The regulatory network played by miRNAs during normal pregnancy and preeclampsia: a comparative study

Background: Preeclampsia is a pregnancy-specific syndrome, characterized by hypertension, proteinuria, and edema. Affecting between 2% and 8% of gestations worldwide, it accounts for 10% to 15% of maternal deaths. Although its etiology remains unclear, it includes complex pathological processes involving microRNAs, small non-coding RNA molecules with post-transcriptional repression effects on target mRNAs. Objective: To assess the expression of miRNAs during normal pregnancies and those complicated by preeclampsia, a sample of Venezuelan women were studied. Method: Nine placental microRNAs (hsa-miR- 20a-5p, 21-3p, 26a-5p, 181a-5p, 199a-5p, 210-3p, 222-5p, 223-3p, 424-3p) were measured in maternal plasma during the second and third trimesters of normal pregnancies, using a SYBR Green®-based real-time PCR, and compared the results against women affected by preeclampsia. Results: All assessed miRNAs were detected in maternal plasma in pregnancies with and without preeclampsia. All except miR-222 were over-expressed during disease when compared to the second and to third-trimester controls. miR-20a, miR-21, miR-26a, and miR-223 were down-regulated in the third trimester in comparison to the second trimester in normal pregnancies. Conclusion: The variation of the miRNAs expression through normal pregnancies suggested their involvement in normal physiological pregnancy processes. In contrast, the significant deregulation of the nine studied miRNAs during preeclampsia indicated the involvement of their target genes in the pathogenesis of the disease. miR-199a and miR-21-3p showed the greatest changes in expression. This study shows for the first time the presence of miR-20a, miR-199, and miR-424 and the variations they undergo in the plasma of pregnant women with preeclampsia.

Predictive Performance of Placental Protein 13 for Screening Preeclampsia in the First Trimester: A Systematic Review and Meta-Analysis

Preeclampsia is a pregnancy-specific syndrome that affects maternal and neonatal mortality. Several serum biomarkers can be used to predict preeclampsia. Among these proteins, placental protein 13 (PP13) has received progressively more interest in recent studies. The decrease in PP13 expression is one of the earliest signs for the development of preeclampsia and has shown its predictive performance for preeclampsia. In this meta-analysis, we collected 17 observational studies with 40,474 pregnant women. The overall sensitivity of PP13 to predict preeclampsia was 0.62 [95% confidence interval (CI) = 0.49–0.74], the specificity was 0.84 (95%CI = 0.81–0.86), and the diagnostic odds ratio was nine (95%CI = 5–15). The area under the curve for summary receiver operating characteristic was 0.84. We then chose the early-onset preeclampsia as a subgroup. The sensitivity of early-onset subgroup was 0.63 (95%CI = 0.58–0.76), the specificity was 0.85 (95%CI = 0.82–0.88), and the diagnostic odds ratio was 10 (95%CI = 6–18). The findings of our meta-analysis indicate that PP13 may be an effective serum biomarker for the predictive screening of preeclampsia. Nonetheless, large prospective cohort studies and randomized controlled trials are expected to uncover its application in clinical practice. The heterogeneity of the original trials may limit the clinical application of PP13.Systematic Review Registration:https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=188948 The meta-analysis was registered in PROSPERO (CRD42020188948).

Ocular manifestations in a case of progeroid syndrome

Progeria syndromes are very rare genetic diseases characterized by premature aging changes. There are several phenotypes and variables noted in literature in some cases difficult to specifically classify a specific syndrome. It occurs due to mutation in DNA repair genes. The most common ocular findings are loss of eyebrow and eyelashes, brow ptosis, lid margin changes, entropion, Meibomian gland dysfunction, severe dry eye, corneal opacity, cataract, poor mydriasis, and rod-cone dystrophy. We report this case with all the above ocular manifestations in 19year old teenager with additional finding being retinal detachment.

Abstract P236: Organofluorine Hydrazones Preventing Oxidant Stress In An In Vitro Model Of Preeclampsia

Background: Preeclampsia (PE) is a pregnancy-specific syndrome affecting 5-7% of all pregnant women, and there is no effective treatment available. Early abnormal placental development is associated with oxidative stress and the release of reactive oxygen species in the placenta. This phenomenon leads to downstream signaling and production of anti-angiogenic factors, which cause endothelial and trophoblast dysfunction and the cardinal features of PE, i.e., hypertension, proteinuria, and in severe cases, eclampsia. Our group developed a novel series of mitochondria-targeted antioxidants and sought to test if these compounds can effectively reduce placental oxidative stress and mitigate PE symptoms in vitro. Methods: We induced in vitro oxidant stress in human trophoblast (HTR8/SVneo) cells with hydrogen peroxide (H 2 O 2 ) and assessed whether augmenting cell-redox function with the proposed antioxidant compounds reduced (i) cell injury (cell cytotoxicity assay), (ii) mitochondrial stress (mitochondrial -derived superoxide production, mitochondria dysfunction) (iii) production of the transcription factor HIF1A and (iv) downstream anti-angiogenic responses (sFLT1 production). These effects were compared with the antioxidants - NAC, Vit E and MitoQ. Results: In our cell-based assays, pretreatment with the hydrazone compounds reduced mitochondrial-derived ROS production in H 2 O 2 -exposed trophoblasts cells, indicating that the key factor in the development of PE, the oxidant stress, can be alleviated by the antioxidant hydrazones. The most effective of these compounds, HY12 also reduced HIF-1A expression and sFLT1 protein expression H 2 O 2 -exposed HTR8 cells. Furthermore, the antioxidant hydrazones improved the mitochondrial electron chain enzyme activity in the stressed HTR8 cells, which is another promising characteristic of the applied hydrazones. Conclusion: In reducing placental trophoblast oxidative stress, hydrazone-based antioxidants present a potential novel therapeutic approach for the treatment of preeclampsia. Future investigation is warranted regarding the in vivo use of these compounds.

Disability pension among gynaecological cancer survivors with or without radiation-induced survivorship syndromes

Purpose Gynaecological cancer patients treated with external radiation therapy to the pelvis may face long-lasting and long-term gastrointestinal syndromes. The aim of this study was to assess the association between such radiation-induced survivorship syndromes and disability pension among gynaecological cancer survivors treated with pelvic radiation therapy. Methods This prospective register study included gynaecological cancer survivors (n=247) treated during 1991–2003, alive at the time of the study, and <65 years of age. In 2006, they completed a postal questionnaire measuring patient-reported outcomes. The self-reported data were linked to the national register on disability pensions. Relative risks and risk differences with 95% confidence intervals (CIs) of being granted a disability pension were estimated using log-binomial regression. Results Gynaecological cancer survivors with gastrointestinal syndromes had a higher risk of disability pension than survivors without such syndromes. Survivors with blood discharge syndrome had a 2.0 (95% CI 1.3–3.2) times higher risk of disability pension than survivors without blood discharge syndrome. The relative risk among survivors with urgency syndrome was 1.9 (1.3–2.9) and for leakage syndrome, 2.1 (1.4–3.1). Adjusting for age did not affect our interpretation of the results. Conclusions Gynaecological cancer survivors with a specific radiation-induced survivorship syndrome have a higher risk of disability pension than survivors without that specific syndrome. Implications for Cancer Survivors The findings highlight the need for more awareness and knowledge regarding the potential role of radiation-induced survivorship syndromes for continuing work among gynaecological cancer survivors. Work-life-related parameters should be considered during radiotherapy and rehabilitation after treatment.

Intoxications by lead and its inorganic compounds

Lead belongs to the group of blood poisons that impair the synthesis of porphyrins and heme. Under industrial conditions, only chronic lead poisoning can develop. Lead belongs to the poisons that have the effect of material cumulation. The half-life of lead is 20 years. Once in the body, it is deposited in many organs in the form of the insoluble tribasic lead phosphates. A significant part of the lead is deposited in the trabeculae of the bones. Under the influence of provoking factors, an intensive lead release from the depot can be observed. In such cases, the amount of lead in the circulating blood increases sharply, and remission is replaced by an exacerbation. There is a wavy course of chronic lead intoxication. Lead and its inorganic compounds belong to the group of poisons that have a polytropic effect on the body, affecting many organs and systems. The blood system (anemia with specific characteristics) and the nervous system (polyneuropathy and encephalopathy) are primarily affected. A number of other organs and systems are also affected. The most severe specific syndrome of gastrointestinal tract damage is lead colic. Due to the impaired synthesis of porphyrins and heme in certain biological substrates of the body — in the blood, erythrocytes and urine, substances unused in the synthesis of heme are accumulated. They are markers of chronic intoxication caused by lead, in the presence of a relevant clinical picture. The diagnosis is based on data from a professional history, sanitary and hygienic characteristics of working conditions, clinical and objective characteristics of the disease and data from laboratory examination. The main thing is to stop contact with lead and remove it from the body. Antidotes for lead poisoning are chelators: tetacinum-calcium, pentacinum, D-penicillamine. In combination with technical and sanitary-hygienic measures to prevent chronic intoxication caused by lead, preliminary and periodic medical examinations of persons in contact with lead are of great importance.

Investigation of a Paternal-Mediated Preeclampsia-Like Pregnancy Phenotype Mouse Model

Preeclampsia, a pregnancy specific syndrome characterized by new onset hypertension and proteinuria, is a leading cause of maternal and neonatal morbidity and mortality. While no animal model perfectly mimics the human syndrome, breeding C1q-/- (male) to C57 (female) mice results in a preeclampsia-like pregnancy including pregnancy-specific hypertension, vascular dysfunction and altering placental phenotype. As the placental genotype is primarily paternally driven, lack of paternal C1q is likely driving this preeclampsia-like phenotype. However, more work is needed to investigate whether a lack of maternal C1q also contributes to this preeclampsia-like phenotype. The aim of this study was to investigate the pregnancy phenotype of genetic control (C1q-/- female bred to C57 male) mice. Blood pressure was monitored during pregnancy and vascular function assessed during late pregnancy (gestation day 17.5) in genetic control females. These data were compared to similar data obtained from control (C57 male bred to C57 female) and preeclampsia-like (C1q-/- male bred to C57 female) pregnant mice. Genetic control blood pressure and vascular function data were similar to that of the control pregnancy group, indicating no significant effect of maternal C1q deficiency on the “preeclampsia-like” pregnancy phenotype. As understanding preeclampsia and its effect on women’s health is critical, the work presented is important to confirm the C1q-/- x C57 mouse model as a useful model for studying this syndrome further.

Determining the effect of Magnesium Sulfate on Doppler Parameters of Fetal Umbilical and Middle Cerebral Arteries in Women with Severe Preeclampsia: A Prospective Study

Background: Preeclampsia is best described as a pregnancy-specific syndrome that can affect every organ system. Although preeclampsia is much more than simply gestational hypertension with proteinuria, appearance of proteinuria remains an important objective diagnostic criterion. The aim of this study is to evaluate Doppler velocimetric parameters (resistance index [RI], pulsatility index [PI], and systolic/diastolic [S/D] ratio) of the umbilical and middle cerebral arteries before and after magnesium sulfate administration in pregnant women with severe preeclampsia. Methods: This prospective study had been included 25 women from the emergency department and Obstetrics outpatient clinic Tanta University. Resistance index [RI], pulsatility index [PI] and systolic/ diastolic [S/D] ratio of middle cerebral artery and umbilical artery before and 20 minutes after intravenous administration of 6 grams of magnesium sulfate (loading dose). Results: The maternal age of cases included in the study ranged between 18 year and 40 year with a mean age of 32.03±6.1. The gravidity of cases included in the study ranged between 1 and 5 with a mean of 2.01±1.03.The parity of cases included in the study ranged between 0 and 6 with a mean of 2.18±1.04.The number of abortions ranged between 0 and 3whith a mean of 0.61±0.03. The serum level of ALT ranged between 11 and 104 mEq/L with a mean of 49.12±27.81. The serum level of AST ranged between 13 and 84 mEq/L with a mean of 42.5±20.17. The resistance index (RI) before MgSo4 administration ranged between 0.45 and 1.0 with a mean of 0.65 ± 0.15while it ranged between 0.4 and 0.9 after MgSo4 administration with a mean of 0.63± 0.13 .There was statistical significant differences between them (p<0.001). The pulsatility index (PI) before MgSo4 administration ranged between 0.6 and 2.15 with a mean of 1.15±0.45 while it ranged between 0.5 and 0.2 after MgSo4 administration with a mean of 1.04± 0.45 .There was statistical significant differences between them (p<0.001) . Conclusions: Infusion of MgSO4 significantly decreases the fetal RI-umbilical and PI-MCA and increases C/U ratio indices obtained with color Doppler ultrasound evaluations.

L-Citrulline supplementation during pregnancy improves perinatal and postpartum maternal vascular function in a mouse model of preeclampsia

Preeclampsia is a spontaneously occurring pregnancy complication diagnosed by new onset hypertension and end-organ dysfunction with or without proteinuria. This pregnancy-specific syndrome contributes to maternal morbidity and mortality and can have detrimental effects on fetal outcome. Preeclampsia is also linked to increased risk of maternal cardiovascular disease throughout life. Despite intense investigation of this disorder, few treatment options are available. The aim of this study was to investigate the potential therapeutic effects of maternal L-citrulline supplementation on pregnancy-specific vascular dysfunction in the ♀ C57BL/6J x ♂ C57BL/6J C1q-/- preeclampsia-like mouse model. L-citrulline is a non-essential amino acid that is converted to L-arginine to promote smooth muscle and blood vessel relaxation and improve nitric oxide (NO) mediated vascular function. To model a preeclampsia-like pregnancy, female C57BL/6J mice were mated to C1q-/- male mice, and a subset of dams were supplemented with L-citrulline throughout pregnancy. Blood pressure, systemic vascular glycocalyx, and ex-vivo vascular function were investigated in late pregnancy, and postpartum at 6 and 10 months of age. Main findings show that L-citrulline reduced blood pressure, increased vascular glycocalyx volume and rescued ex-vivo vascular function at gestation day 17.5 in this preeclampsia-like model. The vascular benefit of L-citrulline also extended postpartum, with improved vascular function and glycocalyx measures at 6 and 10 months of age. L-citrulline mediated vascular improvements appear, in part, attributable to NO pathway signaling. Taken together, L-citrulline supplementation during pregnancy appears to have beneficial effects on maternal vascular health which may have translational implications for improved maternal cardiovascular health.

Elevated Levels of Soluble Axl (sAxl) Regulates Key Angiogenic Molecules to Induce Placental Endothelial Dysfunction and a Preeclampsia-Like Phenotype

Preeclampsia (PE), a severe pregnancy-specific syndrome, is characterized by impaired placental angiogenesis. Although the pathogenesis of this condition remains largely unclear, vascular systemic endothelial injury is thought to be the common contributing factor. Soluble Axl (sAxl), a biomarker of endothelial dysfunction, is known to be abnormally increased in a variety of diseases associated with vascular injury. In a previous study, we found that the plasma levels of sAxl were significantly higher in PE with severe features (sPE) than in pregnant women who did not have PE. The current study aimed to further explore the potential role of sAxl in vascular injury in patients with sPE. We found that the upregulation of sAxl in maternal plasma was positively correlated with the plasma levels of sFlt-1 and negatively correlated with placental NO synthase (eNOS) in women with sPE. Furthermore, elevated levels of sAxl suppressed proliferation and endothelial tube formation and promoted cytotoxicity in human umbilical vein endothelial cells (HUVECs) through the downregulation of p-Akt, p-p70S6K, p-mTOR, and Grb2. Subsequently, we established a pregnant rat model with PE-like characteristics by injecting pregnant rats with an adenovirus expressing sAxl. These rats exhibited a typical PE-like phenotype, including increased blood pressure, proteinuria, and fetal growth restriction, along with abnormal placental and fetal renal morphology. In conclusion, our study demonstrated the role of sAxl in systemic vascular injury through the regulation of the expression of key molecules of angiogenesis and described its potential contribution to the development of sPE.