D-Transposition of the great arteries with restrictive foramen ovale in the fetus: the dilemma of predicting the need for postnatal urgent balloon atrial septostomy.

OBJECTIVE: Restrictive foramen ovale (FO) in dextro-transposition of the great arteries (d-TGA) with intact ventricular septum may lead to severe life-threatening hypoxia within the first hours of life, making urgent balloon atrial septostomy (BAS) inevitable. Reliable prenatal prediction of restrictive FO is crucial in these cases. However, current prenatal echocardiographic markers show low predictive value, and prenatal prediction often fails with fatal consequences for a subset of newborns. In this study, we described our experience and aimed to identify reliable predictive markers for BAS. METHODS: We included 45 fetuses with isolated d-TGA that were diagnosed and delivered between 2010 and 2022 in two large German tertiary referral centers. Inclusion criteria were the availability of former prenatal ultrasound reports, of stored echocardiographic videos and still images, which had to be obtained within the last 14 days prior to delivery and that were of sufficient quality for retrospective re-analysis. Cardiac parameters were retrospectively assessed and their predictive value was evaluated. RESULTS: Among the 45 included fetuses with d-TGA, 22 neonates had restrictive FO postnatally and required urgent BAS within the first 24 h of life. In contrast, 23 neonates had normal FO anatomy, but 4 of them unexpectedly showed inadequate interatrial mixing despite their normal FO anatomy, rapidly developed hypoxia and also required urgent BAS ('bad mixer'). Overall, 26 (58%) neonates required urgent BAS, whereas 19 (42%) achieved good O2 saturation and did not undergo urgent BAS. In the former prenatal ultrasound reports, restrictive FO with subsequent urgent BAS was correctly predicted in 11 of 22 cases (50% sensitivity), whereas a normal FO anatomy was correctly predicted in 19 of 23 cases (83% specificity). After current re-analysis of the stored videos and images, we identified three highly significant markers for restrictive FO: a FO diameter < 7 mm (p < 0.01), a fixed (p = 0.035) and a hypermobile (p = 0.014) FO flap. The maximum systolic flow velocities in the pulmonary veins were also significantly increased in restrictive FO (p = 0.021), but no cut-off value to reliably predict restrictive FO could be identified. If the above markers are applied, all 22 cases with restrictive FO and all 23 cases with normal FO anatomy could correctly be predicted (100% positive predictive value). Correct prediction of urgent BAS also succeeded in all 22 cases with restrictive FO (100% PPV), but naturally failed in 4 of the 23 cases with correctly predicted normal FO ('bad mixer') (82.6% negative predictive value). CONCLUSION: Precise assessment of FO size and FO flap motility allows a reliable prenatal prediction of both restrictive and normal FO anatomy postnatally. Prediction of likelihood of urgent BAS also succeeds reliably in all fetuses with restrictive FO, but identification of the small subset of fetuses that also requires urgent BAS despite their normal FO anatomy fails, because the ability of sufficient postnatal interatrial mixing cannot be predicted prenatally. Therefore, all fetuses with prenatally diagnosed d-TGA should always be delivered in a tertiary center with cardiac catheter stand-by, allowing BAS within the first 24 h after birth, regardless of their predicted FO anatomy.

Single-center outcome analysis of 46 fetuses with megacystis after intrauterine vesico-amniotic shunting with the Somatex®intrauterine shunt.

OBJECTIVES: To assess the spectrum of underlying pathologies, the intrauterine course and postnatal outcome of 46 fetuses with megacystis that underwent intrauterine vesico-amniotic shunting (VAS) with the Somatex® shunt in a single center. METHODS: Retrospective analysis of 46 fetuses with megacystis that underwent VAS either up to 14 + 0 weeks (early VAS), between 14 + 1 and 17 + 0 weeks (intermediate VAS) or after 17 + 0 weeks of gestation (late VAS) in a single tertiary referral center. Intrauterine course, underlying pathology and postnatal outcome were assessed and correlated with the underlying pathology and gestational age at first VAS. RESULTS: 46 fetuses underwent VAS, 41 (89%) were male and 5 (11%) were female. 28 (61%) fetuses had isolated and 18 (39%) had complex megacystis with either aneuploidy (n = 1), anorectal malformations (n = 6), cloacal malformations (n = 3), congenital anomalies overlapping with VACTER association (n = 6) or Megacystis-Microcolon Intestinal-Hypoperistalsis Syndrome (MMIHS) (n = 2). The sonographic 'keyhole sign' significantly predicted isolated megacystis (p < 0.001). 7 pregnancies were terminated, 4 babies died in the neonatal period, 1 baby died at the age of 2.5 months and 34 (74%) infants survived until last follow-up. After exclusion of the terminated pregnancies, intention-to-treat survival rate was 87%. Mean follow-up period was 24 months (range 1-72). The underlying pathology was highly variable and included posterior urethral valve (46%), hypoplastic or atretic urethra (35%), MMIHS or prune belly syndrome (10%) and primary vesico-ureteral reflux (2%). In 7% no pathology could be detected postnatally. No sonographic marker was identified to predict the underlying pathology prenatally. 14 fetuses underwent early, 24 intermediate and 8 late VAS. In the early VAS subgroup, amnion infusion prior to VAS was significantly less often necessary (7%), shunt complications were significantly less common (29%) and immediate kidney replacement therapy postnatally became less often necessary (0%). In contrast, preterm delivery ≤ 32 + 0 weeks was more common (30%) and survival rate was lower (70%) after early VAS compared to intermediate or late VAS. Overall, 90% of liveborn babies had sufficient kidney function without need for kidney replacement therapy until last follow-up, and 95% had sufficient pulmonary function without need for mechanical respiratory support. 18% of babies with complex megacystis suffered from additional health restrictions due to their major concomitant malformations. CONCLUSIONS: Our data suggest that VAS is feasible from the first trimester onward. Early intervention has the potential to preserve neonatal kidney function in the majority of cases and enables neonatal survival in up to 87% of cases. Despite successful fetal intervention, parents should be aware of the potential of mid- or long-term kidney failure and of additional health impairments due to concomitant extra-renal anomalies that cannot be excluded at time of intervention.

Prenatal diagnosis, associated findings and postnatal outcome of fetuses with truncus arteriosus communis (TAC).

PURPOSE: To assess the spectrum of associated anomalies, the intrauterine course, postnatal outcome and management of fetuses with truncus arteriosus communis (TAC) METHODS: All cases of TAC diagnosed prenatally over a period of 8 years were retrospectively collected in two tertiary referral centers. All additional prenatal findings were assessed and correlated with the outcome. The accuracy of prenatal diagnosis was assessed. RESULTS: 39 cases of TAC were diagnosed prenatally. Mean gestational age at first diagnosis was 22 weeks (range, 13-38). Two cases were lost follow-up. Correct prenatal diagnosis of TAC was made in 21 of 24 (87.5%) cases and of TAC subtype in 19 of 21 (90.5%) cases. Prenatal diagnosis of TAC was incorrect in three cases: one newborn had aortic atresia with ventricular septal defect postnatally, one had hypoplastic right ventricle with dextro Transposition of the Great Arteries with coartation of the aorta and a third newborn had Tetralogy of Fallot with abnormal origin of the left pulmonary artery arising from the ascending aorta postnatally. These three cases were excluded from further analysis. In 9 of 34 (26.5%) cases, TAC was an isolated finding. 13 (38.2%) fetuses had additional chromosomal anomalies. Among them, microdeletion 22q11.2 was most common with a prevalence of 17.6% in our cohort. Another 3 fetuses were highly suspicious for non-chromosomal genetic syndromes due to their additional extra-cardiac anomalies, but molecular diagnosis could not be provided. Major cardiac and extra-cardiac anomalies occurred in 3 (8.8%) and in 20 (58.8%) cases, respectively. Predominantly, extra-cardiac anomalies occurred in association with chromosomal anomalies. Additionally, severe IUGR occurred in 6 (17.6%) cases. There were 14 terminations of pregnancy (41.2%), 1 (2.9%) intrauterine fetal death, 5 postnatal deaths (14.7%) and 14 (41.2%) infants were alive at last follow-up. Intention-to-treat survival rate was 70%. Mean follow-up among survivors was 42 months (range, 6-104). Postoperative health status among survivors was excellent in 11 (78.6%) infants, but 5 (46.2%) of them needed repeated re-interventions due to recurrent pulmonary artery or conduit stenosis. The other 3 (21.4%) survivors were significantly impaired due to non-cardiac problems. CONCLUSION: TAC is a rare and complex cardiac anomaly that can be diagnosed prenatally with high precision. TAC is frequently associated with chromosomal and extra-cardiac anomalies, leading to a high intrauterine and postnatal loss rate due to terminations and perioperative mortality. Without severe extra-cardiac anomalies, postoperative short- and medium-term health status is excellent, independent of the subtype of TAC, but the prevalence of repeated interventions due to recurrent stenosis is high.

Prenatal diagnosis, associated findings and postnatal outcome of fetuses with truncus arteriosus communis (TAC).

PURPOSE: To assess the spectrum of associated anomalies, the intrauterine course, postnatal outcome and management of fetuses with truncus arteriosus communis (TAC) METHODS: All cases of TAC diagnosed prenatally over a period of 8 years were retrospectively collected in two tertiary referral centers. All additional prenatal findings were assessed and correlated with the outcome. The accuracy of prenatal diagnosis was assessed. RESULTS: Thirty nine cases of TAC were diagnosed prenatally. Mean gestational age at first diagnosis was 22 weeks (range 13-38). Two cases were lost follow-up. Correct prenatal diagnosis of TAC was made in 87.5% and of TAC subtype in 90.5%. Prenatal diagnosis was incorrect in three cases: one newborn had aortic atresia with ventricular septal defect (VSD) postnatally, one had hypo-plastic right ventricle with dextro transposition of the great arteries (d-TGA) with coarctation of the aorta and a third newborn had tetralogy of fallot (TOF) with abnormal origin of the left pulmonary artery arising from the ascending aorta postnatally. These 3 cases were excluded from further analysis. In 26.5% of cases, TAC was an isolated finding. 38.2% of fetuses had additional chromosomal anomalies. Among them, microdeletion 22q11.2 was most common with a prevalence of 17.6% in our cohort. Another 3 fetuses were highly suspicious for non-chromosomal genetic syndromes due to their additional extra-cardiac anomalies, but molecular diagnosis could not be provided. Major cardiac and extra-cardiac anomalies occurred in between 8.8% and 58.8%, respectively. Predominantly, extra-cardiac anomalies occurred in association with chromosomal anomalies. Additionally, severe IUGR occurred in 17.6%. There were 14 terminations of pregnancy (41.2%), 1 (2.9%) intrauterine fetal death, 5 postnatal deaths (14.7%) and 14 (41.2%) infants were alive at last follow-up. Intention-to-treat survival rate was 70%. Mean follow-up among survivors was 42 months (range 6-104). Postoperative health status among survivors was excellent in 78.6%, but 46.2% needed repeated re-interventions due to recurrent pulmonary artery or conduit stenosis. The other 21.4% of survivors were significantly impaired due to non-cardiac problems. CONCLUSION: Truncus arteriosus communis is a rare and complex cardiac anomaly that can be diagnosed prenatally with high precision. TAC is frequently associated with chromosomal and extra-cardiac anomalies, leading to a high intrauterine and postnatal loss rate due to terminations and perioperative mortality. Without severe extra-cardiac anomalies, postoperative health status is excellent, independent of the subtype of TAC, but the prevalence of repeated interventions due to recurrent stenosis is high.

Sertraline associated with gold nanoparticles reduce cellular toxicity and induce sex-specific responses in behavior and neuroinflammation biomarkers in a mouse model of anxiety.

This study aimed to evaluate the effects of sertraline associated with gold nanoparticles (AuNPs) in vitro cell viability and in vivo behavior and inflammatory biomarkers in a mouse model of anxiety. Sertraline associated with AuNPs were synthesized and characterized. For the in vitro study, NIH3T3 and HT-22 cells were treated with different doses of sertraline, AuNPs, and sertraline + AuNPs and their viability was evaluated using the MTT assay. For the in vivo study, pregnant Swiss mice were administered a single dose of lipopolysaccharide (LPS) on the ninth day of gestation. The female and male offspring were divided into five treatment groups on PND 60 and administered chronic treatment for 28 days. The animals were subjected to behavioral testing and were subsequently euthanized. Their brains were collected and analyzed for inflammatory biomarkers. Sertraline associated with AuNPs exhibited significant changes in surface characteristics and increased diameters. Different doses of sertraline + AuNPs showed higher cell viability in NIH3T3 and HT-22 cells compared with sertraline alone. The offspring of LPS-treated dams exhibited anxiety-like behavior and neuroinflammatory biomarker changes during adulthood, which were ameliorated via sertraline + AuNPs treatment. The treatment response was sex-dependent and brain region-specific. These results suggest that AuNPs, which demonstrate potential to bind to other molecules, low toxicity, and reduced inflammation, can be synergistically used with sertraline to improve drug efficacy and safety by decreasing neuroinflammation and sertraline toxicity.

Selenium-containing chrysin and quercetin derivatives: attractive scaffolds for cancer therapy.

Selenium-containing chrysin (SeChry) and 3,7,3',4'-tetramethylquercetin (SePQue) derivatives were synthesized by a microwave-based methodology. In addition to their improvement in terms of DPPH scavenging and potential GPx-like activities, when tested in a panel of cancer cell lines both selenium-derivatives revealed consistently to be more cytotoxic when compared with their oxo and thio-analogues, evidencing the key role of selenocabonyl moiety for these activities. In particular, SeChry elicited a noteworthy cytotoxic activity with mean IC50 values 18- and 3-fold lower than those observed for chrysin and cisplatin, respectively. Additionally, these seleno-derivatives evidenced an ability to overcome cisplatin and multidrug resistance. Notably, a differential behavior toward malignant and nonmalignant cells was observed for SeChry and SePQue, exhibiting higher selectivity indexes when compared with the chalcogen-derivatives and cisplatin. Our preliminary investigation on the mechanism of cytotoxicity of SeChry and SePQue in MCF-7 human mammary cancer cells demonstrated their capacity to efficiently suppress the clonal expansion along with their ability to hamper TrxR activity leading to apoptotic cell death.

Transient spectroscopy of ninhydrin.

The photochemistry of ninhydrin in benzene and water was studied by laser flash photolysis and electron paramagnetic resonance. Its photochemistry was shown to be dependent on the solvent. In benzene, a triplet excited state was observed, which underwent hydrogen abstraction reactions or reduction to the radical anion. In water, the radical anion of ninhydrin was formed within the laser pulse (15 ns) at neutral pH, whereas the neutral ketyl radical was formed by protonation of the radical anion at low pH. A pKa of 0.77 was determined for the protonation equilibrium. The formation of hydrindantin is proposed to occur through the dimerization of the ketyl radical or the radical anion (or both). In addition, ninhydrin was shown to be a poor precursor for the photogeneration of hydroxyl radicals.

Antioxidant mechanisms of Quercetin and Myricetin in the gas phase and in solution--a comparison and validation of semi-empirical methods.

Flavonoids have long been recognized for their general health-promoting properties, of which their antioxidant activity may play an important role. In this work we have studied the properties of two flavonols, quercetin and myricetin, using semi-empirical methods in order to validate the application of the recent Parametric Model 6 and to understand the fundamental difference between the two molecules. Their geometries have been optimized and important molecular properties have been calculated. The energetic of the possible antioxidant mechanisms have also been analyzed. The two studied flavonols do not differ significantly in their molecular properties, but the antioxidant mechanisms by which they may act in solution can be rather different. Moreover, we also show that the Parametric Model 6 can produce reliable information for this type of compounds.

Demethylation of theophylline (1,3-dimethylxanthine) to 1-methylxanthine: the first step of an antioxidising cascade.

The reaction of theophylline with HO(*) radical, produced by photolytic methods at pH 7, was studied in aqueous solution and the products characterised by HPLC and GC-MS. In addition to the expected 1,3-dimethyluric acid, the formation of 1-methylxanthine and, to a lesser extent, of 3-methylxanthine was observed. Theoretical calculations confirmed the preferred formation of the former compound. Both demethylated products were also observed upon reaction of theophylline with O(*-) radical anion at pH approximately 13, and 1-methylxanthine was consumed faster than 3-methylxanthine after its formation. Molecular oxygen had no significant effect on the formation of the mono-methylxanthine derivatives. A reaction mechanism for the demethylation of theophylline by oxidising radicals is proposed. This demethylation reaction can play an important role in the protection of biological targets against oxidative stress as the first step of an antioxidising cascade.

Scavenging activity of aminoantipyrines against hydroxyl radical.

The pyrazolone derivatives antipyrine and 4-(N,N-dimethyl)-aminoantipyrine (aminopyrine) have long been used as analgesic, antipyretic and anti-inflammatory drugs. However, in spite of its recognized therapeutic benefits, the use of pyrazolones has been associated with agranulocytosis. Though the oxidation of aminopyrine by neutrophil-generated hypochlorous acid (HOCl), leading to the formation of a cation radical, has been considered responsible for the potential bone marrow toxicity, the reaction mechanisms of pyrazolones against other reactive oxygen species (ROS) remains elusive. Thus, the reactions of 4-aminoantipyrine and methylated derivatives with hydroxyl radicals (HO*) were studied as a model of their reactivity against ROS. The results show that 4-(N,N-dimethyl)-aminoantipyrine (aminopyrine) undergoes demethylation when reacting with HO. radical, leading to 4-(N-methyl)-aminoantipyrine, which is further demethylated to 4-aminoantipyrine. In addition, it was also observed that another favorable reaction of 4-aminoantipyrines in these conditions is the hydroxylation on the aromatic ring, a reaction that is common to aminopyrine, 4-(N-methyl)-aminoantipyrine, and 4-aminoantipyrine. Whether these reaction mechanisms give rise to harmful reactive intermediates requires further chemico-biological evaluation.

Structure and redox properties of radicals derived from one-electron oxidised methylxanthines.

The repair of the one electron oxidised form of a xanthine derivative by another xanthine derivative was studied by reacting aqueous binary mixtures of xanthine derivatives with sulphate radical anion (SO(4)( -)) and following the concentration of both compounds as a function of time. The relative behaviour observed enabled the establishment of a qualitative order of antioxidant capacities for the several xanthines studied in acidic and neutral media. The same order was confirmed quantitatively by measuring the reduction potentials of the xanthines by cyclic voltammetry. Theoretical DFT calculations were used to calculate the relative stabilities of the tautomers of each xanthine neutral radical. It was also demonstrated that the deprotonation of a xanthine radical cation never occurs from N1, unless no other possibility is available. At high pH values, it was possible to obtain the ESR spectra of the radical anions derived from 1-methylxanthine, 3-methylxanthine and xanthosine. The theoretical calculations also enabled the assignment of the ESR hyperfine coupling constants of the spectra of these radical anions. The coupling constants calculated are in good agreement with the experimental values.