasia resulting from Mφ depletion. With the higher production of angiogenic growth factors (AGFs, including PDGF-AA, TGF-α, and VEGF), Tim-3+dMφs were more beneficial in promoting the invasion and tube formation ability of trophoblasts. The blockade of AGFs in Tim-3+Mφs led to the narrowing of the labyrinthine layer of the placenta, compromising maternal-fetal tolerance, and increasing the risk of fetal loss. Meanwhile, the AGFs-treated Tim-3-Mφs could resolve the placental dysplasia and fetal loss resulting from Mφ depletion. These findings emphasized the vital roles of Tim-3 in coordinating Mφs-extravillous trophoblasts interaction via AGFs to promote pregnancy maintenance and in extending the role of checkpoint signaling in placental development. The results obtained in our study also firmly demonstrated that careful consideration of reproductive safety should be taken when selecting immune checkpoint and AGF blockade therapies in real-world clinical care.

Violência sexual e aborto legal: possibilidades e desafios da atuação psicológica / Sexual offence and legal abortion: opportunities and challenges from psychological working / Violencia sexual y aborto legal: posibilidades y desafíos de la atención psicológica

A violência sexual e o aborto legal são temas tabus em nossa sociedade. No campo da saúde, a(o) psicóloga(o) atua em fases distintas, seja na avaliação psicológica do pedido pelo aborto legal, que culminará ou não em sua aquiescência; seja no momento posterior à solicitação, no atendimento em enfermarias ou ambulatorial. Partindo de relato de experiência, este artigo tem como objetivo refletir sobre as possibilidades e desafios da atuação psicológica no atendimento em saúde para pessoas em situação de gestação decorrente de violência sexual e que buscam pelo aborto legal. Para tanto, dividimos o artigo em três momentos. No primeiro deles, será possível encontrar dados conceituais, estatísticos e históricos sobre ambos os temas, trazendo recortes nacionais e internacionais. No segundo, trazemos apontamentos sobre o que chamamos de "eixos norteadores", ou seja, dialogamos com aspectos fundamentais para o trabalho nesta seara, sendo eles gênero, família, sexualidade e trauma. Por fim, no terceiro, aprofundamos a reflexão sobre o atendimento psicológico atrelado aos conceitos já discutidos, analisando de forma crítica principalmente um dos pontos mais espinhosos da atuação: a avaliação para aprovação (ou recusa) do pedido pelo aborto. Apoiamo-nos no referencial psicanalítico e defendemos que esta atuação psicológica é primordialmente uma oferta de cuidado, comprometido com as demandas das pessoas atendidas e com a promoção de saúde mental, e consideramos que o papel da psicologia é essencial para o reconhecimento do sofrimento e dos efeitos do abandono socioinstitucional na vida do público atendido.(AU)

Sexual abuse and legal abortion are taboo subjects in our society. On the health area, the psychologist works on different fields, such as psychological evaluation from the request of legal abortion, that will end or not on its approval, and also in a further moment, either the care on wards or ambulatorial treatment. Relying on a case report, this article aims to contemplate the possibilities and challenges from psychological work on healthcare to pregnant women from sexual violence and seek legal abortion. For this purpose, we divide this article in three moments. On the first, it will find definitions, statistics, and historical data about both issues, including national and international information. On the second, we bring notes called 'guiding pillar,' that is, we interact with fundamental aspects from this area, such as gender, family, sexuality, and trauma. On the third one, in-depth discussions we dwell on psychological care tied to the concepts previously addressed, critically analyzing one of the hardest moments of working in this area: the evaluation to approve (or refuse) the request for abortion. We lean over psychoanalytic thoughts and argue that this psychological work is primarily an offer of care, committed to the needs from those who seek us and to promoting good mental health and, also, we consider that psychology is essential to acknowledge the suffering and the effects of social and institutional neglect on the lives of the people seen.(AU)

La violencia sexual y el aborto son temas tabús en nuestra sociedad. En el campo de la salud, el(la) psicólogo(a) actúa en diferentes fases: en la evaluación psicológica de la solicitud del aborto legal, que culminará o no en su obtención, y/o en el momento posterior a la solicitud en la atención en enfermería o ambulatorio. Desde un reporte de experiencia, este artículo pretende reflexionar sobre las posibilidades y los desafíos de la Psicología en la atención en salud para personas en estado de embarazo producto de violencia sexual y que buscan un aborto legal. Para ello, este artículo está dividido en tres momentos. En el primer, presenta datos conceptuales, estadísticos e históricos sobre los dos temas, trayendo recortes nacionales e internacionales. En el segundo, comenta los llamados "ejes temáticos", es decir, se establece un diálogo con aspectos fundamentales para el trabajo en este ámbito, como género, familia, sexualidad y trauma. Por último, en el tercer, profundiza en la reflexión sobre la atención psicológica asociada a los conceptos discutidos, analizando de forma crítica uno de los puntos más espinosos de la actuación: la evaluación para la aprobación (o negativa) de la solicitud de aborto. Se utilizó el referencial psicoanalítico y se argumenta que esta atención psicológica es sobre todo una forma de cuidado, comprometida con las demandas de las personas atendidas y la promoción de la salud mental, y el papel de la Psicología es esencial para reconocer el sufrimiento y los efectos del abandono socioinstitucional en la vida del público atendido.(AU)

Intervenções psicológicas necessárias: a prática como residente no serviço de medicina fetal / Necessary psychological interventions: the practice as a resident in the fetal medicine service / Intervenciones psicológicas necesarias: la práctica como residente en el servicio de medicina fetal

Com os avanços tecnológicos e o aprimoramento da prática médica via ultrassonografia, já é possível detectar possíveis problemas no feto desde a gestação. O objetivo deste estudo foi analisar a prática do psicólogo no contexto de gestações que envolvem riscos fetais. Trata-se de um estudo qualitativo sob formato de relato de experiência como psicólogo residente no Serviço de Medicina Fetal da Maternidade Escola da Universidade Federal do Rio de Janeiro (UFRJ). Os registros, feitos por observação participante e diário de campo, foram analisados em dois eixos temáticos: 1) intervenções psicológicas no trabalho em equipe em consulta de pré-natal, exame de ultrassonografia e procedimento de amniocentese; e 2) intervenções psicológicas em casos de bebês incompatíveis com a vida. Os resultados indicaram que o psicólogo nesse serviço é essencial para atuar de forma multiprofissional na assistência pré-natal para gravidezes de alto risco fetal. Ademais, a preceptoria do residente é relevante para sua formação e treinamento para atuação profissional no campo da psicologia perinatal.(AU)

Face to the technological advances and the improvement of medical practice via ultrasound, it is already possible to detect possible problems in the fetus since pregnancy. The objective of this study was to analyze the psychologist's practice in the context of pregnancies which involve fetal risks. It is a qualitative study based on an experience report as a psychologist trainee at the Fetal Medicine Service of the Maternity School of UFRJ. The records, based on the participant observation and field diary, were analyzed in two thematic axes: 1) psychological interventions in the teamwork in the prenatal attendance, ultrasound examination and amniocentesis procedure; and 2) psychological interventions in cases of babies incompatible to the life. The results indicated that the psychologist in this service is essential to work in a multidisciplinary way at the prenatal care for high fetal risk pregnancies. Furthermore, the resident's preceptorship is relevant to their education and training for professional performance in the field of Perinatal Psychology.(AU)

Con los avances tecnológicos y la mejora de la práctica médica a través de la ecografía, ya se puede detectar posibles problemas en el feto desde el embarazo. El objetivo de este estudio fue analizar la práctica del psicólogo en el contexto de embarazos de riesgos fetal. Es un estudio cualitativo basado en un relato de experiencia como residente de psicología en el Servicio de Medicina Fetal de la Escuela de Maternidad de la Universidade Federal do Rio de Janeiro (UFRJ). Los registros, realizados en la observación participante y el diario de campo, se analizaron en dos ejes temáticos: 1) intervenciones psicológicas en el trabajo en equipo, en la consulta prenatal, ecografía y los procedimientos de amniocentesis; y 2) intervenciones psicológicas en casos de bebés incompatibles con la vida. Los resultados señalaron como fundamental la presencia del psicólogo en este servicio trabajando de forma multidisciplinar en la atención prenatal en el contexto de embarazos de alto riesgo fetal. Además, la tutela del residente es relevante para su educación y formación para el desempeño profesional en el campo de la Psicología Perinatal.(AU)

Tim-3+ decidual Mφs induced Th2 and Treg bias in decidual CD4+T cells and promoted pregnancy maintenance via CD132.

T-cell immunoglobulin mucin-3 (Tim-3) plays roles in the functional regulation of both adaptive and innate immune cells and is greatly involved in many diseases. However, the precise roles of Tim-3 on macrophages (Mφs) in pregnancy remain unstated. In the current study, we found the higher frequency of Tim-3+ decidual Mφs (dMφs) in response to trophoblasts. The reduced abundance of Tim-3 on Mφs was accompanied by disordered anti- and pro-inflammatory cytokine profiles in miscarriage. Adoptive transfer of Tim-3+Mφs, but not Tim-3-Mφs, relieved murine embryo absorption induced by Mφ depletion. Our flow cytometry results and the extensive microarray analysis confirmed that Tim-3+ and Tim-3-dMφs were neither precisely pro-inflammatory (M1) nor anti-inflammatory (M2) Mφs. However, with higher CD132 expression, Tim-3+dMφs subset induced Th2 and Treg bias in decidual CD4+T cells and promoted pregnancy maintenance. Blockade of Tim-3 or CD132 pathways leaded to the dysfunction of maternal-fetal tolerance and increased fetal loss. These findings underscored the important roles of Tim-3 in regulating dMφ function and maintaining normal pregnancy, and suggested that Tim-3 on Mφs is a potential biomarker for diagnosis of miscarriage. Our study also emphasized the importance of careful consideration of reproductive safety when choosing immune checkpoint blockade therapies in real world clinical care. Though IL-4 treated Tim-3-Mφs could rescue the fetal resorption induced by Mφ depletion, whether IL-4 represent novel therapeutic strategy to prevent pregnancy loss induced by checkpoint inhibition still needs further research.

Pregnancy maintenance following sequential induced prostaglandin pulses in beef cows.

The relationship between the maternal endocrine environment and late embryonic mortality (> 28 d of gestation) in cattle is poorly defined. A definitive rise and alterations in secretion patterns of prostaglandin F2α (PGF2α) concentration without luteal regression is a trademark of this period. The objective was to evaluate whether consecutively induced PGF2α pulses would alter steroid hormone production and luteal blood perfusion potentially influencing pregnancy success. Pregnant beef cows (n = 12) were selected to receive either an oxytocin injection (OT, n = 8) or saline injection (CON, n = 4) on d 30 and 31 of gestation to stimulate sequential prostaglandin releases 24 h apart. Blood samples were collected every 30 min for 1 h before and continuing for 4 h post oxytocin administration. Luteal blood perfusion was measured via Doppler ultrasound at the beginning and end of the OT challenge. Concentrations of prostaglandin F2α metabolite (PGFM) were quantified to show effectiveness of the treatment while concentrations of progesterone, estradiol and pregnancy-associated glycoproteins (PAG) were measured to examine the effect of PGF2α release. Control animals exhibited no changes in any quantified hormone and an expected numerical increase in circulating PAG concentrations. Peak concentrations of PGFM in OT cows were observed 2 h post OT administration and concentrations returned to basal levels by the end of the sampling period. Peak concentrations of PGFM were decreased on d 31 compared to d 30. Following OT administration, progesterone and estradiol concentrations did not change in response to PGF2α release but were decreased on d 31 compared to d 30. There were no changes in luteal blood perfusion in response to PGF release on d 30 or d 31. Repeated PGF2α release may alter steroid hormone production; however, it does not negatively affect pregnancy status during the transition between early and late embryonic development.

GAS6-mediated dialogue between decidual stromal cells and macrophages is essential for early pregnancy maintenance by inducing M2-like polarization and cell proliferation of decidual macrophages.

Maternal immunotolerance towards the semi-allogeneic foetus is critical for normal pregnancy (NP). As a secretory protein, growth arrest-specific factor 6 (GAS6) promotes cancer progression by inducing the conversion of tumour-associated macrophages to an immunosuppressive M2-like phenotype. However, little is known about whether GAS6 regulates decidual macrophages (dMφs) in the early maternal-foetal interface. In this study, first-trimester decidual tissues were obtained from normal pregnant women undergoing elective terminations and patients with miscarriages. The expression of GAS6 and its receptors (AXL, TYRO3 and MERTK) in decidua and GAS6 secretion by decidual stromal cells (DSCs) was measured. Then, we investigated the effect of recombinant human GAS6 (rhGAS6) on dMφs isolated from NP and THP-1 cells, and revealed the underlying mechanism. Both the expression of GAS6 in DSCs and MERTK in dMφs, in addition to GAS6 secretion by DSCs, was found to be significantly decreased in miscarriage patients compared to that in NPs. Additionally, we observed that rhGAS6 polarized dMφs and THP-1 cells towards an M2-like phenotype, as evidenced by the up-regulated CD163 expression. Moreover, rhGAS6 enhanced the clearance of toxic cell-free haemoglobin by dMφs by up-regulating CD163 expression, and rhGAS6 also boosted cell proliferation of dMφs and THP-1 cells. Finally, we demonstrated that rhGAS6 stimulated CD163 expression and cell proliferation by activating the PI3K/Akt signalling pathway. Collectively, these findings suggest that GAS6-mediated dialogue between DSCs and dMφs is crucial for the establishment and maintenance of maternal-foetal immunotolerance, and decreased GAS6 secretion by DSCs may lead to the occurrence of miscarriage in the first trimester.

Gravidez heterotópica espontânea: implicações de um diagnóstico tardio / Spontaneous heterotopic pregnancy: implications of a late diagnosis

A gestação heterotópica é uma entidade rara, principalmente se resultante de concepção natural. O diagnóstico é ultrassonográfico, porém a gestação intrauterina concomitante contribui para a dificuldade propedêutica. Neste relato de caso, a detecção foi tardia, a ultrassonografia não identificou a gestação heterotópica e apenas durante a avaliação intraoperatória, por meio de uma cirurgia de emergência devido a choque hemorrágico, houve o reconhecimento. A suspeita de uma gestação heterotópica deve ser sempre aventada quando sinais clínicos típicos (sangramento, dor abdominal) estão presentes, mesmo na ausência de fatores de risco ou imagens anômalas na ecografia. Assim, uma intervenção precoce menos invasiva pode ser realizada, reduzindo a morbimortalidade materna e do feto intrauterino. Este relato de caso destaca uma situação incomum dentro dessa patologia rara: diagnóstico tardio, apenas no segundo trimestre de gestação, sem evidência prévia ultrassonográfica, certificada apenas durante o intraoperatório. O manejo cirúrgico preciso permitiu a manutenção da gravidez intrauterina.(AU)

Heterotopic pregnancy is a rare entity, especially if it is resulted from natural conception. The diagnosis is ultrasonographic, but the concomitant intrauterine pregnancy contributes to the propaedeutic difficulty. In this case report, the detection was late, the ultrasonography did not identify heterotopic pregnancy and, only during intraoperative evaluation through emergency surgery, exploratory laparotomy, there was recognition. The suspicion of a heterotopic pregnancy should always be raised when typical clinical signs (bleeding, abdominal pain) are present, even in absentia of risk factors or anomalous images on ultrasound. Thus, a less invasive early intervention can be performed, reducing maternal and intrauterine fetus morbimortality. This case report highlights an unusual situation within this rare pathology: late diagnosis, only in the second trimester of pregnancy, without previous ultrasound evidence, certified only during the intraoperative period. Precise surgical management allowed the maintenance of intrauterine pregnancy.(AU)

Genetic variants in the p53 pathway influence implantation and pregnancy maintenance in IVF treatments using donor oocytes.

PURPOSE: Single-nucleotide polymorphisms (SNPs) in the p53 pathways have shown to play a role in endometrial receptivity and implantation in infertile women undergoing in vitro fertilization (IVF). The present study aimed to assess the influence of these gene variants over pregnancy success through a receptivity model in recipients of egg donation treatments, when factors such as age and quality of the oocytes are standardized. METHODS: A nested case-control study was performed on 234 female patients undergoing their first fresh IVF treatment as recipients of donor oocytes. Genotyping of TP53 Arg72Pro (rs1042522), LIF (rs929271), MDM4 (rs1563828), and USP7 (rs1529916) SNPs in the recipients allowed comparison of allele and genotype frequencies and their association with the IVF treatment outcome. RESULTS: Grouped by genotypes, patients showed differences in IVF outcomes after the embryo transfer. Arg72Pro (rs1042522) gene variant was associated to changes in implantation and clinical pregnancy rates. The polymorphisms USP7 (rs1529916) and MDM4 (rs1563828) were associated to differential ongoing pregnancy rates and variable miscarriage events, respectively. CONCLUSIONS: This study highlights the association between gene polymorphisms related to P53 function and their influence over IVF reproductive outcomes. Arg72Pro variant may influence early events, as lower implantation rates were found in homozygous for Pro72 allele. By contrast, MDM4 (rs1563828) and USP7 (rs1529916) gene variants were associated with the later maintenance of pregnancy.

GnRH agonist and hCG (dual trigger) versus hCG trigger for follicular maturation: a systematic review and meta-analysis of randomized trials.

BACKGROUND: Traditionally, final follicular maturation is triggered by a single bolus of human chorionic gonadotropin (hCG). This acts as a surrogate to the naturally occurring luteinizing hormone (LH) surge to induce luteinization of the granulosa cells, resumption of meiosis and final oocyte maturation. More recently, a bolus of gonadotropin-releasing hormone (GnRH) agonist in combination with hCG (dual trigger) has been suggested as an alternative regimen to achieve final follicular maturation. METHODS: This study was a systematic review and meta-analysis of randomized trials evaluating the effect of dual trigger versus hCG trigger for follicular maturation on pregnancy outcomes in women undergoing in vitro fertilization (IVF). The primary outcome was the live birth rate (LBR) per started cycle. RESULTS: A total of 1048 participants were included in the analysis, with 519 in the dual trigger group and 529 in the hCG trigger group. Dual trigger treatment was associated with a significantly higher LBR per started cycle compared with the hCG trigger treatment (risk ratio (RR) = 1.37 [1.07, 1.76], I2 = 0%, moderate evidence). There was a trend towards an increase in both ongoing pregnancy rate (RR = 1.34 [0.96, 1.89], I2 = 0%, low evidence) and implantation rate (RR = 1.31 [0.90, 1.91], I2 = 76%, low evidence) with dual trigger treatment compared with hCG trigger treatment. Dual trigger treatment was associated with a significant increase in clinical pregnancy rate (RR = 1.29 [1.10, 1.52], I2 = 13%, low evidence), number of oocytes collected (mean difference (MD) = 1.52 [0.59, 2.46), I2 = 53%, low evidence), number of mature oocytes collected (MD = 1.01 [0.43, 1.58], I2 = 18%, low evidence), number of fertilized oocytes (MD = 0.73 [0.16, 1.30], I2 = 7%, low evidence) and significantly more usable embryos (MD = 0.90 [0.42, 1.38], I2 = 0%, low evidence). CONCLUSION: Dual trigger treatment with GnRH agonist and HCG is associated with an increased live birth rate compared with conventional hCG trigger. TRIAL REGISTRATION: CRD42020204452 .

Alteraciones musculoesqueléticas y adaptaciones biomecánicas durante los trimestres de embarazo: una revisión sistemática / Musculoskeletal changes and biomechanic adaptations during the three trimesters of pregnancy: a sistematic review

Resumen Quesada Salazar, N. (2021). Alteraciones musculoesqueléticas y adaptaciones biomecánicas durante los trimestres de embarazo: una revisión sistemática. PENSAR EN MOVIMIENTO: Revista de Ciencias del Ejercicio y la Salud, 19(1), 1-27. El embarazo es un proceso progresivo que involucra cambios de tipo hormonal, mecánico, fisiológico y emocional en la mujer y que causa que el sistema musculoesquelético se adapte constantemente. Estos cambios suelen identificarse a través de la postura y la biomecánica de los movimientos en la vida diaria. En esta investigación, se realizó una revisión sistemática para encontrar las principales alteraciones y adaptaciones durante el embarazo, incluyendo artículos del 2008 al 2018, con mujeres gestantes sanas, con un solo feto, sin alteraciones musculoesqueléticas previas, de Índice de Masa Corporal (IMC) normal y cualquier metodología de investigación excepto estudios de caso. Se identificaron 13 estudios que refieren evaluar las tres etapas de gestación, edades desde los 20 a los 35 años, así como con diversos objetivos de investigación. La postura de la mujer gestante presenta un aumento de la lordosis lumbar, la curvatura torácica y el ángulo de inclinación anterior de la pelvis. La tarea de sentarse y levantarse de una silla requiere de mayor control del movimiento, así como de tiempo de ejecución. La oscilación y las fuerzas de reacción del suelo del Centro de Presión corporal aumentan al estar de pie, lo que resulta en una mayor distancia entre los pies, como estrategia de control del equilibrio. Finalmente, la biomecánica de la marcha se adapta a una menor velocidad, longitud de paso y etapa de despegue de los pies del piso, con un aumento del ancho de paso y una mayor base de apoyo. En la gestación, la mujer desarrolla adaptaciones de tipo anatómicas y mecánicas como respuesta a los cambios progresivos experimentados.

Abstract Quesada Salazar, N. (2021). Musculoskeletal changes and biomechanic adaptations during the three trimesters of pregnancy: a sistematic review. PENSAR EN MOVIMIENTO: Revista de Ciencias del Ejercicio y la Salud, 19(1), 1-27. Pregnancy is a progressive process involving hormonal, mechanical, physiological, and emotional changes in women that stimulates the musculoskeletal system to adapt constantly. These changes are usually identified through posture and the biomechanics of day-to-day movements. This study consists of a systematic review of the main alterations and adaptations during pregnancy, including articles from 2008 to 2018 that involved healthy pregnant women without previous musculoskeletal affections, with a single fetus and normal BMI, and any methods of study excluding case studies. Thirteen studies were identified which indicate evaluation of participants ages from 20 to 35 years during their three trimesters of pregnancy, as well as different study objectives. Posture in a pregnant woman shows an increase in the lumbar lordosis, thoracic curvature, and anterior tilt of the pelvis. The task of sitting and rising from a chair requires more control to complete the movement as well as increased execution time. Oscillation movement and ground reaction forces of the center of pressure of the body increase during standing posture, which results in a greater distance between the feet as a strategy to control the balance. Finally, gait biomechanics adapt to a slower speed, smaller step length, and less time with feet off the ground, but a wider step and support base. During pregnancy, women develop anatomic and mechanic adaptations in response to the progressive changes they experience.

Resumo Quesada Salazar, N. (2021). Alterações musculoesqueléticas e adaptações biomecânicas durante os trimestres de gravidez: uma revisão sistemática. PENSAR EN MOVIMIENTO: Revista de Ciencias del Ejercicio y la Salud, 19(1), 1-27. A gravidez é um processo progressivo que envolve mudanças de tipo hormonal, mecânico, fisiológico e emocional na mulher e que faz com que o sistema musculoesquelético se adapte constantemente. Essas mudanças tendem a ser identificadas por meio da postura e a biomecânica dos movimentos na vida diária. Nesta pesquisa foi realizada uma revisão sistemática para encontrar as principais alterações e adaptações durante a gravidez, incluindo artigos de 2008 a 2018, com mulheres gestantes saudáveis, com um único feto, sem alterações musculoesqueléticas prévias, com Índice de Massa Corporal (IMC) normal e qualquer metodologia de pesquisa, exceto estudos de caso. Foram identificados 13 estudos que registram avaliar as três etapas de gestação, com idades desde os 20 aos 35 anos, igualmente com diversos objetivos de pesquisa. A postura da mulher gestante apresenta um aumento de lordose lombar, curvatura toráxica e ângulo de inclinação anterior da pelve. A tarefa de sentar-se e levantar-se de uma cadeira exige maior controle do movimento, assim como de tempo de execução. A oscilação e as forças de reação do solo do Centro de Pressão corporal aumentam ao estar de pé, resultando em uma maior distância entre os pés, como estratégia de controle do equilíbrio. Finalmente, a biomecânica da marcha se adapta a uma menor velocidade, longitude de passo e fase de retirada dos pés do chão, com um aumento da largura do passo e uma maior base de apoio. Na gestação, a mulher desenvolve adaptações de tipo anatômicas e mecânicas como resposta para mudanças progressivas experimentadas.

Early pregnancy loss in 15-hydroxyprostaglandin dehydrogenase knockout (15-HPGD-/-) mice due to requirement for embryo 15-HPGD activity.

Prostaglandins (PGs) have critical signaling functions in a variety of processes including the establishment and maintenance of pregnancy, and the initiation of labor. Most PGs are non-enzymatically degraded, however, the two PGs most prominently implicated in the termination of pregnancy, including the initiation of labor, prostaglandin E2 (PGE2) and prostaglandin F2α (PGF2α), are enzymatically degraded by 15-hydroxyprostaglandin dehydrogenase (15-HPGD). The role of PG metabolism by 15-HPGD in the maintenance of pregnancy remains largely unknown, as direct functional studies are lacking. To test the hypothesis that 15-PGDH-mediated PG metabolism is essential for pregnancy maintenance and normal labor timing, we generated and analyzed pregnancy in 15-HPGD knockout mice (Hpgd-/-). We report here that pregnancies resulting from matings between 15-HPGD KO mice (Hpgd-/- X Hpgd-/-KO mating) are terminated at mid gestation due to a requirement for embryo derived 15-HPGD. Aside from altered implantation site spacing, pregnancies from KO matings look grossly and histologically normal at days post coitum (dpc) 6.5 and 7.5 of pregnancy. However, virtually all of these pregnancies are resorbed by dpc 8.5. This resorption is preceded by elevation of PGF2∝ but is not preceded by a decrease in circulating progesterone, suggesting that pregnancy loss is a local inflammatory phenomenon rather than a centrally mediated phenomena. This pregnancy loss can be temporarily deferred by indomethacin treatment, but treated pregnancies are not maintained to term and indomethacin treatment increases maternal mortality. We conclude that PG metabolism to inactive products by embryo derived 15-HPGD is essential for pregnancy maintenance in mice, and may serve a similar function during human pregnancy.

[The relationship between inflammatory and immunological processes during pregnancy. Practical aspects]. / A gyulladásos és immunológiai folyamatok kapcsolata a várandósság alatt. Gyakorlati vonatkozások.

The aim of this review is to explore, in addition to revealing the biological background, new conceptual and therapeutic approaches for reproductive clinicians to provide better and more effective care for sterile and infertile couples. In humans, 75% of unsuccessful pregnancies are the result of failures of implantation, and implantation failure is the limiting factor for in vitro fertilization treatment. A modified "good" inflammation is necessary for implantation and parturition, but for most of pregnancy, inflammation threatens the continuation of pregnancy. During this period, maintaining the non-inflammatory condition is extremely important, enabling the maternal epigenetic effects to occur in the fetus, making it possible for the offspring to adapt as much as possible to the extrauterine life. In the maintenance of the non-inflammatory condition of pregnancy, a large amount of progesterone hormone produced by the placenta (after the luteo-placental shift) plays a crucial role. It has been reported that the role of inflammation during implantation is an ancestral response to the embryo as a foreign body. During normal pregnancy, this inflammation is initiated by the trophoblast and involves the suppression of neutrophil infiltration, the recruitment of natural killer cells to the site of implantation as well as the production of a range of proinflammatory cytokines. During the "implantation window", the uterus is primed to produce several inflammatory signals such as prostaglandin E2 and a range of proinflammatory cytokines, including TNF, IL6 and IFNγ. The feto-placental unit is a semi-foreign graft called a "semi allograft", and the recognition of pregnancy by the mother (host) and the resulting maternal immune tolerance is an essential part of successful pregnancy and the birth of a healthy fetus. Because of the functional or absolute reduction of circulating progesterone (due to the decreasing hormone production of the physiologically "aging" placenta after around the 36th week of pregnancy) progesterone effects become insufficient. Therefore it is unable to suppress the production of IL8 and other inflammatory cytokines and the term inflammation, leading to cervical ripening, uterus contractions and parturition ("good" inflammation). Orv Hetil. 2019; 160(32): 1247-1259.

New perspective on conceptus estrogens in maternal recognition and pregnancy establishment in the pig†.

The proposed signal for maternal recognition of pregnancy in pigs is estrogen (E2), produced by the elongating conceptuses between days 11 to 12 of pregnancy with a more sustained increase during conceptus attachment and placental development on days 15 to 30. To understand the role of E2 in porcine conceptus elongation and pregnancy establishment, a loss-of-function study was conducted by editing aromatase (CYP19A1) using CRISPR/Cas9 technology. Wild-type (CYP19A1+/+) and (CYP19A1-/-) fibroblast cells were used to create embryos through somatic cell nuclear transfer, which were transferred into recipient gilts. Elongated and attaching conceptuses were recovered from gilts containing CYP19A1+/+ or CYP19A1-/- embryos on day 14 and 17 of pregnancy. Total E2 in the uterine flushings of gilts with CYP19A1-/- embryos was lower than recipients containing CYP19A1+/+ embryos with no difference in testosterone, PGF2α, or PGE2 on either day 14 or 17. Despite the loss of conceptus E2 production, CYP19A1-/- conceptuses were capable of maintaining the corpora lutea. However, gilts gestating CYP19A1-/- embryos aborted between days 27 and 31 of gestation. Attempts to rescue the pregnancy of CYP19A1-/- gestating gilts with exogenous E2 failed to maintain pregnancy. However, CYP19A1-/- embryos could be rescued when co-transferred with embryos derived by in vitro fertilization. Endometrial transcriptome analysis revealed that ablation of conceptus E2 resulted in disruption of a number biological pathways. Results demonstrate that intrinsic E2 conceptus production is not essential for pre-implantation development, conceptus elongation, and early CL maintenance, but is essential for maintenance of pregnancy beyond 30 days .

Bone-marrow-derived endothelial progenitor cells contribute to vasculogenesis of pregnant mouse uterus†.

Angiogenesis is essential for cyclic endometrial growth, implantation, and pregnancy maintenance. Vasculogenesis, the formation of new blood vessels by bone marrow (BM)-derived endothelial progenitor cells (EPCs), has been shown to contribute to endometrial vasculature. However, it is unknown whether vasculogenesis occurs in neovascularization of the decidua during pregnancy. To investigate the contribution of BM-derived EPCs to vascularization of the pregnant uterus, we induced non-gonadotoxic submyeloablation by 5-fluorouracil administration to wild-type FVB/N female mice recipients followed by BM transplantation from transgenic mice expressing green fluorescent protein (GFP) under regulation of Tie2 endothelial-specific promoter. Following 1 month, Tie2-GFP BM-transplanted mice were bred and sacrificed at various gestational days (ED6.5, ED10.5, ED13.5, ED18.5, and postpartum). Bone-marrow-transplanted non-pregnant and saline-injected pregnant mice served as controls (n = 5-6/group). Implantation sites were analyzed by flow cytometry, immunohistochemistry, and immunofluorescence. While no GFP-positive EPCs were found in non-pregnant or early pregnant uteri of BM-transplanted mice, GFP-positive EPCs were first detected in pregnant uterus on ED10.5 (0.12%) and increased as the pregnancy progressed (1.14% on ED13.5), peaking on ED18.5 (1.42%) followed by decrease in the postpartum (0.9%). The percentage of endothelial cells that were BM-derived out of the total endothelial cell population in the implantation sites (GFP+CD31+/CD31+) were 9.3%, 15.8%, and 6.1% on ED13.5, ED18.5, and postpartum, respectively. Immunohistochemistry demonstrated that EPCs incorporated into decidual vasculature, and immunofluorescence showed that GFP-positive EPCs colocalized with CD31 in vascular endothelium of uterine implantation sites, confirming their endothelial lineage. Our findings indicate that BM-derived EPCs contribute to vasculogenesis of the pregnant mouse decidua.

Mechanisms for the establishment and maintenance of pregnancy: synergies from scientific collaborations.

Research on the functions of interferon tau (IFNT) led to the theory of pregnancy recognition signaling in ruminant species. But IFNT does much more as it induces expression of interferon regulatory factor 2 (IRF2) in uterine luminal (LE), superficial glandular (sGE), but not glandular (GE) epithelia. First, IRF2 silences transcription of the estrogen receptor alpha gene and, indirectly, transcription of the oxytocin receptor gene to abrogate development of the luteolytic mechanism to prevent regression of the corpus luteum and its production of progesterone for establishing and maintaining pregnancy. Second, IRF2 silences expression of classical interferon-stimulated genes in uterine LE and sGE; however, uterine LE and sGE respond to progesterone (P4) and IFNT to increase expression of genes for transport of nutrients into the uterine lumen such as amino acids and glucose. Other genes expressed by uterine LE and sGE encode for adhesion molecules such as galectin 15, cathepsins, and cystatins for tissue remodeling, and hypoxia-inducible factor relevant to angiogenesis and survival of blastocysts in a hypoxic environment. IFNT is also key to a servomechanism that allows uterine epithelia, particularly GE, to proliferate and to express genes in response to placental lactogen and placental growth hormone in sheep. The roles of secreted phosphoprotein 1 are also discussed regarding its role in implantation in sheep and pigs, as well as its stimulation of expression of mechanistic target of rapamycin mRNA and protein which is central to proliferation, migration, and gene expression in the trophectoderm cells.