NKX2-5 regulates the expression of beta-catenin and GATA4 in ventricular myocytes.

BackgroundThe molecular pathway that controls cardiogenesis is temporally and spatially regulated by master transcriptional regulators such as NKX2-5, Isl1, MEF2C, GATA4, and beta-catenin. The interplay between these factors and their downstream targets are not completely understood. Here, we studied regulation of beta-catenin and GATA4 by NKX2-5 in human fetal cardiac myocytes.Methodology/principal findingsUsing antisense inhibition we disrupted the expression of NKX2-5 and studied changes in expression of cardiac-associated genes. Down-regulation of NKX2-5 resulted in increased beta-catenin while GATA4 was decreased. We demonstrated that this regulation was conferred by binding of NKX2-5 to specific elements (NKEs) in the promoter region of the beta-catenin and GATA4 genes. Using promoter-luciferase reporter assay combined with mutational analysis of the NKEs we demonstrated that the identified NKX2-5 binding sites were essential for the suppression of beta-catenin, and upregulation of GATA4 by NKX2-5.ConclusionsThis study suggests that NKX2-5 modulates the beta-catenin and GATA4 transcriptional activities in developing human cardiac myocytes

Tricuspid valve disease with significant tricuspid insufficiency in the fetus: Diagnosis and outcome

AbstractThe echocardiographic studies and clinical course of 27 fetuses (mean gestationl age 26.9 weeks) diagnosed in utero with tricuspid valve disease and significant tricuspid regurgitation were reviewed. The diagnosis of Ebstein's anomaly was made in 17 of the fetuses, 7 had tricuspid valve dysplasia with poorly developed but normally attached leaflets and 2 had an unguarded tricuspid valve orifice with little or no identifiable tricuspid tissue. One fetus was excluded from data analysis because a more complex heart lesion was documented at autopsy. All fetuses had massive right atrial dilation and most who were serially studied had progressive right-sided cardiomegaly. Hydrops fetalis was found in six cases and atrial flutter in five.Associated cardiac lesions included pulmonary stenosis in five cases and pulmonary alresia in six. Four fetuses with normal forward pulmonary artery flow at the initial examination were found at subsequent study to have retrograde pulmonary artery and ductal flow in association with the development of pulmonary stenosis (n = 1) and pulmonary atresia (n = 3). On review of the clinical course of the 23 fetuses (excluding 3 with elective abortion), 48% of the fetuses died in utero and 35% who were liveborn died despite vigorous medical and, when necessary, surgical management, many of whom had severe congestive heart failure. Of the four infants who survived the neonatal period, three had a benign neonatal course, all of whom were diagnosed with mild to moderate Ebstein's anomaly; only one had pulmonary outflow obstruction. An additional finding at autopsy was significant lung hypoplasia documented in 10 of 19 autopsy reports.Tricuspid valve anomalies with tricuspid insufficiency can be identified echocardiographically in the fetus and should be searched for in the presence of right atrial enlargement. The prognosis for the fetus diagnosed in utero with significant tricuspid valve disease is extremely poor, with a prenatal course that includes progressive right heart dilation, with cardiac failure and lung hypoplasia in many and development of pulmonary stenose or pulmonary atresia later in gestation in some

Depressed Left and Right Ventricular Cardiac Output in Fetuses of Diabetic Mothers

INTRODUCTION: We compared right and left ventricular cardiac output (RVCO and LVCO) in fetuses of diabetic mothers (FDM) to a large normal cohort. METHODS: We prospectively enrolled 264 normal fetuses and 30 FDM. Fetal CO parameters: semilunar valve velocity time integrals (AVVTI, PVVTI), ventricular outflow diameters (LVOTD, RVOTD), stroke volumes (AVSV, PVSV) were measured, and LVCO and RVCO calculated. These were normalized using nonlinear regression to estimated fetal weight (EFW) to provide means and standard deviations. Among FDMs, mean Z-scores and 95% confidence limits (CL) were calculated, and compared to zero. RESULTS: LVCO, RVCO, and parameters they were calculated from, increased predictably and non-linearly with increasing EFW. In FDM, LVCO was depressed (mean Z -1.679, 95% CL -2.404, -0.955, p CONCLUSION: Normal biventricular stroke volumes and outputs follow a nonlinear regression with EFW. FDM have significantly lower right and left heart stroke volumes and outputs for weight than do normal fetuses

Persistent Aortic Stiffness and Left Ventricular Hypertrophy in Children of Diabetic Mothers

Publisher Copyright: © 2020 Canadian Cardiovascular SocietyBackground: Fetuses of diabetic mothers develop left ventricular (LV) hypertrophy and are at increased long-term risk of cardiovascular disease. In our previous longitudinal study from midgestation to late infancy we showed persistence of LV hypertrophy and increased aortic stiffness compared with infants of healthy mothers, the latter of which correlated with third trimester maternal hemoglobin A1c. In the present study, we reexamined the same cohort in early childhood to determine if these cardiovascular abnormalities persisted. Methods: Height, weight, and right arm blood pressure were recorded. A full functional and structural echocardiogram was performed with offline analysis of LV posterior wall and interventricular septal diastolic thickness (IVSd), systolic and diastolic function, and aortic pulse wave velocity. Vascular reactivity was assessed using digital thermal monitoring. Participants also completed a physical activity questionnaire. Results: Twenty-five children of diabetic mothers (CDMs) and 20 children from healthy pregnancies (mean age, 5.6 ± 1.7 and 5.3 ± 1.3 years, respectively; P = not significant) were assessed. Compared with controls, IVSd z score was increased in CDMs (1.2 ± 0.6 vs 0.5 ± 0.3, respectively; P = 0.006), with one-fifth having a z score of more than +2.0. Aortic pulse wave velocity was increased in CDMs (3.2 ± 0.6 m/s vs 2.2 ± 0.4 m/s; P = 0.001), and correlated with IVSd z score (R2 = 0.81; P = 0.001) and third trimester maternal A1c (R2 = 0.65; P < 0.0001). Body surface area, height, weight, blood pressure, vascular reactivity, and physical activity scores did not differ between groups. Our longitudinal analysis showed that individuals with greater IVSd, and aortic stiffness in utero, early and late infancy also tended to have greater measures in early childhood (P < 0.001 and P < 0.0001, respectively). Conclusions: CDMs show persistently increased interventricular septal thickness and aortic stiffness in early childhood.Peer reviewe

Electrophysiological evidence for flexible goal-directed cue processing during episodic retrieval

A widely held assumption is that memory retrieval is aided by cognitive control processes that are engaged flexibly in service of memory retrieval and memory decisions. While there is some empirical support for this view, a notable exception is the absence of evidence for the flexible use of retrieval control in functional neuroimaging experiments requiring frequent switches between tasks with different cognitive demands. This absence is troublesome in so far as frequent switches between tasks mimic some of the challenges that are typically placed on memory outside the laboratory. In this experiment we instructed participants to alternate frequently between three episodic memory tasks requiring item recognition or retrieval of one of two different kinds of contextual information encoded in a prior study phase (screen location or encoding task). Event-related potentials (ERPs) elicited by unstudied items in the two tasks requiring retrieval of study context were reliably different, demonstrating for the first time that ERPs index task-specific processing of retrieval cues when retrieval goals change frequently. The inclusion of the item recognition task was a novel and important addition in this study, because only the ERPs elicited by unstudied items in one of the two context conditions diverged from those in the item recognition condition. This outcome constrains functional interpretations of the differences that emerged between the two context conditions and emphasises the utility of this baseline in functional imaging studies of retrieval processing operations

A network model of language policy and planning: The United Nations as a case study

This paper contributes to recent critical discussion of ‘agency’ in LPP research and practice. It argues that whilst scholars have widened their purview to consider the impact of individual actors on LPP in different contexts, the field has not developed or embraced theoretical and methodological frameworks which satisfactorily model or investigate the network of actor impact on LPP. This article analyses the current status of LPP at the United Nations (UN). Taking the ‘Actor-Stage Model’ (Zhao & Baldauf, 2012) as a theoretical point of departure, the paper discusses and analyses the most recent review of LPP within the UN. It becomes apparent that a network of agents is responsible for LPP development, influence and implementation within the organisation. This ‘web of influence’ is schematised using a network model which accounts for the implicit and explicit responsibility of multiple actors/’experts’ within and outside of the organisation. A sub-analysis of institutional LPP goals reveals the ‘polycentric’ and ‘relational’ nature of influence within and across multiple ’nodes’. It is argued that the network model and the concept of ‘web of influence’ is crucial in de- and re-constructing particular LPP goals and serves as a useful heuristic for those investigating or working within similar sites of inter/transnational integration as well as LPP in other macro, meso or micro-contexts

Intrauterine exposure to chronic hypoxia in the rat leads to progressive diastolic function and increased aortic stiffness from early postnatal developmental stages

Aim We sought to explore whether fetal hypoxia exposure, an insult of placental insufficiency, is associated with left ventricular dysfunction and increased aortic stiffness at early postnatal ages. Methods Pregnant Sprague Dawley rats were exposed to hypoxic conditions (11.5% FiO2) from embryonic day E15‐21 or normoxic conditions (controls). After delivery, left ventricular function and aortic pulse wave velocity (measure of aortic stiffness) were assessed longitudinally by echocardiography from day 1 through week 8. A mixed ANOVA with repeated measures was performed to compare findings between groups across time. Myocardial hematoxylin and eosin and picro‐sirius staining were performed to evaluate myocyte nuclear shape and collagen fiber characteristics, respectively. Results Systolic function parameters transiently increased following hypoxia exposure primarily at week 2 (p \u3c .008). In contrast, diastolic dysfunction progressed following fetal hypoxia exposure beginning weeks 1–2 with lower early inflow Doppler velocities, and less of an increase in early to late inflow velocity ratios and annular and septal E’/A’ tissue velocities compared to controls (p \u3c .008). As further evidence of altered diastolic function, isovolumetric relaxation time was significantly shorter relative to the cardiac cycle following hypoxia exposure from week 1 onward (p \u3c .008). Aortic stiffness was greater following hypoxia from day 1 through week 8 (p \u3c .008, except week 4). Hypoxia exposure was also associated with altered nuclear shape at week 2 and increased collagen fiber thickness at week 4. Conclusion Chronic fetal hypoxia is associated with progressive LV diastolic dysfunction, which corresponds with changes in nuclear shape and collagen fiber thickness, and increased aortic stiffness from early postnatal stages

Cardiovascular Health of Offspring of Diabetic Mothers From the Fetal Through Late-Infancy Stages

Non peer reviewe

Prenatal Diagnosis Improves the Postnatal Cardiac Function in a Population-Based Cohort of Infants with Hypoplastic Left Heart Syndrome

Background: Prenatal diagnosis of hypoplastic left heart syndrome (HLHS) enables planning of perinatal care and is known to be associated with more stable preoperative hemodynamics. The impact on postnatal myocardial function is poorly known. The aim of this study was to determine the impact of prenatal diagnosis of HLHS on postnatal myocardial function.Methods: A consecutively encountered cohort of 66 infants with HLHS born between 2003 and 2010 in Finland was retrospectively reviewed. Twenty-five infants had prenatal diagnoses. Postnatal global and segmental right ventricular fractional area change, strain rate, and myocardial velocity were analyzed from the apical four-chamber view using Velocity Vector Imaging. Preoperative hemodynamic status and end-organ damagemeasurements were the lowest arterial pH, highest lactate, alanine aminotransferase, and creatinine. Early mortality was studied until 30 days after Norwood procedure.Results: Prenatally diagnosed infants had better cardiac function (fractional area change, 27.9 &plusmn; 7.4% vs 21.1 &plusmn; 6.3%, P = .0004; strain rate, 1.1 &plusmn; 0.6/1.3 &plusmn; 1.0 vs 0.7 &plusmn; 0.2/0.7 &plusmn; 0.3 1/sec, P = .004/.003; myocardial velocity, 1.6 &plusmn; 0.6/2.0 &plusmn; 1.1 vs 1.3 &plusmn; 0.4/1.4 &plusmn; 0.4 cm/sec, P = .0035/.0009). Mechanical dyssynchrony was similar in both groups (P &gt; .30). Infants diagnosed prenatally had less acidosis (pH = 7.30 vs 7.25, P = .005) and end-organ dysfunction (alanine aminotransferase, 33 &plusmn; 38 vs 139 &plusmn; 174 U/L, P = .0001;creatinine, 78 &plusmn; 18 vs 81 &plusmn; 44 mmol/L, P = .05). No deaths occurred among the prenatally diagnosed infants, but four deaths were recorded among postnatally diagnosed infants (P = .15).Conclusions: A prenatal diagnosis of HLHS is associated with improved postnatal right ventricular function, reduced metabolic acidosis, and end-organ dysfunction. (J Am Soc Echocardiogr 2013;26:1073-9.)Keywords: Hypoplastic left heart syndrome, Prenatal diagnosis, Cardiac function, Velocity Vector Imaging<br /

Challenges and Opportunities in the Hydrologic Sciences

This is the Table of Contents and Introduction of a Report published as Hornberger, G. M., E. Bernhardt, W. E. Dietrich, D. Entekhabi, G. E. Fogg, E. Foufoula-Georgiou, W. J. Gutowski, W. B. Lyons, K. W. Potter, S. W. Tyler, H. J. Vaux, C. J. Vorosmarty, C. Welty, C. A. Woodhouse, C. Zheng, Challenges and Opportunities in the Hydrologic Sciences. 2012: Water Science and Technology Board, Division on Earth and Life Studies, National Academy of Sciences, Washington, DC. 173 pp. Posted with permission.</p