Fetal echocardiographic prediction score for perinatal mortality in tricuspid valve dysplasia and Ebstein's anomaly.

OBJECTIVES: Tricuspid valve dysplasia (TVD) and Ebstein's anomaly (EA) diagnosed by fetal echocardiography vary greatly in terms of clinical severity and prognosis. The Celermajer index and Simpson-Andrews-Sharland (SAS) score have been reported previously for the prediction of prognosis in cases of TVD/EA; however, they do not take into account the hemodynamic impact of left ventricular (LV) function, which has recently been implicated as being important in the pathophysiology of TVD/EA. The aim of this study was to develop a novel scoring system that includes LV function for the prediction of perinatal death in fetuses diagnosed with TVD/EA. METHODS: The clinical records of 36 fetuses diagnosed prenatally with TVD/EA between 2000 and 2015 in our hospital were reviewed. Univariate analysis was used to assess the association between perinatal death (defined as death between 22 weeks' gestation and 4 weeks after delivery) and gestational age at diagnosis, cardiothoracic area ratio (CTAR), degree of pulmonary artery flow, direction of ductal flow, right-to-left ventricular diameter ratio, tricuspid regurgitation (TR) maximum velocity, Celermajer index, SAS score and LV-Tei index. A new prognostic score, the TRIPP score (TRIcuspid malformation Prognosis Prediction score), was developed using the parameters found to be associated significantly with perinatal death. The predictive value of this score was assessed in an additional nine fetuses diagnosed with TVD/EA. RESULTS: Thirty-six fetuses were diagnosed prenatally with TVD/EA, two of which were terminated, one was lost to follow-up and two died before 22 weeks' gestation. Of the 31 included fetuses, 10 (32%) died in the perinatal period. Univariate analysis demonstrated that TR maximum velocity was significantly lower (2.22 ± 0.17 m/s vs 3.26 ± 0.12 m/s; P < 0.001) and SAS score was significantly higher (5.7 ± 0.6 points vs 2.8 ± 0.4 points; P = 0.0014) in cases of perinatal death than in surviving fetuses. The degree of pulmonary artery flow and the direction of ductal flow were also associated significantly with perinatal death (P < 0.01 for both). Notably, LV-Tei index was significantly higher in cases of perinatal death than in surviving fetuses (0.81 ± 0.08 vs 0.50 ± 0.05; P < 0.001). In contrast, there was no significant difference in Celermajer index, CTAR or right-to-left ventricular diameter ratio. Finally, we established a novel combinatorial scoring system, the TRIPP score, including the four significant factors: TR maximum velocity, pulmonary artery flow, direction of ductal flow and LV-Tei index. The TRIPP score was found to predict efficiently perinatal mortality in fetuses with TVD/EA. CONCLUSIONS: Our novel combinatorial score of echocardiographic parameters, the TRIPP score, including LV-Tei index, is easy to measure and provides a good tool for the prediction of perinatal mortality in fetuses diagnosed prenatally with TVD/EA. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

'Post-LA space index' as a potential novel marker for the prenatal diagnosis of isolated total anomalous pulmonary venous connection.

OBJECTIVES: To review the fetal echocardiograms of patients with total anomalous pulmonary venous connection (TAPVC) in order to determine whether the distance between the left atrium and the descending aorta would be useful in the prenatal diagnosis of fetal TAPVC. METHODS: We reviewed the fetal echocardiograms of eight cases of TAPVC (five supracardiac type and three infracardiac type) with no other cardiac malformations. We evaluated the ratio of the left atrium-descending aorta distance to the diameter of the descending aorta ('post-LA space index') in 101 normal and eight TAPVC fetuses, and compared the values between groups. In addition, we examined the tricuspid valve/mitral valve diameter ratio (TVD/MVD) and the right ventricular end-diastolic diameter/left ventricular end-diastolic diameter ratio (RVDd/LVDd). RESULTS: The echocardiograms for fetuses with TAPVC and normal fetuses were performed at mean gestational ages of 27.5 weeks and 29.6 weeks, respectively. There were no significant differences in the TVD/MVD and RVDd/LVDd ratios between the groups. However, the post-LA space index was significantly higher in the TAPVC cases (mean, 1.51) than it was in the normal fetuses (mean, 0.71 ± 0.23) (P < 0.0001). On an analysis of the receiver-operating characteristics curve, a post-LA space index cut-off of 1.27 was found to be optimal for distinguishing between TAPVC and normal hearts, with a sensitivity of 100% and specificity of 99%. CONCLUSIONS: The novel post-LA space index could potentially be used for the prenatal diagnosis of TAPVC. A diagnosis of TAPVC is very likely in cases with a post-LA space index of > 1.27.

'I-shaped' sign in the upper mediastinum: a novel potential marker for antenatal diagnosis of d-transposition of the great arteries.

OBJECTIVES: To investigate the 'I-shaped' sign as a novel echocardiographic marker for antenatal diagnosis of d-transposition of the great arteries (dTGA) in routine cardiac examination, and to compare its prevalence in fetuses with dTGA, those with other congenital heart diseases (CHDs) and those with normal structural hearts. METHODS: This retrospective evaluation involved 1134 fetuses undergoing echocardiography to screen for CHD over a 4-year period. I-shaped sign was defined as the characteristic appearance of the aortic arch, resembling the letter 'I', from the most anterior to the most posterior point of the descending aorta visible in the three vessels and trachea view. The frequency of this sign was evaluated in cases with dTGA, those with other cardiac defects and those with normal cardiac structures. RESULTS: CHD was diagnosed in 671 (59.1%) cases, of which 31 (4.6%) had dTGA. I-shaped sign was observed in 30/31 (96.8%) cases of dTGA, compared with 31/640 (4.8%) cases with other cardiac anomalies, which included single ventricle with pulmonary atresia or severe pulmonary stenosis, hypoplastic left heart syndrome with aortic atresia, corrected transposition of the great arteries, and double outlet right ventricle with malposition of the great arteries. I-shaped sign was detected significantly more frequently in the dTGA group compared with the normal group and with the other CHDs group (both P < 0.001) and had 96.8% sensitivity and 97.1% specificity for diagnosis of dTGA. Importantly, I-shaped sign was never observed in fetuses with structurally normal hearts. CONCLUSIONS: Detection on echocardiography of an extremely long vessel with a marked I-shape should raise suspicion of cardiac anomaly, especially dTGA. This marker may therefore aid in the prenatal diagnosis of dTGA during routine ultrasound examination.

Suppression of temperature-sensitive defects of polypeptide release factors RF-1 and RF-2 by mutations or by an excess of RF-3 in Escherichia coli.

The termination of protein synthesis in bacteria requires two codon-specific polypeptide-release factors, RF-1 and RF-2. A third factor, RF-3, stimulates the RF-1 and RF-2 activities in vitro. To clarify the in vivo role of RF-3 for the RF-2 dependent termination, we isolated and characterized suppressor mutations for the temperature-sensitive RF-2 mutation prfB286. One of the intergenic suppressor mutations, srb-1, acquired an up-promoter alteration in the RF-3 gene, which enhanced the RF-3 expression four- to fivefold. Consistently a threefold increase in the RF-3 level by a promoter-controlled expression plasmid suppressed prfB286. On the other hand, a temperature-sensitive mutation in RF-1, prfA1, was suppressed only slightly by the high-level expression of wild-type RF-3. The RF-3 mutations that suppress prfA1 were isolated and named sra. They were classified into four specific alleles; two each in the N and C-terminal regions. These altered RF-3 proteins restored the RF-1-dependent termination at UAG in prfA1 cells. Moreover, they enhanced the RF-2-dependent UGA termination in both wild-type and prfB286 cells. The termination-stimulating activity of RF-3 was further additively increased by the double sra mutations, suggesting that they affected two distinct protein domains that modulate the termination reaction. Taking these and other results into consideration, RF-3 is likely to interact functionally and cooperatively with the release factors RF-1 and RF-2 in Escherichia coli.

Regulation of translation termination: conserved structural motifs in bacterial and eukaryotic polypeptide release factors.

Translation termination requires codon-dependent polypeptide release factors. The mechanism of stop codon recognition by release factors is unknown and holds considerable interest since it entails protein-RNA recognition rather than the well-understood mRNA-tRNA interaction in codon-anticodon pairing. Bacteria have two codon-specific release factors and our picture of prokaryotic translation is changing because a third factor, which stimulates the other two, has now been found. Moreover, a highly conserved eukaryotic protein family possessing properties of polypeptide release factor has now been sought. This review summarizes our current understanding of the structural and functional organization of release factors as well as our recent findings of highly conserved structural motifs in bacterial and eukaryotic polypeptide release factors.

Comparative characterization of release factor RF-3 genes of Escherichia coli, Salmonella typhimurium, and Dichelobacter nodosus.

The termination of protein synthesis in bacteria requires two codon-specific release factors, RF-1 and RF-2. A gene for a third factor, RF-3, that stimulates the RF-1 and RF-2 activities has been isolated from the gram-negative bacteria Escherichia coli and Dichelobacter nodosus. In this work, we isolated the RF-3 gene from Salmonella typhimurium and compared the three encoded RF-3 proteins by immunoblotting and intergeneric complementation and suppression. A murine polyclonal antibody against E. coli RF-3 reacted with both S. typhimurium and D. nodosus RF-3 proteins. The heterologous RF-3 genes complemented a null RF-3 mutation of E. coli regardless of having different sequence identities at the protein level. Additionally, multicopy expression of either of these RF-3 genes suppressed temperature-sensitive RF-2 mutations of E. coli and S. typhimurium by restoring adequate peptide chain release. These findings strongly suggest that the RF-3 proteins of these gram-negative bacteria share common structural and functional domains necessary for RF-3 activity and support the notion that RF-3 interacts functionally and/or physically with RF-2 during translation termination.

The bioavailability of diazepam from uncoated tablets in humans--Part I: correlation with the dissolution rates of the tablets.

Dissolution studies of 15 preparations of commercial uncoated tablets of diazepam (5 mg) were performed by six methods (beaker, rotating basket, oscillating basket, solubility simulator, rotating flask, and single basket). Diazepam dissolved rapidly at pH 1.2; the T50 (the time of 50% dissolution) values were less than 5 min. But at pH 4.6, T50 estimated by rotating basket method lasted 3-120 min. Four different tablets of diazepam were chosen for the bioavailability tests in humans. The bioavailabilities of the four tablet preparations were estimated by serum level measurements after a single dose to 12 adult male volunteers. Statistical analysis of the data showed significant differences in the rate of bioavailability (peak concentrations and serum concentrations at 1, 2, and 3 h after administration), but not in the amount of available (AUC). The mean peak concentration and serum concentration at 1 h showed significant correlation with T50 and T70 determined by the rotating flask method at pH 4.6 in log-log regression. The peak concentration and serum concentration at 1 h were also correlated with T70 determined by the rotating flask method at pH 4.6 and T70 determined by the rotating basket method at pH 4.6 on normal-normal regression. In contrast, the dissolution rates determined at pH 1.2 did not show a good correlation with in vitro parameters.

Influence of neuroticism on oral absorption of diazepam.

The subjects were 24 healthy males, 19 to 21 yr old. Twelve subjects had high neuroticism (HN) levels determined by Maudsley Personality Inventory, and 12 had low neuroticism (LN) levels. Subjects took a single 5-mg dose of diazepam (DZP) after a standardized breakfast. The mean plasma concentration for DZP was significantly higher in HN subjects at 1.5 hr after drug than in LN subjects. No difference was found in the DZP plasma levels of these 2 groups after administering the drug directly into the duodenum through a tube. No clear relationship between plasma DZP concentrations and DZP-induced sedative effects determined by Choice Reaction Time Test (CRTT) was demonstrated in the study. The results suggest that the absorption rate of DZP from the gastrointestinal tract is faster in HN subjects than in LN subjects due to the faster gastric emptying time in HN subjects in our experimental situation, which might have induced mild stress.

Effects of antianxiety drug and personality on stress-inducing psychomotor performance test.

The present study was carried out to clarify the effects of an antianxiety drug and of personality characteristics on a psychomotor performance test. Forty-eight healthy women college students were chosen from 64 volunteers as having either high or low levels of trait anxiety, neuroticism, or extroversion. Subjects with high trait anxiety and/or neuroticism tended to show a decrease in both speed and accuracy of the mirror drawing test (MDT) in the initial nondrug trials. Bromazepam, 5 mg, a benzodiazepine derivative, decreased this decrement in highly anxious subjects but worsened the speed in less anxious subjects. The personality traits of subjects, as well as the degree to which a performance test will induce stress, must be considered when evaluating the effects of antianxiety drugs on the performance of normal volunteers. The clinical anxiety-reducing efficacy of drugs may be predicted by using the MDT in subjects with high levels of anxiety and/or neuroticism.