Early N-terminal pro-B-type natriuretic peptide is associated with cardiac complications and function during pregnancy in congenital heart disease.

BACKGROUND: Elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels at 20 weeks' gestation predict adverse cardiovascular (CV) complications during pregnancy in women with congenital heart disease (CHD). To improve early risk assessment in these women, we investigated the predictive value of first-trimester NT-proBNP for CV complications and its association with ventricular function during pregnancy. METHODS: Pregnant women with CHD, previously enrolled in a prospective national study or evaluated by an identical protocol, were included. Clinical data, echocardiographic evaluation and NT-proBNP measurements were obtained at 12, 20 and 32 weeks' gestation. Elevated NT-proBNP was defined as > 235 pg/ml (95th percentile reference value of healthy pregnant women in the literature). RESULTS: We examined 126 females (mean age 29 years). Elevated NT-proBNP at 12 weeks was associated with CV complications (n = 7, 5.6%, odds ratio 10.9, p = 0.004). Arrhythmias were the most common complication (71%). The negative predictive value of low NT-proBNP to exclude CV complications was 97.2%. In women with CV complications, NT-proBNP levels remained high throughout pregnancy, while a decrease was seen in women without CV complications (p < 0.001 for interaction between group and time). At 12 weeks, higher NT-proBNP levels were associated with impaired subpulmonary ventricular function (p < 0.001) and also with a decline in subpulmonary ventricular function later in pregnancy (p = 0.012). CONCLUSIONS: In this study, first-trimester NT-proBNP levels were associated with adverse CV complications and a decline in subpulmonary ventricular function later in pregnancy in women with CHD. Early NT-proBNP evaluation is useful for tailored care in pregnant women with CHD.

Maternal right ventricular function, uteroplacental circulation in first trimester and pregnancy outcome in women with congenital heart disease.

OBJECTIVE: Pregnant women with congenital heart disease (CHD) have an increased risk of abnormal uteroplacental flow, measured from the second trimester onwards, which is associated with pregnancy complications affecting the mother and the fetus. Maternal right ventricular (RV) dysfunction has been suggested as a predisposing factor for impaired uteroplacental flow in these women. The aim of this study was to investigate the association of first-trimester uteroplacental flow measurements with prepregnancy maternal cardiac function and pregnancy complications in women with CHD, with particular focus on the potential role of RV (dys)function. METHODS: This study included 138 pregnant women with CHD from the prospective ZAHARA III study (Zwangerschap bij Aangeboren HARtAfwijkingen; Pregnancy and CHD). Prepregnancy clinical and echocardiographic data were collected. Clinical evaluation, echocardiography (focused on RV function, as assessed by tricuspid annular plane systolic excursion (TAPSE)) and uterine artery (UtA) pulsatility index (PI) measurements were performed at 12, 20 and 32 weeks of gestation. Univariable and multivariable regression analyses were performed to assess the association between prepregnancy variables and UtA-PI during pregnancy. The association between UtA-PI at 12 weeks and cardiovascular, obstetric and neonatal complications was also assessed. RESULTS: On multivariable regression analysis, prepregnancy TAPSE was associated negatively with UtA-PI at 12 weeks of gestation (ß = -0.026; P = 0.036). Women with lower prepregnancy TAPSE (≤ 20 mm vs > 20 mm) had higher UtA-PI at 12 weeks (1.5 ± 0.5 vs 1.2 ± 0.6; P = 0.047). Increased UtA-PI at 12 weeks was associated with obstetric complications (P = 0.003), particularly hypertensive disorders (pregnancy-induced hypertension and pre-eclampsia, P = 0.019 and P = 0.026, respectively). CONCLUSIONS: In women with CHD, RV dysfunction before pregnancy seems to impact placentation, resulting in increased resistance in UtA flow, which is detectable as early as in the first trimester. This, in turn, is associated with pregnancy complications. Early monitoring of uteroplacental flow might be of value in women with CHD with pre-existing subclinical RV dysfunction to identify pregnancies that would benefit from close obstetric surveillance. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Uteroplacental Doppler flow and pregnancy outcome in women with tetralogy of Fallot.

OBJECTIVE: Pregnancy in women with surgically corrected tetralogy of Fallot (ToF) is associated with cardiac, obstetric and neonatal complications. We compared uteroplacental Doppler flow (UDF) measurements and pregnancy outcome in women with ToF and in healthy women and aimed to assess whether a relationship exists between cardiac function and UDF in women with ToF. METHODS: We evaluated prospectively pregnant women with ToF and healthy pregnant women from the ZAHARA studies. Clinical evaluation, standardized echocardiography and UDF measurements were performed at 20 and 32 weeks' gestation. RESULTS: We included 62 women with ToF and 69 healthy controls. Cardiac complications, mostly arrhythmia, occurred in 8.1% of women with ToF. There was a higher incidence of small-for-gestational age (21.0% vs 4.4%, P = 0.004) and low birth weight (16.1% vs 2.9%, P = 0.009) in the group of women with ToF than in healthy controls. In women with ToF, early diastolic notching of uterine artery waveform at 20 and 32 weeks occurred more frequently (9.8% vs 1.5%, P = 0.034 and 7.0% vs 0%, P = 0.025, respectively) and the umbilical artery pulsatility index at 32 weeks was higher (1.02 ± 0.20 vs 0.94 ± 0.17, P = 0.015) than in healthy controls. Right ventricular function parameters prepregnancy and at 20 weeks' gestation were significantly associated with abnormal UDF. UDF parameters were associated with adverse neonatal outcome. CONCLUSION: The majority of women with surgically corrected ToF tolerate pregnancy well. However, UDF indices are more frequently abnormal in these women, suggesting impaired placentation. The association of impaired right ventricular function parameters with abnormal UDF suggests that cardiac dysfunction contributes to defective placentation or placental perfusion mismatch and may explain the increased incidence of obstetric and neonatal complications. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

A new paradigm (Westphal-Paradigm) to study the neural correlates of panic disorder with agoraphobia.

Agoraphobia (with and without panic disorder) is a highly prevalent and disabling anxiety disorder. Its neural complexity can be characterized by specific cues in fMRI studies. Therefore, we developed a fMRI paradigm with agoraphobia-specific stimuli. Pictures of potential agoraphobic situations were generated. Twenty-six patients, suffering from panic disorder and agoraphobia, and 22 healthy controls rated the pictures with respect to arousal, valence, and agoraphobia-related anxiety. The 96 pictures, which discriminated best between groups were chosen, split into two parallel sets and supplemented with matched neutral pictures from the International Affective Picture System. Reliability, criterion, and construct validity of the picture set were determined in a second sample (44 patients, 28 controls). The resulting event-related "Westphal-Paradigm" with cued and uncued pictures was tested in a fMRI pilot study with 16 patients. Internal consistency of the sets was very high; parallelism was given. Positive correlations of picture ratings with Mobility Inventory and Hamilton anxiety scores support construct validity. FMRI data revealed activations in areas associated with the fear circuit including amygdala, insula, and hippocampal areas. Psychometric properties of the Westphal-Paradigm meet necessary quality requirements for further scientific use. The paradigm reliably produces behavioral and fMRI patterns in response to agoraphobia-specific stimuli. To our knowledge, it is the first fMRI paradigm with these properties. This paradigm can be used to further characterize the functional neuroanatomy of panic disorder and agoraphobia and might be useful to contribute data to the differentiation of panic disorder and agoraphobia as related, but conceptually different clinical disorders.

AKT/GSK-3beta/beta-catenin signalling within hippocampus and amygdala reflects genetically determined differences in posttraumatic stress disorder like symptoms.

Only a small percentage of individuals develop posttraumatic stress disorder (PTSD) in the aftermath of a trauma. It is still largely unknown to what extent gene-environment interactions contribute to the inter-individual differences in PTSD susceptibility and resilience and what cellular processes may underlie long-term maintenance of the disorder. Here we employed a mouse model of PTSD to unravel the contribution of genetic background and maternal influences on long-lasting changes in kinase and transcription factor activities in PTSD-susceptible C57BL/6NCrl (B6N) and resilient C57BL/6JOlaHsd (B6JOla) mice. Mice received an inescapable foot shock and were tested for activity changes in the AKT/GSK-3beta/beta-catenin-pathway in specific brain structures 42 days later. To control for prenatal and postnatal environmental (i.e. maternal) factors part of the experiments were performed with animals originating from within-strain and between-strain embryo transfers. In PTSD-susceptible B6N mice, long-term maintenance of contextual and sensitized fear was accompanied by (i) increased levels of phosphorylated AKT within the dorsal hippocampus and (ii) higher levels of phosphorylated AKT and GSK-3beta and increased beta-catenin levels within the basolateral amygdala. In animals originating from embryo transfers, levels of phosphorylated GSK-3beta and of beta-catenin were decreased in the dorsal hippocampus, but increased in the basolateral amygdala of shocked B6N mice compared to shocked B6JOla mice. This was independent of the genotype of the recipient mothers. At the behavioural level, these differences coincided with sustained sensitized and more pronounced contextual fear of B6N compared to B6JOla mice. Taken together our study identifies lasting changes in the AKT/GSK-3beta/beta-catenin cascade within the hippocampus and amygdala as molecular correlates of genetically determined differences in the severity of PTSD-like symptoms.

The trigonometric responder approach: a new method for detecting responders to pharmacological or experimental challenges.

The paper presents a newly developed response measure that is particularly suitable for the evaluation of pharmacokinetic data. This method is based on trigonometric considerations, defining a hormone response as the difference between the angle of the slope of the curve before and after drug intake. In addition, the size of this difference is compared to the difference obtained in placebo conditions. In this way, the trigonometric response measure overcomes one of the most problematic shortcomings of the 'area under the curve' (AUC) approach, the problem of the initial value. We will present the mathematical background of the trigonometric method and demonstrate its usefulness by evaluating empirical data (a pharmacological challenge test using the dopamine agonist lisuride) and comparing it to classical AUC measures. This has been achieved by contrasting both approaches with responder definitions according to binary time series analysis and the peak value of the curve.

Loss of Drs2p does not abolish transfer of fluorescence-labeled phospholipids across the plasma membrane of Saccharomyces cerevisiae.

The yeast DRS2 gene, which is required for growth at 23 degreesC or below, encodes a member of a P-type ATPase subgroup reported to transport aminophospholipids between the leaflets of the plasma membrane. Here, we evaluated the potential role of Drs2p in phospholipid transport. When examined by fluorescence microscopy, a drs2 null mutant showed no defect in the uptake or distribution of fluorescent-labeled 1-palmitoyl-2[6-(7-nitrobenz-2-oxa-1, 3-diazol-4-yl (NBD))aminocaproyl]phosphatidylserine) or 1-myristoyl-2[6-NBD-aminocaproyl]phosphatidylethanolamine. Quantification of the amount of cell-associated NBD fluorescence using flow cytometry indicated a significant decrease in the absence of Drs2p, but this decrease was not restricted to the aminophospholipids (phosphatidylserine and phosphatidylethanolamine) and was dependent on culture conditions. Furthermore, the absence of Drs2p had no effect on the amount of endogenous PE exposed to the outer leaflet of the plasma membrane as detected by labeling with trinitrobenzene sulfonic acid. The steady state pool of Drs2p, which was shown to reside predominantly in the plasma membrane, increased upon shift to low temperature or exposure to various divalent cations (Mn2+, Co2+, Ni2+, and Zn2+ but not Ca2+ or Mg2+), conditions that also inhibited the growth of a drs2 null mutant. The data presented here call into question the identification of Drs2p as the exclusive or major aminophospholipid translocase in yeast plasma membranes (Tang, X., Halleck, M. S., Schlegel, R. A., and Williamson, P. (1996) Science 272, 1495-1497).

[Candida and the gastrointestinal tract. A medical-research evaluation]. / Candida und der Intestinaltrakt. Eine medizinisch-wissenschaftliche Bewertung.

In immunocompetent persons, Candida species are members of the normal flora of the gastrointestinal tract. Budding yeasts, in particular Candida albicans, can, however, in patients with a corresponding disposition, spread topically and systemically, that is, they may become pathogenic. In hematological/oncological patients with severe immunodeficiency, for example, the mycelium may infiltrate the muscularis mucosae, with involvement also of the vascular system. The relationships between recurrent diarrhea and Candida are still discussed controversial; various data do, however, suggest that massive colonization with Candida might well represent a(n additional) diarrhea-provoking factor. Similar considerations may also be assumed to apply to diarrhea induced by antibiotic therapy. For immunocompetent persons, guidelines exist for the yeast cell count in the stools. The interpretation of quantitative findings must, however, always be made on an individual basis and against the background of clinical symptoms and/or any particular predisposition of the patient. Reliable treatment of superficial candidasis can be achieved with oral polyene antifungal antibiotics (nystatin, amphotericin B).

Solid phase organic synthesis (SPOS): a novel route to diketopiperazines and diketomorpholines.

The solid phase synthesis of libraries containing a 1,3,4,6-tetrasubstituted-2,5-diketo-1,4-piperazine scaffold (DKP) or a 3,4,6-trisubstituted-2,5-diketo-1,4-morpholine scaffold (DKM) from alpha-bromocarboxylic acids and amines is described. Using a design strategy which we refer to as divergent library design, both templates were prepared from a common intermediate. The general utility of this synthetic route in creating novel, non-peptidyl chemical libraries is discussed.