Prenatal Coffin-Siris Syndrome: Expanding the Phenotypic and Genotypic Spectrum of the Disease.

Coffin-Siris syndrome is an autosomal dominant disorder with neurological, cardiovascular, and gastrointestinal symptoms. Patients with Coffin-Siris syndrome typically have variable degree of developmental delay or intellectual disability, muscular hypotonia, dysmorphic facial features, sparse scalp hair, but otherwise hirsutism and fifth digit nail or distal phalanx hypoplasia or aplasia. Coffin-Siris syndrome is caused by pathogenic variants in 12 different genes including SMARCB1 and ARID1A. Pathogenic SMARCB1 gene variants cause Coffin-Siris syndrome 3 whereas pathogenic ARID1A gene variants cause Coffin-Siris syndrome 2. Here, we present two prenatal Coffin-Siris syndrome cases with autosomal dominant pathogenic variants: SMARCB1 gene c.1066_1067del, p.(Leu356AspfsTer4) variant, and a novel ARID1A gene c.1920+3_1920+6del variant. The prenatal phenotype in Coffin-Siris syndrome has been rarely described. This article widens the phenotypic spectrum of prenatal Coffin-Siris syndrome with severely hypoplastic right ventricle with VSD and truncus arteriosus type III, persisting left superior and inferior caval vein, bilateral olfactory nerve aplasia, and hypoplastic thymus. A detailed clinical description of the patients with ultrasound, MRI, and post mortem pictures of the affected fetuses showing the wide phenotypic spectrum of the disease is presented.

Gestational anemia and maternal antenatal and postpartum psychological distress in a prospective FinnBrain Birth Cohort Study.

BACKGROUND: Gestational anemia, most commonly caused by iron deficiency, may increase the risk of maternal anxiety and depression and have a potentially far-reaching impact on mother's and newborn's health. Several mechanisms, such as effects of iron deficiency on cerebral neurotransmitter metabolism, have been suggested. None of the earlier studies have assessed the association between gestational anemia and depression, anxiety and pregnancy-related anxiety simultaneously. METHODS: Women, participating in the FinnBrain Birth Cohort Study and attending maternity welfare clinics in Turku, whose hemoglobin (Hb) values during pregnancy were available were included in this study (n = 1273). The study group consisted of 301 women with Hb levels < 11.0 g/dL at any time during pregnancy, and 972 women with Hb ≥ 11.0 g/dL were included in the control group. Symptoms of depression, anxiety, and pregnancy-related anxiety were assessed using the Edinburgh Postnatal Depression Scale (EPDS), Symptom Checklist-90 (SCL), and Pregnancy-Related Anxiety Questionnaire (PRAQ) questionnaires at 14, 24, and 34 gestational weeks, and EPDS and SCL were also performed 3 and 6 months postpartum. RESULTS: Gestational anemia was not associated with an increased risk of depression either prenatally or postpartum when the analyses were adjusted for maternal age at birth, parity, smoking during pregnancy, maternal education, and gestational age. However, a weak connection was found between gestational anemia and prenatal anxiety in the early pregnancy. Furthermore, the analysis between women with Hb < 10.0 g/dL and those with Hb ≥ 10.0 g/dL showed an association between gestational anemia and anxiety in the late pregnancy, but otherwise no difference in psychological distress was found. CONCLUSIONS: No evidence supporting the association between gestational anemia and antenatal or postpartum depression was found. However, a weak connection between gestational anemia and antenatal anxiety was observed. This finding needs further investigation to establish timing and investigate causality.

Gestational iron deficiency anemia is associated with preterm birth, fetal growth restriction, and postpartum infections.

OBJECTIVES: Gestational IDA has been linked to adverse maternal and neonatal outcomes, but the impact of iron supplementation on outcome measures remains unclear. Our objective was to assess the effects of gestational IDA on pregnancy outcomes and compare outcomes in pregnancies treated with either oral or intravenous iron supplementation. METHODS: We evaluated maternal and neonatal outcomes in 215 pregnancies complicated with gestational IDA (Hb<100 g/L) and delivered in our tertiary unit between January 2016 and October 2018. All pregnancies from the same period served as a reference group (n=11,545). 163 anemic mothers received oral iron supplementation, and 52 mothers received intravenous iron supplementation. RESULTS: Gestational IDA was associated with an increased risk of preterm birth (10.2% vs. 6.1%, p=0.009) and fetal growth restriction (FGR) (1.9% vs. 0.3%, p=0.006). The gestational IDA group that received intravenous iron supplementation had a greater increase in Hb levels compared to those who received oral medication (18.0 g/L vs. 10.0 g/L, p<0.001), but no statistically significant differences in maternal and neonatal outcomes were detected. CONCLUSIONS: Compared to the reference group, prematurity, FGR, postpartum infections, and extended hospital stays were more common among mothers with gestational IDA, causing an additional burden on the families and the healthcare system.

Transcriptomic and Phenotypic Analyses of the Sigma B-Dependent Characteristics and the Synergism between Sigma B and Sigma L in Listeria monocytogenes EGD-e.

Numerous gene expression and stress adaptation responses in L. monocytogenes are regulated through alternative sigma factors σB and σL. Stress response phenotypes and transcriptomes were compared between L. monocytogenes EGD-e and its ΔsigB and ΔsigBL mutants. Targeted growth phenotypic analysis revealed that the ΔsigB and ΔsigBL mutants are impaired during growth under cold and organic-acid stress conditions. Phenotypic microarrays revealed increased sensitivity in both mutants to various antimicrobial compounds. Genes de-regulated in these two mutants were identified by genome-wide transcriptome analysis during exponential growth in BHI. The ΔsigB and ΔsigBL strains repressed 198 and 254 genes, respectively, compared to the parent EGD-e strain at 3 °C, whereas 86 and 139 genes, respectively, were repressed in these mutants during growth at 37 °C. Genes repressed in these mutants are involved in various cellular functions including transcription regulation, energy metabolism and nutrient transport functions, and viral-associated processes. Exposure to cold stress induced a significant increase in σB and σL co-dependent genes of L. monocytogenes EGD-e since most (62%) of the down-regulated genes uncovered at 3 °C were detected in the ΔsigBL double-deletion mutant but not in ΔsigB or ΔsigL single-deletion mutants. Overall, the current study provides an expanded insight into σB and σL phenotypic roles and functional interactions in L. monocytogenes. Besides previously known σB- and σL-dependent genes, the transcriptomes defined in ΔsigB and ΔsigBL mutants reveal several new genes that are positively regulated by σB alone, as well as those co-regulated through σB- and σL-dependent mechanisms during L. monocytogenes growth under optimal and cold-stress temperature conditions.

The efficacy of misoprostol vaginal insert compared with oral misoprostol in the induction of labor of nulliparous women: A randomized national multicenter trial.

INTRODUCTION: Our objective was to compare the efficacy of a 200-µg misoprostol vaginal insert vs oral misoprostol regarding the cesarean section rate and the time interval to vaginal delivery in nulliparous women with unfavorable cervix. MATERIAL AND METHODS: In this prospective multicenter trial, 283 nulliparous women at term with Bishop score <6 were randomized to induction of labor with either a misoprostol vaginal insert (n = 140) or oral misoprostol (n = 143). In the oral misoprostol group, a 50-µg dose of oral misoprostol was administered every 4 hours up to three times during the first day; during the second day, the dose was increased to 100-µg every 4 hours up to three times during the first day, if necessary. Primary outcome was the cesarean section rate. Secondary outcomes were the time from induction of labor to vaginal delivery, the rate of other induction methods needed, labor augmentation with oxytocin and/or amniotomy, use of tocolytics and adverse neonatal and maternal events. RESULTS: In the misoprostol vaginal insert group, median time to vaginal delivery was shorter (24.5 hours vs 44.2 hours, P < 0.001), whereas no difference was found in the cesarean section rate (33.8% vs 29.6%, odds ratio [OR] 1.21, 95% confidence interval [CI] 0.66-1.91, P = 0.67). Other induction methods and labor augmentation with oxytocin and/or amniotomy were less frequent in the misoprostol vaginal insert group (OR 0.32, 95% CI 0.18-0.59 and OR 0.56, 95% CI 0.32-0.99, respectively). Need for tocolysis and meconium-stained amniotic fluid were more common in the misoprostol vaginal insert group (OR 3.63, 95% CI 1.12-11.79 and OR 2.38, 95% CI 1.32-4.29, respectively). Maternal and neonatal adverse events did not differ between groups. CONCLUSIONS: Misoprostol vaginal insert proved to shorten the time to vaginal delivery and to reduce the use of other methods of labor induction and augmentation, but it did not reduce the cesarean section rate compared with oral misoprostol. The benefit of more rapid delivery associated with misoprostol vaginal insert should be weighed against the greater risks for uterine hyperstimulation and meconium-stained amniotic fluid.

Pregnancy outcomes after liver transplantation in Finland.

INTRODUCTION: Pregnancy after liver transplantation is possible but associated with increased risk of obstetrical complications. We report here for the first time the pregnancy outcomes after liver transplantation in Finland. MATERIAL AND METHODS: All of the 25 pregnancies ending in deliveries after liver transplantation in Finland in 1998-2015 were analyzed. The data were collected from the mothers' medical records. The main outcome measures included pregnancy complications and the mode of delivery. Neonatal outcome measures were birthweight, 5-min Apgar score and umbilical artery pH. RESULTS: Twenty-six infants were born. Of all deliveries, 76% occurred at the ≥37 weeks of gestation and the average birthweight was 3040 g. Apgar scores were ≥7 in 25/26 (96%) of the infants and cases of birth asphyxia (umbilical artery pH ≤ 7.05) were not detected. Cesarean section rate was 32%. Preeclampsia occurred in 12% of the women and the preterm delivery rate was 24%. Co-morbidities (hypertension, intrahepatic cholestasis of pregnancy, Hodgkin's disease, colitis ulcerosa, epileptic attacks, cholangitis, splenic artery rupture, renal insufficiency and graft rejection) complicated 52% of pregnancies. CONCLUSION: Pregnancies after liver transplantation in Finland result in good perinatal outcome with healthy, mostly full-term, normally grown offspring; however, serious maternal complications related to underlying liver pathology, transplant surgery and immunosuppressive medication occur frequently.

Pregnancy outcomes in breech presentation analyzed according to intended mode of delivery.

INTRODUCTION: Optimal mode of delivery in breech presentation has been widely examined and debated. The aim of this study was to compare perinatal and maternal outcomes with either a policy of planned vaginal delivery or planned cesarean section in breech presentation. MATERIAL AND METHODS: This was a registry-based retrospective cohort study from Turku University Hospital, Finland with 1418 singleton breech deliveries at term over a period of 11 years (January 2002 to December 2012). Data were collected from the mothers' medical records. RESULTS: Apgar scores at 5 min as well as umbilical artery pH values were significantly lower in the planned vaginal breech delivery group compared with the planned cesarean section group, suggesting a short-lasting delayed recovery after birth. There were more puerperal infections in planned cesarean section group compared with the planned vaginal delivery group. CONCLUSIONS: The results confirm that planned vaginal breech delivery results in short-lasting delayed recovery after birth compared with planned cesarean section.

Phenotypic and transcriptomic analyses of Sigma L-dependent characteristics in Listeria monocytogenes EGD-e.

In this study the phenotypic and transcriptomic traits associated with the alternative sigma factor protein Sigma L in Listeria monocytogenes EGD-e were investigated. It was demonstrated that Sigma L is required for efficient growth in presence of stress associated with food preservative measures such as low temperature and organic acids. Furthermore, besides attenuation of swarming motility, the disruption of Sigma L in this bacterium also reduces resistance to a diverse range of toxic compounds, including some of the antibiotics used in listeriosis treatment. Genes under Sigma L-dependent transcriptional regulation were identified based on comparison of transcriptomes between exponentially growing cells of the EGD-e sigL null mutant and its parental strain cultivated under cold stress (3 °C) and optimized (37 °C) temperature conditions. Four hundred and forty genes under positive Sigma L-dependent transcriptional regulation were identified. The Sigma L regulon as revealed under these conditions comprises genes that code for proteins with diverse cellular functions including protein synthesis, nutrient transport, energy metabolism, cell envelope synthesis, and motility. The diverse range of transcriptome alterations induced by a sigL null mutation is thus consistent with the multiple phenotypic defects observed in the EGD-e ΔsigL mutant. These results demonstrate that Sigma L provides important global transcription regulatory functions in L. monocytogenes EGD-e. These promote execution of various cellular processes and stress adaptation responses thereby enabling this bacterium to overcome various food preservation measures as well as antibiotics and other toxic chemicals.

Genes encoding putative DEAD-box RNA helicases in Listeria monocytogenes EGD-e are needed for growth and motility at 3°C.

Quantitative RT-PCR revealed that transcripts of all four putative DEAD-box RNA helicase genes of the psychrotrophic pathogen Listeria monocytogenes EGD-e are found at higher levels in organisms grown at 3°C than at 37°C. At 3°C, growth of the three corresponding gene deletion mutants Δlmo0866, Δlmo1450 and Δlmo1722 was clearly restricted. The minimum growth temperatures of the three mutants were also higher than that of the wild-type EGD-e. In addition to inability to grow at 3°C, growth of Δlmo0866 and Δlmo1722 was reduced at 25°C, suggesting special roles of Lmo0866 and Lmo1722 in growth at suboptimal temperatures. Growth of Δlmo1450 was restricted not only at 3°C and 25°C, but also at 37°C, suggesting that Lmo1450 plays a universal role in growth of L. monocytogenes EGD-e. Moreover, cold-sensitive Δlmo0866, Δlmo1450 and Δlmo1722 were impaired in motility. The Δlmo0866 and Δlmo1450 strains were non-motile, while Δlmo1722 showed reduced motility. This study shows that the putative DEAD-box RNA helicase genes lmo0866, lmo1450 and lmo1722 are necessary for cold tolerance and motility of L. monocytogenes EGD-e.

Role of flhA and motA in growth of Listeria monocytogenes at low temperatures.

While temperature-dependent induction of flagella is a well-characterized phenomenon in Listeria monocytogenes, the essentiality of increased flagellum production during growth at low temperatures remains unclear. To study this relationship, we compared the relative expression levels of two motility genes, flhA and motA, at 3°C, 25°C and 37°C in L. monocytogenes strain EGD-e by using qRT-PCR, and compared the growth curves, motility, and flagellation between the wild-type and flhA and motA deletion mutants. The relative expression levels of flhA and motA at 3°C were significantly higher than at 37°C (p<0.01). At 3°C, the level of flhA transcripts was also significantly higher than at 25°C (p<0.01). Growth curve analysis showed that at 3°C both the growth rates and maximum optical densities of ΔflhA and ΔmotA strains at 600 nm were significantly lower than those of the wild-type (p<0.001), while no significant differences were observed between the wild-type and the mutants at 37°C, and 25°C. Mutant strains ΔflhA and ΔmotA were nonmotile at all three temperatures. At 25°C, the number of flagellated cells of ΔmotA was notably reduced compared with the wild-type, whereas ΔflhA appeared nonflagellated at all temperatures. The results suggest that flhA and motA play a role in the cold tolerance of L. monocytogenes strain EGD-e, and that motile flagella may be needed for optimal cold stress response of L. monocytogenes.

Role of fibroblast growth factor 8 in growth and progression of hormonal cancer.

Hormonal cancers such as breast and prostate cancer arise from steroid hormone-regulated tissues. In addition to breast and prostate cancer hormonal regulation has also a role in endometrial, ovarian, testis and thyroid carcinomas. The effects of estrogens, androgens and progestagens on tumor growth are largely mediated by paracrine and autocrine target molecules which include growth factors and growth factor receptors. During cancer progression the hormonal growth regulation is often lost or overcome by an inappropriate activation of growth factor signaling cascades. One of the growth factors which have been associated with the regulation of growth and progression of hormonal cancer is fibroblast growth factor 8 (FGF8) which has also been recognized as an oncogene. FGF8 is widely expressed during embryonic development. It has been shown to mediate embryonic epithelial-mesenchymal transition and to have a crucial role in gastrulation and early organization and differentiation of midbrain/hindbrain, pharyngeal, cardiac, urogenital and limb structures. During adulthood FGF8 expression is much more restricted but in hormonal cancers it becomes frequently activated. High level of FGF8 expression in tumors is associated with a poor prognosis at least in prostate cancer. In experimental models FGF8 induces and facilitates prostate tumorigenesis and increases growth and angiogenesis of tumors. Several lines of evidence for autocrine and paracrine loops in the growth regulation of breast, prostate and ovarian cancer by FGF8 have been suggested.

Androgen and fibroblast growth factor 8 (FGF8) downregulation of thrombospondin 1 (TSP1) in mouse breast cancer cells.

In the search for androgen target genes responsible for malignant growth in S115 mouse mammary tumor cells we found that thrombospondin 1 (TSP1) expression was strongly downregulated by testosterone (Te). Experiments with cycloheximide suggested that Te repression of TSP1 was dependent on de novo protein synthesis. TSP1 repression by Te was preceded by the induction of fibroblast growth factor 8 (FGF8) expression. FGF8 has previously been shown to mediate androgen effects on proliferation of S115 cells by autocrine/paracrine mechanisms. It has also been shown to increase breast cancer cell growth as tumors in nude mice and to stimulate tumor angiogenesis. We studied here the possibility that FGF8 belonged to the Te-induced de novo synthesized proteins that mediate the effect of Te on TSP1 expression in these cells. We found that addition of FGF8b to in vitro cultures or ectopic expression of FGF8b in S115 cells repressed TSP1 expression at mRNA and protein levels even in the absence of Te. FGF2, another angiogenic member of FGF family, also downregulated TSP1 mRNA level in the in vitro cultures of S115 cells. The antisense oligonucleotides for FGF8 did not, however, prevent Te-repression of TSP1 mRNA expression and a neutralizing anti-FGF8b antibody only partially opposed Te induced downregulation of TSP1. These results suggest that both androgen and FGF8 inhibit TSP1 expression independently. They also suggest that opposite to many other androgen-induced responses in S115 cells, the effect of Te on the expression TSP1 is not mediated by FGF8.

VEGF-C induced lymphangiogenesis is associated with lymph node metastasis in orthotopic MCF-7 tumors.

The spread of cancer cells to regional lymph nodes through the lymphatic system is the first step in the dissemination of breast cancer. In several human cancers including those of the breast and prostate, the expression of vascular endothelial growth factor C (VEGF-C) is associated with lymph node metastasis. Our study was undertaken to evaluate the effect of VEGF-C on metastasis of poorly invasive, estrogen dependent human MCF-7 breast cancer cells. MCF-7 breast cancer cells transfected with VEGF-C (MCF-7-VEGF-C) were grown as tumors in the mammary fat pads of nude mice implanted with subcutaneous estrogen pellets. Tumor lymphangiogenesis and lymph node metastasis were studied immunohistochemically using antibodies against lymphatic vessel hyaluronan receptor -1 (LYVE-1), VEGF receptor-3 (VEGFR-3), PECAM-1, pan-cytokeratin and estrogen dependent pS2 protein. Overexpression of VEGF-C in transfected MCF-7 cells stimulated in vivo tumor growth in xenotransplanted mice without affecting estrogen responsiveness. The resulting tumors metastasized to the regional lymph nodes in 75% (in 6 mice out of 8, Experiment I) and in 62% (in 5 mice out of 8, Experiment II) of mice bearing orthotopic tumors formed by MCF-7-VEGF-C cells whereas no metastases were observed in mice bearing tumors of control vector-transfected MCF-7 cells (MCF-7-Mock). The density of intratumoral and peritumoral lymphatic vessels was increased in tumors derived from MCF-7-VEGF-C cells but not MCF-7-Mock cells. Taken together, our results show that VEGF-C overexpression stimulates tumor lymphangiogenesis and induces normally poorly metastatic estrogen-dependent MCF-7 tumors to disseminate to local lymph nodes. These data suggest that VEGF-C has an important role in lymph node metastasis of breast cancer even at its hormone-dependent early stage.