First Trimester Screening and its Impact on Uptake of Diagnostic Testing

Introduction: First Trimester Screening (FTS) combines maternal age with fetal nuchal translucency (NT) and maternal analytes to identify pregnancies at an increased risk for Down syndrome and trisomy 18. Though the accuracy of this screening is high, it cannot replace the conclusive accuracy of prenatal diagnostic testing (PDT). Since FTS has been available, a decrease in the number of women who pursue PDT has been observed. This study sought to determine if there has been a significant change in the amount of PDT performed in our clinics, if the type of FTS result affects the patient’s decision regarding PDT, and what the patient’s intentions are regarding PDT. Material and Methods: A database review was performed for the two years prior and the two years after the January 2007 American College of Obstetricians and Gynecologists (ACOG) guidelines regarding FTS were issued. We compared the number of women who were AMA and the number of women who were AMA and had PDT between those time periods. We also determined the number of positive and negative FTS results, and determined how many of those patients had PDT. Finally, we surveyed our patients and referring physicians to determine: what the patient understands about FTS, what the patient’s intentions are regarding FTS, and how physicians present the option of FTS to their patients. Results: We determined that there was a 19.6% decrease in the amount of PDT performed when we compared the two time periods at our three specified clinics. Many of our patients were against having PDT prior to their genetic counseling session, but after they received genetic counseling, 76% of our population became open to the possibility of having PDT. Conclusion: Similar to previous studies, we determined that there has been a significant decrease in the number of PDT procedures performed at our clinics, which coincides with the release of the January 2007 ACOG statement regarding FTS. While our patients regarded FTS as a way to gain early information about their pregnancy in a non-invasive manner, they also stated they would use their results as a way to aid in their decision regarding PDT.

The Role of Acidic Fibroblast Growth Factor and Fibroblast Growth Factor Receptor 4 in High Grade Serous Carcinoma

Background: High grade serous carcinoma whether ovarian, tubal or primary peritoneal, continues to be the most lethal gynecologic malignancy in the USA. Although combination chemotherapy and aggressive surgical resection has improved survival in the past decade the majority of patients still succumb to chemo-resistant disease recurrence. It has recently been reported that amplification of 5q31-5q35.3 is associated with poor prognosis in patients with high grade serous ovarian carcinoma. Although the amplicon contains over 50 genes, it is notable for the presence of several members of the fibroblast growth factor signaling axis. In particular acidic fibroblast growth factor (FGF1) has been demonstrated to be one of the driving genes in mediating the observed prognostic effect of the amplicon in ovarian cancer patients. This study seeks to further validate the prognostic value of fibroblast growth receptor 4 (FGFR4), another candidate gene of the FGF/FGFR axis located in the same amplicon. The emphasis will be delineating the role the FGF1/FGFR4 signaling axis plays in high grade serous ovarian carcinoma; and test the feasibility of targeting the FGF1/FGFR4 axis therapeutically. Materials and Methods: Spearman and Pearson correlation studies on data generated from array CGH and transcriptome profiling analyses on 51 microdissected tumor samples were used to identify genes located on chromosome 5q31-35.3 that showed significant correlation between DNA and mRNA copy numbers. Significant correlation between FGF1 and FGFR4 DNA copy numbers was further validated by qPCR analysis on DNA isolated from 51 microdissected tumor samples. Immunolocalization and quantification of FGFR4 expression were performed on paraffin embedded tissue samples from 183 cases of high-grade serous ovarian carcinoma. The expression was then correlated with clinical data to assess impact on survival. The expression of FGF1 and FGFR4 in vitro was quantified by real-time PCR and western blotting in six high-grade serous ovarian carcinoma cell lines and compared to those in human ovarian surface epithelial cells to identify overexpression. The effect of FGF1 on these cell lines after serum starvation was quantified for in vitro cellular proliferation, migration/invasion, chemoresistance and survival utilizing a combination of commercially available colorimetric, fluorometric and electrical impedance assays. FGFR4 expression was then transiently silenced via siRNA transfection and the effects on response to FGF1, cellular proliferation, and migration were quantified. To identify relevant cellular pathways involved, responsive cell lines were transduced with different transcription response elements using the Cignal-Lenti reporter system and treated with FGF1 with and without transient FGFR4 knock down. This was followed by western blot confirmation for the relevant phosphoproteins. Anti-FGF1 antibodies and FGFR trap proteins were used to attempt inhibition of FGF mediated phenotypic changes and relevant signaling in vitro. Orthotopic intraperitoneal tumors were established in nude mice using serous cell lines that have been previously transfected with luciferase expressing constructs. The mice were then treated with FGFR trap protein. Tumor progression was then followed via bioluminescent imaging. The FGFR4 gene from 52 clinical samples was sequenced to screen for mutations. Results: FGFR4 DNA and mRNA copy numbers were significantly correlated and FGFR4 DNA copy number was significantly correlated with that of FGF1. Survival of patients with high FGFR4 expressing tumors was significantly shorter that those with low expression(median survival 28 vs 55 month p< 0.001) In a multivariate cox regression model FGFR expression significantly increased risk of death (HR 2.1, p<0.001). FGFR4 expression was significantly higher in all cell lines tested compared to HOSE, OVCA432 cell line in particular had very high expression suggesting amplification. FGF1 was also particularly overexpressed in OVCA432. FGF1 significantly increased cell survival after serum deprivation in all cell lines. Transient knock down of FGFR4 caused significant reduction in cell migration and proliferation in vitro and significantly decreased the proliferative effects of FGF1 in vitro. FGFR1, FGFR4 traps and anti-FGF1 antibodies did not show activity in vitro. OVCA432 transfected with the cignal lenti reporter system revealed significant activation of MAPK, NFkB and WNT pathways, western blotting confirmed the results. Reverse phase protein array (RPPA) analysis also showed activation of MAPK, AKT, WNT pathways and down regulation of E Cadherin. FGFR trap protein significantly reduced tumor growth in vivo in an orthotopic mouse model. Conclusions: Overexpression and amplification of several members of the FGF signaling axis present on the amplicon 5q31-35.3 is a negative prognostic indicator in high grade serous ovarian carcinoma and may drive poor survival associated with that amplicon. Activation of The FGF signaling pathway leads to downstream activation of MAPK, AKT, WNT and NFkB pathways leading to a more aggressive cancer phenotype with increased tumor growth, evasion of apoptosis and increased migration and invasion. Inhibition of FGF pathway in vivo via FGFR trap protein leads to significantly decreased tumor growth in an orthotopic mouse model.

Addressing Obesity: Fear of Crime, Perceptions of Disorder and Disaparities in Child and Adolescent Use of Public Parks

Abstract The objectives of this study were: 1) To determine factors which inhibit and facilitate child and adolescent use of outdoor spaces for healthy physical activity by race and ethnicity in four Houston communities and 2) To propose guidelines for encouraging and maintaining child and adolescent outdoor physical activity. Using local health data and Houston Police Department crime statistics, four communities were identified for the study that had the highest concentration of crime and the racial/ ethnic groups of interest. The researchers then identified public parks in the communities. At least two parks were observed in each of the four communities from 2010 to 2011 during spring, summer, fall and winter. The parks were observed for use by children and adolescents and to describe the condition of the park spaces. The communities were Alief (Asian), Sunnyside (Black), Eldridge- West Oaks (White) and Northside- Northline (Hispanic). Observations were made at varying hours of both day and night, weekdays and weekends. Photographs were taken and the condition of the spaces noted in detail. One hundred and twenty persons, 18 years and over, using the spaces or otherwise in these communities were conveniently sampled and interviewed about their health and the extent to which they, or any children or adolescents under their care, used the outdoor spaces of interest. Data were analyzed qualitatively and with basic descriptive statistics. The photographs, journal notes and observation notes of all investigators and key personnel were analyzed. Interview data were also coded to identify patterns and themes in the responses. The findings indicate disparities in the quality and quantity of park equipment and the maintenance of the areas. Where perceptions of disorder were described, there was often visible evidence to support the perceptions. In many cases, residents' perceptions of crime were corroborated by police data. While interview reports did not seem to support the expectation that the condition of the parks was a significant deterrent to their use by children and adolescents, the condition of the parks might be said to limit the extent of that use. Specific reports of disorder that inhibited use included hearing gunfire, seeing drug dependent homeless persons and/or suspected prostitutes in an area.

Prenatal management of monoamniotic twin pregnancies

OBJECTIVE To evaluate antenatal surveillance strategies and the optimal timing of delivery for monoamniotic twin pregnancies. METHODS Obstetric and perinatal outcomes were retrospectively retrieved for 193 monoamniotic twin pregnancies. Fetal and neonatal outcomes were compared between fetuses followed in an inpatient setting and those undergoing intensive outpatient follow-up from 26 to 28 weeks of gestation until planned cesarean delivery between 32 and 35 weeks of gestation. The risk of fetal death was compared with the risk of neonatal complications. RESULTS Fetal deaths occurred in 18.1% of fetuses (70/386). Two hundred ninety-five neonates from 153 pregnancies were born alive after 23 weeks of gestation. There were 17 neonatal deaths (5.8%), five of whom had major congenital anomalies. The prospective risk of a nonrespiratory neonatal complication was lower than the prospective risk of fetal death after 32 4/7 weeks of gestation (95% confidence interval 32 0/7-33 4/7). The incidence of death or a nonrespiratory neonatal complication was not significantly different between fetuses managed as outpatients (14/106 [13.2%]) or inpatients (15/142 [10.5%]; P=.55). Our statistical power to detect a difference in outcomes between these groups was low. CONCLUSIONS The in utero risk of a monoamniotic twin fetus exceeds the risk of a postnatal nonrespiratory complication at 32 4/7 weeks of gestation. If close fetal surveillance is instituted after 26-28 weeks of gestation and delivery takes place at approximately 33 weeks of gestation, the risk of fetal or neonatal death is low, no matter the surveillance setting. LEVEL OF EVIDENCE II.

Safe vaginal uterine morcellation following total laparoscopic hysterectomy.

The minimally invasive approach for hysterectomy with proven benefits and lower morbidity has become the gold standard, even in women with large uterine masses. Most women with a malignant condition present with abnormal vaginal bleeding and/or suspicious imaging such that few are diagnosed by final histopathology after surgery. However, if a malignancy is not diagnosed preoperatively, intraabdominal morcellation for uterus extraction has an increased risk for potential tumor spread and peritoneal metastases, especially in cases of unexpected leiomyosarcoma. We describe a simple method to wrap the uterus in a contained environment with a plastic bag through the posterior vaginal fornix prior to conventional coring morcellation for vaginal extraction in total laparoscopic hysterectomy. We further describe our experience with a risk stratification and treatment algorithm to implement this procedure in daily routine. A video and an illustrating sketch demonstrate the simplicity and safety of the procedure.

Synthesis, spectral, and anti-microbial studies of thioiminium iodides and amine hydrochlorides

To avoid the undesired deprotonation during the addition of organolithium and organomagnesium reagents to ketones, the thioiminium salts, easily prepared from lactams and amides are converted into 2,2-disubstituted and 2-monosubstituted amines by reaction with simple nucleophiles such as organocerium and organocopper reagents. The reaction of thioiminium iodides with organocerium reagents derived by transmetalation of corresponding lithium reagents with anhydrous cerium(III) chloride has been investigated. These thioiminium iodides act as good electrophiles and accept alkylceriums towards bisaddition. The newly synthesized amines have been characterized by 1H and 13C NMR, IR and mass spectra. The amines have been converted into their hydrochlorides and characterized by COSY. These hydrochlorides have been subjected to antimicrobial screening with clinically isolated microorganisms, Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa, Salmonella typhi and Candida albicans. The hydrochlorides show quite good activity against these bacteria and fungus.

First-trimester glycosylated hemoglobin in women at high risk for gestational diabetes.

INTRODUCTION Our aim was to investigate the prognostic value of first-trimester glycosylated hemoglobin (HbA1c) in pregnant women with risk factors for developing gestational diabetes mellitus (GDM). MATERIAL AND METHODS This is an observational retrospective cohort study conducted at the Department of Obstetrics and Gynecology, University Hospital Bern, Switzerland. We included pregnant women at high risk for GDM (n = 208), who had an HbA1c measurement in the first trimester. We compared HbA1c values of women who later developed GDM with those who did not develop GDM. Diagnosis of GDM was made on the basis of a 75-g oral glucose tolerance test performed between 24 and 28 weeks of gestation. We further examined the prevalence of GDM in relation to the first-trimester HbA1c value. RESULTS The prevalence of GDM in our high-risk group was 14.7%. Women who developed GDM had significantly higher first-trimester HbA1c values [5.43 ± 0.31% (36 ± 3 mmol/mol) vs. 5.23 ± 0.28% (34 ± 3 mmol/mol); p = 0.0026]. Moreover, all pregnant women with HbA1c ≥6.0% (42 mmol/mol) developed GDM, whereas those with <4.5% (26 mmol/mol) did not. CONCLUSIONS Women at risk for GDM have higher first-trimester HbA1c levels and values ≥6.0% (42 mmol/mol) are predictive of GDM. This information may be useful for counseling these women and providing appropriate advice on diet and lifestyle modification early in pregnancy.

A Case Study on Using the Via Christi Breastfeeding Assessment Tool in a Clinical Setting

Aims- The goal of this study is to obtain a subjective point of view of the use, benefits, and shortcomings of the Via Christi breastfeeding Assessment Tool in a clinical setting. Methods- This case study is based on a single yet detailed interview with a lactation consultant who has utilized the Via Christi Breastfeeding Tool in a clinical setting. Findings- Advantages of the Via Christi Breastfeeding Assessment Tool include that the tool is practical and concrete, encompassing both a subjective dimension and the basic elements of breastfeeding. Shortcomings of the tool include its non-specificity in focus on the feeding technique only and excluding other factors involved with the birth and mother- baby couplet. Conclusion- The Via Christi Breastfeeding Tool serves as a good initial screening of breastfeeding, which in result leads to the recommendation of further and more extensive study of a specific mother-baby couplet breastfeeding measures if needed.

Studies on the enzymatic and transcriptional activity of the dimerization cofactor for hepatocyte nuclear factor 1

The relationship between the enzymatic and the transcriptional activity of the bifunctional protein pterin-4a-carbinolamine dehydratase/dimerization cofactor for hepatocyte nuclear factor 1 (DCoH) has been elucidated by site-directed mutagenesis. DCoH dimers harbor a binding site for hepatocyte nuclear factor 1 (HNF1), two active centers that bind pterins, and a saddle-shaped surface that resembles nucleic acid binding domains. Two domains of the protein have been selectively targeted to determine if a change in one activity affects the other. No strong correlation has been found, supporting the idea that carbinolamine dehydratase activity is not required for HNF1 binding in vitro or transcriptional coactivation in vivo. Double mutations in the active center, however, influence the in vivo transcriptional activity but not HNF1 binding. This finding suggests that some active center residues also are used during transcription, possibly for binding of another (macro)molecule. Several mutations in the saddle led to a surprising increase in transcription, therefore linking this domain to transcriptional regulation as well. The transcriptional function of DCoH therefore is composed of two parts, HNF1 binding and another contributing effect that involves the active site and, indirectly, the saddle.