Knowledge and Perception of the Role of Targeted Ultrasound in Detecting Down Syndrome Among a High Risk Population

The purpose of this study was to determine the perception and knowledge of targeted ultrasound in women who screen positive for Down syndrome in the first or second trimester, and to assess the perceived detection rate of Down syndrome by targeted ultrasound in this population. While several studies have reported patient perceptions’ of routine ultrasound, no study has specifically examined knowledge regarding the targeted ultrasound and its role in detecting Down syndrome. A targeted ultrasound is a special ultrasound during the second trimester offered to women who may be at a higher-than-average risk of having a baby with some type of birth defect or complication. The purpose of the ultrasound is to evaluate the overall growth and development of the baby as well as screen for birth defects and genetic conditions. Women under the age of 35 referred for an abnormal first or second trimester maternal serum screen to several Houston area clinics were asked to complete a questionnaire to obtain demographic and ultrasound knowledge information as well as assess perceived detection rate of Down syndrome by ultrasound. Seventy-seven women completed the questionnaire and participated in the study. Our findings revealed that women have limited background knowledge about the targeted ultrasound and its role in detecting Down syndrome. These findings are consistent with other studies that have reported a lack of understanding about the purpose of ultrasound examinations. One factor that seems to increase background knowledge about the targeted ultrasound is individuals having a higher level of education. However, most participants regardless of race, education, income, and exposure to targeted ultrasound information did not know the capabilities of a targeted ultrasound. This study confirmed women lack background knowledge about the targeted ultrasound and do not know enough about the technology to form a perception regarding its ability to detect Down syndrome. Additional studies to identify appropriate education techniques are necessary to determine how to best inform our patient population about targeted ultrasound.

Maternal exposure to hazardous air pollutants and oral clefts among offspring: Texas, 1999-2008

Birth defects are a leading cause of infant mortality in the United States. About one in 33 births in the United States is diagnosed with birth defects. Common birth defects include neural tube defects, Down syndrome and oral clefts. The present study focused on oral clefts. ^ Oral clefts refer to the malformation of lip, mouth or both. Birth prevalence of oral clefts in Texas is about 11 per 10,000 births. Etiologically, oral clefts have been classified into two groups, cleft lip with or without cleft palate (CL±P) and isolated cleft palate (CP). In spite of their high prevalence and clinical significance, the etiology of oral clefts in humans has not been well understood. Though a number of risk factors have been identified in epidemiological studies, most of them do not explain the majority of the cases. The need to identify novel risk factors associated with oral clefts provided the motivation for this study. The present study focused on maternal exposure to several hazardous air pollutants. A common subgroup of hazardous air pollutants is the volatile organic compounds found in petroleum derivatives. Four important hydrocarbons in this group are benzene, toluene, ethyl benzene and xylenes (BTEX). ^ The specific aim of this study was to evaluate the association between maternal exposure to environmental levels of BTEX and oral clefts among offspring in Texas for the period 1999-2008. ^ A case-control study design was used to assess if maternal exposure to BTEX increased the risk of oral clefts. The Texas Birth Defects Registry provided data on cases of non-syndromic oral clefts delivered in Texas during the period 1999-2008. Census tract level maternal exposure to BTEX concentrations were obtained from the Hazardous Air Pollutant Exposure Model (HAPEM) developed by the U.S. Environmental Protection Agency. Unconditional logistic regression was used to assess the relationship between maternal exposure to BTEX levels and risk of oral clefts in offspring. ^ In the selected population, mothers who had high estimated exposure to any of the BTEX compounds were not more likely to deliver an offspring with oral clefts. Future research efforts will focus on additional birth defects and thorough assessment of additional potential confounders.^

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.

Mechanisms regulating the p120-catenin/Kaiso pathway

The Wnt pathways contribute to many processes in cancer and developmental biology, with β-catenin being a key canonical component. P120-catenin, which is structurally similar to β-catenin, regulates the expression of certain Wnt target genes, relieving repression conferred by the POZ/ zinc-finger transcription factor Kaiso. In my first project, employing Xenopus embryos and mammalian cell lines, I found that the degradation machinery of the canonical Wnt pathway modulates p120-catenin protein stability, especially p120 isoform-1, through mechanisms shared with b-catenin. Exogenous expression of destruction-complex components such as GSK3b or Axin promotes p120-catenin degradation, and consequently, is able to rescue developmental phenotypes resulting from p120 over-expression during early Xenopus embryonic development. Conversely, as predicted, the in vivo depletion of either Axin or GSK3b coordinately increased p120 and b-catenin levels, while p120 levels decreased upon LRP5/6 depletion, which are positive modulators in the canonical Wnt pathway. At the primary sequence level, I resolved conserved GSK3b phosphorylation sites in p120’s (isoform 1) amino-terminal region. Point-mutagenesis of these residues inhibited the association of destruction complex proteins including those involved in ubiquitination, resulting in p120-catenin stabilization. Importantly, we found that two additional p120-catenin family members, ARVCF-catenin and d-catenin, in common with b-catenin and p120, associate with Axin, and are degraded in Axin’s presence. Thus, by similar means, it appears that canonical Wnt signals coordinately modulate multiple catenin proteins having roles in development and conceivably disease states. In my second project, I found that the Dyrk1A kinase exhibits a positive effect upon p120-catenin levels. That is, unlike the negative regulator GSK3b kinase, a candidate screen revealed that Dyrk1A kinase enhances p120-catenin protein levels via increased half-life. Dyrk1A is encoded by a gene located within the trisomy of chromosome 21, which contributes to mental retardation in Down Syndrome patients. I found that Dyrk1A expression results in increased p120 protein levels, and that Dyrk1A specifically associates with p120 as opposed to other p120-catenin family members or b-catenin. Consistently, Dyrk1A depletion in mammalian cell lines and Xenopus embryos decreased p120-catenin levels. I further confirmed that Dyrk overexpression and knock-down modulates both Siamois and Wnt11 gene expression in the expected manner based upon the resulting latered levels of p120-catenin. I determined that Dyrk expression rescues Kaiso depletion effects (gastrulation failure; increased endogenous Wnt11 expression), and vice versa. I then identified a putative Dyrk phosphorylation region within the N-terminus of p120-catenin, which may also be responsible for Dyrk1A association. I went on to make a phosphomimic mutant, which when over-expressed, had the predicted enhanced capacity to positively modulate endogenous Wnt11 and Siamois expression, and thereby generate gastrulation defects. Given that Dyrk1A modulates Siamois expression through stabilization of p120-catenin, I further observed that ectopic expression of Dyrk can positively influence b-catenin’s capacity to generate ectopic dorsal axes when ventrally expressed in early Xenopus embryos. Future work will investigate how Dyrk1A modulates the Wnt signaling pathway through p120-catenin, and possibly begin to address how dysfunction of Dyrk1A with respect to p120-catenin might relate to aspects of Down syndrome. In summary, the second phase of my graduate work appears to have revealed a novel aspect of Dyrk1A/p120-catenin action in embryonic development, with a functional linkage to canonical Wnt signaling. What I have identified as a “Dyrk1A/p120-catenin/Kaiso pathway” may conceivably assist in our larger understanding of the impact of Dyrk1A dosage imbalance in Down syndrome.

EFFECT OF ANCHORING ON PERCEIVED AMNIOCENTESIS RELATED MISCARRIAGE RISK WITHIN A LATINA POPULATION

Most recognized pregnancies are completed without difficulty, yet there is always a 3-5% background risk to have a child with a birth defect. Amniocentesis, the most common type of prenatal diagnostic test, is used to detect chromosomal abnormalities, such as Down syndrome. Amniocentesis is associated with a risk of complications that can lead to a miscarriage, which is typically quoted to be between 1 in 300 and 1 in 500. Amniocentesis uptake rates are typically lowest within the Latina community, and although the factors related to this have been studied before, no specific conclusions have been reached. The general population has a difficult time interpreting risks, as individuals vary in numeracy skills as well as personal factors that can influence risk perception. A recent study by Nuccio (2010) investigated the effect of anchoring, where a patient’s prior knowledge about a subject affects her risk perception, and how it relates to the uptake of amniocentesis within a diverse population in Houston, TX. The effect of anchoring on perceived amniocentesis-related miscarriage risk within the Latina population has not been previously examined. A two-part questionnaire was completed by 96 Latinas receiving prenatal genetic counseling due to an increased risk to have a baby with a chromosome abnormality at various clinics in Houston, TX. The genetic counselor involved in the session completed a separate survey. This population was largely unfamiliar with surveys, risk figures, and prenatal testing. Only one individual was able to quantify the risk associated with amniocentesis prior to the genetic counseling. While the majority of women felt that the risk association with amniocentesis is very low to average, only 7 individuals pursued diagnostic testing through amniocentesis. Most women did not feel like the information gained from an amniocentesis would change the management of their pregnancy and/or they did not believe that their baby had a problem. Women, regardless of ethnicity, deserve individualized genetic counseling sessions that cater to their needs and desires regarding their prenatal care.

An assessment of obesity and hyperphagia in individuals with Smith-Magenis syndrome

Smith-Magenis syndrome (SMS;OMIM# 182290) is a multiple congenital anomalies and mental retardation syndrome caused by a 3.7- Mb deletion on chromosome 17p11.2 or a mutation in the RAI1 gene. Although the majority of the SMS phenotype has been well described, limited studies are available describing growth patterns in SMS. There is some evidence that individuals with SMS develop obesity. Thus, this study aims to characterize the growth and potential influence of hyperphagia in a cohort of individuals with SMS. A retrospective chart review was conducted of 78 individuals with SMS through Baylor College of Medicine (BCM) at Texas Children¡¯s Hospital (TCH.) All documented height and weight measurements were abstracted and Z-scores (SD units) for height-for-age, length-for-age and BMI-for-age were calculated. Mail-out questionnaires were provided to the corresponding parents of the cohort to assess for the presence of hyperphagia through a validated hyperphagia questionnaire (HQ). Analysis of this data demonstrates that by the age ¡Ý 20 years males with SMS have mean BMI¡¯s in the 85th-90th percentile corresponding to an overweight BMI, and females with SMS had mean BMI¡¯s in the 95th -97th percentile corresponding to an obese BMI. Parents indicated that hyperphagia is present in individuals with SMS as 76% of parent¡¯s report having to lock food away from their child. Females¡¯ age ¡Ý 20 years of age had the highest mean behavior, drive and severity scores as well as the highest BMI. Thus, this study concludes that it appears overweight and obesity, as well as hyperphagia, are present in this cohort of SMS individuals. The results of this study will hopefully enable parents and caregivers of children with SMS to take preventative measures in order to control food related behaviors present in their children as well as to prevent overweight and obesity and the associated negative health consequences.

Assessment of US Air Force student pilots with intermittent monofixation syndrome on a non-stereoptic dependent flight maneuver in pilot training

The United States Air Force School of Aerospace Medicine (USAFSAM) and Aeromedical Consult Service (ACS) have developed waiver criteria for pilots with subtle substandard depth perception. This is to allow United States Air Force (USAF) pilots with mild depth perception deficiency to continue flying duties while limiting the risk to flight safety and ensuring the availability of costly human resources. From 1999 to 2005, 166 aviators were given waivers for intermittent monofixation syndrome (IMFS). Of these, 96 were student pilots who performed slightly worse at stereoptic dependent flight maneuvers than student pilots (8,907) with normal depth perception (Lowry, 2006).^ This study's purpose is to evaluate the performance of the extended-trail maneuver, a non-stereoptic dependent flying maneuver, as executed by a cohort of 12 United States Air Force student pilots with intermittent monofixation syndrome versus the cohort of 100 student pilots with normal depth perception. These subjects are extracted from the cohorts examined by Lowry (2006) and the null hypothesis predicts no statistical difference in the performance of the non-stereoptic dependant flight maneuver extended-trail between student pilots with intermittent monofixation syndrome and those without the condition. ^

Folate pathway polymorphisms and neuropsychological impairment after leukemia therapy

Neuropsychological impairment occurs in 20%-40% of childhood acute lymphoblastic leukemia (ALL) survivors, possibly mediated by folate depletion following methotrexate chemotherapy. We evaluated the relationship between two folate pathway polymorphisms and neuropsychological impairment after childhood ALL chemotherapy. Eighty-six childhood ALL survivors were recruited between 2004-2007 at Texas Children's Hospital after exclusion for central nervous system leukemia, cranial irradiation, and age<1 year at diagnosis. Neuropsychological evaluation at a median of 5.3 years off therapy included a parental questionnaire and the following child performance measures: Trail Making Tests A and B, Grooved Pegboard Test Dominant-Hand and Nondominant-Hand, and Digit Span subtest. We performed genotyping for polymorphisms in two folate pathway genes: reduced folate carrier (RFC1 80G>A, rs1051266) and dihydrofolate reductase (DHFR Intron-1 19bp deletion). Fisher exact test, logistic regression, Student's t-test, and ANOVA were used to compare neuropsychological test scores by genotype, using a dominant model to group genotypes. In univariate analysis, survivors with cumulative methotrexate exposure ≥9000 mg/m2 had an increased risk of attention disorder (OR=6.2, 95% CI 1.2 – 31.3), compared to survivors with methotrexate exposure <9000 mg/m2. On average, female survivors scored 8.5 points higher than males on the Digit Span subtest, a test of working memory (p=0.02). The RFC1 80G>A and DHFR Intron-1 deletion polymorphisms were not related to attention disorder or impairment on tests of attention, processing speed, fine motor speed, or memory. These data imply a strong relationship between methotrexate dose intensity and impairment in attention after childhood ALL therapy. We did not find an association between the RFC1 80G>A or DHFR Intron-1 deletion polymorphisms and long-term neuropsychological impairment in childhood ALL survivors.^