The effect of mode of delivery in twin pregnancies on the latency period between diagnosis of preterm labor and birth.

INTRODUCTION: The optimal mode of delivery in twin pregnancies presenting with preterm labor is controversial. Current literature regarding these cases is based on observational studies, innately prone to bias. A possibly substantial, yet hitherto unexplored, source of bias is an effect of mode of delivery on the timing of delivery. The aim of our study is to examine whether the mode of delivery affects the latency period between preterm labor (PTL) presentation and actual delivery and to assess the possible effect of latency on neonatal outcome. MATERIAL AND METHODS: A retrospective cohort study at a single tertiary center from the year 2011 to 2018. All twin pregnancies (dichorionic or monochorionic-diamniotic) between 24 and 36 weeks of gestation admitted due to PTL were included in the study. RESULTS: A total of 469 twin deliveries met the study criteria, of them, 204 delivered by cesarean section and 265 delivered vaginally. Cesarean delivery significantly decreased the chances of reaching a latency period of 1 or more days (OR = 0.53, 95% CI = 0.33-0.84), 2 or more days (OR = 0.47, 95% CI = 0.27-0.82) and 3 or more days (OR = 0.28, 95% CI = 0.09-0.9). In a regression model adjusting for gestational age at delivery, mode of delivery was not associated with neonatal morbidity or mortality. However, in a regression model adjusting for gestational age at PTL presentation, thereby accounting for differences in the latency period, cesarean delivery was found to significantly increase the risk of respiratory distress syndrome (OR = 1.62, 95% CI = 1.04-2.54). CONCLUSIONS: In PTL of twin pregnancies, the latency period is significantly longer in vaginal deliveries compared to cesarean deliveries. The possibility of longer latency period in vaginal deliveries should be considered when counseling patients on the mode of delivery in preterm twin pregnancies.

Fetal brain biometry in isolated mega cisterna magna: MRI and US study.

OBJECTIVE: To characterize the biometric parameters in ultrasound and brain MRI of fetuses with isolated mega cisterna magna (MCM). METHODS: Cross-sectional historical cohort study conducted at a single tertiary medical center between 2011 and 2018. All fetuses underwent US and brain MRI scans. Matching analysis was performed according to gender and gestational age. RESULTS: The study included a total of 103 fetuses; 44 fetuses with isolated MCM in the study group, and a control group of 59 fetuses with normal CNS. The study group had larger biparietal diameter (BPD) (86 vs. 79.8 mm, p = .001) and head circumference (HC) (318 vs. 292 mm, p < .001) on ultrasound. On MRI, study group had larger occipitofrontal diameter (OFD) (99 vs. 92 mm, p < .001) and BPD (77 vs. 72 mm, p < .001). Male fetuses' prevalence was higher in the study group (77.3% vs. 47.5%). After matching 20 fetuses from each group, the study group had larger HC (310.1 versus 300.7 mm, p = .029) and OFD (113.4 versus 108.3 mm, p = .009) on ultrasound, and larger OFD (97.4 versus 94.6, p = .013) on brain MRI. CONCLUSIONS: Isolated MCM may be related to other large fetal CNS biometric measurements in both ultrasound and MRI and might be influenced by fetal gender.

The normal fetal Cavum Septum Pellucidum in MR imaging - New biometric data.

BACKGROUND AND PURPOSE: The cavum septum pellucidum (CSP) is an important landmark in the evaluation of the fetal neural axis. A deviation from the ultrasonic normal values may be associated with unfavorable outcomes, and a normal CSP provides reassurance of normal central forebrain development. Today, there is biometric data regarding the normal values for the width of the CSP in fetal ultrasound, but there is no such data for fetal MRI. The aim of this study was to determine the normal values for the measurements of the fetal CSP on MRI. MATERIALS AND METHODS: We retrospectively examined 307 MRI scans of fetuses between 25 and 41 weeks gestation. Data was collected from the electronic charts of patients who underwent fetal MR imaging at a single tertiary Medical Center. The width and length of the CSP were measured in the axial plane, and the width and height were measured in the coronal plane. RESULTS: The width and height of the CSP in fetuses tend to decrease starting from the 27th week of gestation onwards. High levels of intraobserver and interobserver agreements were calculated. The sex of the fetus does not appear to influence the biometry of the CSP. CONCLUSION: This study provides MRI reference values for the dimensions of the CSP starting from the 25th week of gestation. Knowing the normal values for MRI could provide valuable information for researchers and in the decision-making process in patient's consultations.

Secure Instant Messaging Application in Prenatal Care.

The use of mobile phone for medical purposes is rapidly expanding as the number of medical applications rise. Studies show improvement of patient management and communication between medical team members using instant messaging applications. There are currently several smartphone applications routinely used by doctors and nurses. WhatsApp is by far the most common, however, it has several limitations when it comes to medical confidentiality. The aim of this paper is to introduce "Siilo" as an alternative secure messaging application and its advantages in the medical field, specifically in obstetrics. The typical course of consultation for an abnormal fetal finding is very long, cumbersome, frustrating and depends a lot on the patient, whereas, via Siilo the process is fast, efficient, depends more on the medical caregivers and helps ensuring minimum lost to follow-up. This paper demonstrates for the first time the utility of the use of Siilo application in medical management.

Do poor-responder patients undergoing IVF benefit from splitting and increasing the daily gonadotropin dose?

We aim to retrospectively evaluate the role of increasing the gonadotropin daily dose from 450 IU/day to 300 IU twice a day on IVF-ET outcome in poor responder patients. All consecutive women admitted to our IVF unit and underwent COH consisting of daily gonadotropin dose of 450 IU, followed by an IVF cycle using 300 IU twice a day, were included. Ovarian stimulation characteristics, number of oocytes retrieved, number of embryo transferred and pregnancy rate was assessed. Twenty-three patients undergoing both cycles were evaluated. While there was no between-group difference in the duration of COH, number of 2PN embryos, fertilization rate and number of embryos transferred, patients receiving daily gonadotropin 300 IU twice a day achieved a significantly higher peak estradiol levels (3350.39 ± 2364.26 vs. 2223.74 ± 1299.91; p < .03, respectively), and yielded significantly higher number of follicles >15 mm in diameter on day of hCG administration (3.2 ± 2.4 vs 1.8 ± 1; p < .03, respectively) and higher number of oocytes retrieved (3.48 ± 2.54 vs 1.87 ± 1.1; p < .02, respectively) with an acceptable live birth rate (5%). To conclude, in poor responders undergoing COH a daily gonadotropin dose of 450 IU, increasing the dose to 300 IU twice daily may result in higher oocyte yield, with the possible improvement in IVF outcome.

Can sonographic measurements and changes in cervical length during pregnancy predict preterm labour in an asymptomatic low-risk population?

OBJECTIVE: This study measured cervical length (CL) at 14-16 and 21-24 weeks of gestation and assessed whether the difference between the measurements is predictive of preterm delivery (PTD). METHODS: This retrospective, cohort study included patients with two consecutive CL measured with transvaginal sonography at 14-16 weeks of gestation (CL1) and 21-24 weeks (CL2). Electronic medical records were reviewed for demographic, medical and obstetric history; complications during the current pregnancy and delivery data. CL1, CL2 and the change between scans were evaluated and correlated to PTD prediction. RESULTS: Among the 216 patients, 196 (90.7%) delivered at term (≥37 weeks) and 20 (9.3%) preterm (<37 weeks). CL1 was not a good predictor of PTD (p = .70). CL2 was significantly shorter in the PTD group (p < .05). The correlation between CL change and PTD was not significant (p = .55). Perinatal outcomes between term and preterm deliveries were similar. CONCLUSIONS: Sonographic measurement of CL at 14- to 16-week gestation and the difference between CL in the first and second scans are not reliable predictors of PTD. However, cervical length at 21-24 weeks in low-risk women is predictive of this complication.

Chemotherapeutic agents induce the expression and activity of their clearing enzyme CYP3A4 by activating p53.

Cytochrome P450 (P450) enzymes are abundantly expressed in the human liver where they hydroxylate organic substrates. In a microarray screen performed in human liver cells, we found a group of eleven P450 genes whose expression was induced by p53 (CYP3A4, CYP3A43, CYP3A5, CYP3A7, CYP4F2, CYP4F3, CYP4F11, CYP4F12, CYP19A1, CYP21A2 and CYP24A1). The mode of regulation of four representative genes (CYP3A4, CYP3A7, CYP4F2 and CYP4F3) was further characterized. The genes were induced in a p53-dependent manner in HepG2 and Huh6 cells (both are cancer-derived human liver cells) and in primary liver cells isolated from human donors. Furthermore, p53 was found to bind to p53-responsive elements in the genes' DNA-regulatory regions and to enhance their transcription in a reporter gene assay. Importantly, when p53 was activated following the administration of either of three different anticancer chemotherapeutic agents (cisplatin, etoposide or doxorubicin), it was able to induce CYP3A genes, which are the main factors in systemic clearance of these agents. Finally, the p53-dependent induction of P450 genes following either Nutlin or chemotherapy treatment led to enhanced P450 enzymatic activity. Thus, in addition to the well-established role of p53 at the tumor site, our data unravels a novel function of hepatic p53 in inducing P450 enzymes and position p53 as a major factor in the hepatic response to xenobiotic and metabolic signals. Importantly, this study reveals a novel pathway for the induction of CYP3As by their substrates through p53, warranting the need for careful consideration when designing systemically administered chemotherapeutic regimens.

p53, a novel regulator of lipid metabolism pathways.

BACKGROUND & AIMS: In this study we aimed at characterizing the regulation of hepatic metabolic pathways by the p53 transcription factor. METHODS: Analysis of gene expression following alteration of p53 status in several human- and mouse-derived cells using microarray analysis, quantitative real-time PCR, chromatin immunoprecipitation, and reporter gene assays. A functional assay was performed to determine lipid transfer activity. RESULTS: We identified a novel role for the p53 protein in regulating lipid and lipoprotein metabolism, a process not yet conceived as related to p53, which is known mainly for its tumor suppressive functions. We revealed a group of 341 genes whose expression was induced by p53 in the liver-derived cell line HepG2. Twenty of these genes encode proteins involved in many aspects of lipid homeostasis. The mode of regulation of three representative genes (Pltp, Abca12, and Cel) was further characterized. In addition to HepG2, the genes were induced following activation of p53 in human primary hepatic cells isolated from liver donors. p53-dependent regulation of these genes was evident in other cell types namely Hep3B cells, mouse hepatocytes, and fibroblasts. Furthermore, p53 was found to bind to the genes' promoters in designated p53 responsive elements and thereby increase transcription. Importantly, p53 augmented the activity of secreted PLTP, which plays a major role in lipoprotein biology and atherosclerosis pathology. CONCLUSIONS: These findings expose another facet of p53 functions unrelated to tumor suppression and render it a novel regulator of hepatic lipid metabolism and consequently of systemic lipid homeostasis and atherosclerosis development.

Mutant p53 facilitates somatic cell reprogramming and augments the malignant potential of reprogrammed cells.

p53 deficiency enhances the efficiency of somatic cell reprogramming to a pluripotent state. As p53 is usually mutated in human tumors and many mutated forms of p53 gain novel activities, we studied the influence of mutant p53 (mut-p53) on somatic cell reprogramming. Our data indicate a novel gain of function (GOF) property for mut-p53, which markedly enhanced the efficiency of the reprogramming process compared with p53 deficiency. Importantly, this novel activity of mut-p53 induced alterations in the characteristics of the reprogrammed cells. Although p53 knockout (KO) cells reprogrammed with only Oct4 and Sox2 maintained their pluripotent capacity in vivo, reprogrammed cells expressing mutant p53 lost this capability and gave rise to malignant tumors. This novel GOF of mut-p53 is not attributed to its effect on proliferation, as both p53 KO and mut-p53 cells displayed similar proliferation rates. In addition, we demonstrate an oncogenic activity of Klf4, as its overexpression in either p53 KO or mut-p53 cells induced aggressive tumors. Overall, our data show that reprogrammed cells with the capacity to differentiate into the three germ layers in vitro can form malignant tumors, suggesting that in genetically unstable cells, such as those in which p53 is mutated, reprogramming may result in the generation of cells with malignant tumor-forming potential.

Modulated expression of WFDC1 during carcinogenesis and cellular senescence.

Fibroblasts located adjacent to the tumor [cancer-associated fibroblasts (CAFs)] that constitute a large proportion of the cancer-associated stroma facilitate the transformation process. In this study, we compared the biological behavior of CAFs that were isolated from a prostate tumor to their normal-associated fibroblast (NAF) counterparts. CAFs formed more colonies when seeded at low cell density, exhibited a higher proliferation rate and were less prone to contact inhibition. In contrast to the general notion that high levels of alpha-smooth muscle actin serve as a marker for CAFs, we found that prostate CAFs express it at a lower level compared with prostate NAFs. Microarray analysis revealed a set of 161 genes that were altered in CAFs compared with NAFs. We focused on whey acidic protein four-disulfide core domain 1 (WFDC1), a known secreted protease inhibitor, and found it to be downregulated in the CAFs. WFDC1 expression was also dramatically downregulated in highly prolific mesenchymal cells and in various cancers including fibrosarcomas and in tumors of the lung, bladder and brain. Overexpression of WFDC1 inhibited the growth rate of the fibrosarcoma HT1080 cell line. Furthermore, WFDC1 level was upregulated in senescent fibroblasts. Taken together, our data suggest an important role for WFDC1 in inhibiting proliferation of both tumors and senescent cells. Finally, we suggest that the downregulation of WFDC1 might serve as a biomarker for cellular transformation.