Hye Heo

Minireview: Epigenetics of Obesity and Diabetes in Humans

Understanding the determinants of human health and disease is overwhelmingly complex, particularly for common, late-onset, chronic disorders, such as obesity and diabetes. Elucidating the genetic and environmental factors that influence susceptibility to disruptions in energy homeostasis and metabolic regulation remain a challenge, and progress will entail the integration of multiple assessments of temporally dynamic environmental exposures in the context of each individuals genotype. To meet this challenge, researchers are increasingly exploring the epigenome, which is the malleable interface of gene-environment interactions. Epigenetic variation, whether innate or induced, contributes to variation in gene expression, the range of potential individual responses to internal and external cues, and risk for metabolic disease. Ultimately, advancement in our understanding of chronic disease susceptibility in humans will depend on refinement of exposure assessment tools and systems biology approaches to interpretation. In this review, we present recent progress in epigenetics of human obesity and diabetes, existing challenges, and the potential for new approaches to unravel the complex biology of metabolic dysregulation.

Using Simulation Training to Improve Shoulder Dystocia Documentation

OBJECTIVE: To estimate whether shoulder dystocia documentation could be improved with a simulation-based educational experience. METHODS: Obstetricians at our institution (n=71) participated in an unanticipated simulated shoulder dystocia followed by an educational debriefing session. A second shoulder dystocia simulation was completed at a later date. Delivery notes were a required component of each simulation. Notes were evaluated using a standardized checklist for 16 key components. One point was awarded for each element present. Wilcoxon signed rank tests were used to compare documentation between simulations. RESULTS: Participants consisted of 43 (61%) attending and 28 (39%) resident physicians. Ages ranged from 25–63 years (mean±standard deviation 37.0±9.0), and 75% were female. Years of obstetric experience for our attendings ranged from 4 to 31 years (14.5±8.1). Documentation scores were significantly improved after training. Attendings’ baseline documentation scores were 8.5±2.2 and improved to 9.4±2.3, P=.03. Residents’ documentation scores also improved (9.0±2.1 compared with 10.6±2.2, P=.001). In particular, improvement was seen in two components of documentation: 1) providers present for shoulder dystocia (P=.007) and 2) which shoulder was anterior (P<.001). No improvement was seen in standard delivery note components (eg, date, time) or infant characteristics (eg, weight, Apgar scores). CONCLUSION: Although we showed a significant improvement in the quality of documentation through this simulation program, notes were still suboptimal. Use of standardized forms for shoulder dystocia delivery notes may provide the best solution to ensure appropriate documentation. LEVEL OF EVIDENCE: II

Resident training for eclampsia and magnesium toxicity management: simulation or traditional lecture?

OBJECTIVE To compare eclampsia and magnesium toxicity management among residents randomly assigned to lecture or simulation-based education. STUDY DESIGN Statified by year, residents (n = 38) were randomly assigned to 3 educational intervention groups: Simulation→Lecture, Simulation, and Lecture. Postintervention simulations were performed for all and scored using standardized lists. Maternal, fetal, eclampsia management, and magnesium toxcity scores were assigned. Mann-Whitney U, Wilcoxon rank sum and χ(2) tests were used for analysis. RESULTS Postintervention maternal (16 and 15 vs 12; P < .05) and eclampsia (19 vs 16; P < .05) scores were significantly better in simulation based compared with lecture groups. Postintervention magnesium toxcitiy and fetal scores were not different among groups. Lecture added to simulation did not lead to incremental benefit when eclampsia scores were compared between Simulation→Lecture and Simulation (19 vs 19; P = nonsignificant). CONCLUSION Simulation training is superior to traditional lecture alone for teaching crucial skills for the optimal management of both eclampsia and magnesium toxicity, 2 life-threatening obstetric emergencies.

Sexual dimorphism in epigenomic responses of stem cells to extreme fetal growth.

Extreme fetal growth is associated with increased susceptibility to a range of adult diseases through an unknown mechanism of cellular memory. We tested whether heritable epigenetic processes in long-lived CD34+ hematopoietic stem/progenitor cells (HSPCs) showed evidence for re-programming associated with the extremes of fetal growth. Here we show that both fetal growth restriction and over-growth are associated with global shifts towards DNA hypermethylation, targeting cis-regulatory elements in proximity to genes involved in glucose homeostasis and stem cell function. We find a sexually dimorphic response; intrauterine growth restriction (IUGR) is associated with substantially greater epigenetic dysregulation in males, whereas large for gestational age (LGA) growth predominantly affects females. The findings are consistent with extreme fetal growth interacting with variable fetal susceptibility to influence cellular aging and metabolic characteristics through epigenetic mechanisms, potentially generating biomarkers that could identify infants at higher risk for chronic disease later in life.

Advanced aging phenotype is revealed by epigenetic modifications in rat liver after in utero malnutrition

Adverse environmental exposures of mothers during fetal period predispose offspring to a range of age‐related diseases earlier in life. Here, we set to determine whether a deregulated epigenetic pattern is similar in young animals whose mothers’ nutrition was modulated during fetal growth to that acquired during normal aging in animals. Using a rodent model of maternal undernutrition (UN) or overnutrition (ON), we examined cytosine methylation profiles of liver from young female offspring and compared them to age‐matched young controls and aged (20‐month‐old) animals. HELP‐tagging, a genomewide restriction enzyme and sequencing assay demonstrates that fetal exposure to two different maternal diets is associated with nonrandom dysregulation of methylation levels with profiles similar to those seen in normal aging animals and occur in regions mapped to genes relevant to metabolic diseases and aging. Functional consequences were assessed by gene expression at 9 weeks old with more significant changes at 6 months of age. Early developmental exposures to unfavorable maternal diets result in altered methylation profiles and transcriptional dysregulation in Prkcb, Pc, Ncor2, and Smad3 that is also seen with normal aging. These Notch pathway and lipogenesis genes may be useful for prediction of later susceptibility to chronic disease.

P18.15: Successful ablation of complicated placental chorioangioma using ethyl alcohol as a sclerosant

catheter was not confirmed by US. When CS was performed at 32 weeks, a catheter was found in maternal peritoneum. Another catheter which was placed in neonatal thoraic cavity was confirmed by X-ray. Case 4: At 31 weeks of gestation, TAS was performed. US confirmed that a catheter fell off into uterine cavity during TAS procedure. When CS was performed at 32 weeks, a catheter was found in uterine cavity. Case 5: At 31 weeks of gestation, TAS was performed. During TAS procedure, US confirmed that a catheter nearly fell off thoracic wall into uterine cavity, but soon after that confirmed that the catheter was placed in fetal thoracic wall. At 33 weeks, the catheter was not found in fetal thoracic wall and intra thoracic cavity. After rupture of membrane at 35 weeks, the catheter was found in maternal birth canal. Conclusion: It is necessary to take the shunt catheter troubles into account at TAS.

Intrauterine hyperglycemia is associated with an impaired postnatal response to oxidative damage.

Hyperglycemia and other adverse exposures early in life that reprogram stem cells may lead to long-lasting phenotypic influences over the lifetime of an individual. Hyperglycemia and oxidative stress cause DNA damage when they exceed the protective capabilities of the cell, in turn affecting cellular function. DNA damage in response to hyperglycemia and oxidative stress was studied in human umbilical cord mesenchymal stem cells (hUC-MSCs) from large-for-gestational-age (LGA) infants of mothers with gestational diabetes mellitus (LGA-GDM) and control subjects. We tested the response of these cells to hyperglycemia and oxidative stress, measuring reactive oxygen species (ROS) levels and antioxidant enzyme activities. We find that hUC-MSCs from LGA-GDM infants have increased DNA damage when exposed to oxidative stress. With the addition of hyperglycemic conditions, these cells have an increase in ROS and a decrease in antioxidant glutathione peroxidase (GPx) activity, indicating a mechanism for the increased ROS and DNA damage. This study demonstrates that a memory of in utero hyperglycemia, mediated through downregulation of GPx activity, leads to an increased susceptibility to oxidative stress. The alteration of GPx function in self-renewing stem cells, can mediate the effect of intrauterine hyperglycemia to be propagated into adulthood and contribute to disease susceptibility.

Immediate Postpartum Glucose Tolerance Testing in Women with Gestational Diabetes: A Pilot Study

Objective Due to poor adherence for glucose testing at 6‐ to 12‐week postpartum among women with gestational diabetes, we sought to determine whether a 2‐hour glucose tolerance test (GTT) during postpartum hospitalization is predictive of 6‐ to 12‐week postpartum glucose testing. Study Design An institutional review board‐approved prospective cohort study was performed over 3 years. Patients underwent an inpatient fasting 75‐g, 2‐hour GTT on either postpartum days 2 through 4 and instructed to follow up in 6‐ to 12‐weeks for postpartum glucose testing. Sensitivity, specificity, positive predictive value (PPV), and negative predictive values (NPV) of the immediate GTT to predict abnormal 6‐ to 12‐week postpartum glucose testing were determined. Results Eighty women enrolled in the study completed the immediate GTT; of these, only 35 (44%) underwent 6‐ to 12‐week postpartum glucose testing. The sensitivity, specificity, PPV, and NPV of the immediate GTT were 100, 42.8, 30.4, and 100%, respectively. Conclusion More than 50% of our study patients did not undergo recommended postpartum glucose testing, coinciding with similar poor follow‐up reported in the literature. With a high NPV and high sensitivity, a negative immediate GTT may obviate the need for the 6‐ to 12‐week GTT, while a positive GTT may identify women who should follow up closely.

Additional file 5: Figure S3. of Amnion as a surrogate tissue reporter of the effects of maternal preeclampsia on the fetus

Genes with local variable HpaII sites. HpaII sites with variable DNA methylation are shown at specific loci with HELP-tagging (angle values = (1 − DNA methylation value)) and corresponding bisulfite MassArray verification results. The var-HpaII track indicates loci that could be analyzed by bisulfite MassArray in red, and those that could not be analyzed in gray (PCR amplification problem or more than 2 CpG sites in a MassArray fragment). The blue loci are those in which the analysis of the amplicon indicated the likely presence of a sequence polymorphism [93]. Top panel: SALL3 region, bottom panel: KCNMA1 region. (PDF 1.33 MB)