The fetal electrocardiogram to detect the effects of betamethasone on fetal heart rate variability.

BACKGROUND: Betamethasone is widely used to enhance fetal lung maturation in case of threatened preterm birth. Antenatal corticosteroids are known to reduce fetal heart rate variability (fHRV) in the days following administration. Since decreased fHRV is a marker for fetal distress, this transient decrease of fHRV can cause unnecessary medical intervention. AIM: To describe the effect of betamethasone on fHRV, by applying spectral analysis on non-invasive fetal electrocardiogram (fECG) recordings. STUDY DESIGN: Secondary analysis of a prospective cohort study. SUBJECTS: Women with a singleton pregnancy, at risk for preterm delivery and receiving betamethasone, admitted to the obstetric high care unit in the period from March 2013 until July 2016. OUTCOME MEASURES: The primary outcome measure was fHRV in both time- and frequency-domain. Secondary outcome measures included basal fetal heart rate (fHR) and fHR variance. FHRV parameters were then calculated separately for the quiet and active state. RESULTS: Following 68 inclusions, 22 patients remained with complete series of measurements and sufficient data quality. FHRV parameters and fHR showed a decrease on day 2 compared to day 1, significant for short-term variability and high-frequency power. Similar results were found when analyzing for separate behavioral states. The number of segments in quiet state increased during days 1 and 2. Normalized values showed no difference for all behavioral states. CONCLUSION: FHRV decreases on day 2 after betamethasone administration, while periods of fetal quiescence increase. No changes were found in the normalized values, indicating that the influence of autonomic modulation is minor. Clinical trial registration number NL43294.015.13.

Detection rate of fetal distress using contraction-dependent fetal heart rate variability analysis.

OBJECTIVE: Monitoring of the fetal condition during labor is currently performed by cardiotocograpy (CTG). Despite the use of CTG in clinical practice, CTG interpretation suffers from a high inter- and intra-observer variability and a low specificity. In addition to CTG, analysis of fetal heart rate variability (HRV) has been shown to provide information on fetal distress. However, fetal HRV can be strongly influenced by uterine contractions, particularly during the second stage of labor. Therefore, the aim of this study is to examine if distinguishing contractions from rest periods can improve the detection rate of HRV features for fetal distress during the second stage of labor. APPROACH: We used a dataset of 100 recordings, containing 20 cases of fetuses with adverse outcome. The most informative HRV features were selected by a genetic algorithm and classification performance was evaluated using support vector machines. MAIN RESULTS: Classification performance of fetal heart rate segments closest to birth improved from a geometric mean of 70% to 79%. If the classifier was used to indicate fetal distress over time, the geometric mean at 15 minutes before birth improved from 60% to 72%. SIGNIFICANCE: Our results show that combining contraction-dependent HRV features with HRV features calculated over the entire fetal heart rate signal improves the detection rate of fetal distress.

A Fixed-Lag Kalman Smoother to Filter Power Line Interference in Electrocardiogram Recordings.

OBJECTIVE: Filtering power line interference (PLI) from electrocardiogram (ECG) recordings can lead to significant distortions of the ECG and mask clinically relevant features in ECG waveform morphology. The objective of this study is to filter PLI from ECG recordings with minimal distortion of the ECG waveform. METHODS: In this paper, we propose a fixed-lag Kalman smoother with adaptive noise estimation. The performance of this Kalman smoother in filtering PLI is compared to that of a fixed-bandwidth notch filter and several adaptive PLI filters that have been proposed in the literature. To evaluate the performance, we corrupted clean neonatal ECG recordings with various simulated PLI. Furthermore, examples are shown of filtering real PLI from an adult and a fetal ECG recording. RESULTS: The fixed-lag Kalman smoother outperforms other PLI filters in terms of step response settling time (improvements that range from 0.1 to 1 s) and signal-to-noise ratio (improvements that range from 17 to 23 dB). Our fixed-lag Kalman smoother can be used for semi real-time applications with a limited delay of 0.4 s. CONCLUSION AND SIGNIFICANCE: The fixed-lag Kalman smoother presented in this study outperforms other methods for filtering PLI and leads to minimal distortion of the ECG waveform.

Using uterine activity to improve fetal heart rate variability analysis for detection of asphyxia during labor.

During labor, uterine contractions can cause temporary oxygen deficiency for the fetus. In case of severe and prolonged oxygen deficiency this can lead to asphyxia. The currently used technique for detection of asphyxia, cardiotocography (CTG), suffers from a low specificity. Recent studies suggest that analysis of fetal heart rate variability (HRV) in addition to CTG can provide information on fetal distress. However, interpretation of fetal HRV during labor is difficult due to the influence of uterine contractions on fetal HRV. The aim of this study is therefore to investigate whether HRV features differ during contraction and rest periods, and whether these differences can improve the detection of asphyxia. To this end, a case-control study was performed, using 14 cases with asphyxia that were matched with 14 healthy fetuses. We did not find significant differences for individual HRV features when calculated over the fetal heart rate without separating contractions and rest periods (p > 0.30 for all HRV features). Separating contractions from rest periods did result in a significant difference. In particular the ratio between HRV features calculated during and outside contractions can improve discrimination between fetuses with and without asphyxia (p < 0.04 for three out of four ratio HRV features that were studied in this paper).

Selective heart rate variability analysis to account for uterine activity during labor and improve classification of fetal distress.

Cardiotocography (CTG) is currently the most often used technique for detection of fetal distress. Unfortunately, CTG has a poor specificity. Recent studies suggest that, in addition to CTG, information on fetal distress can be obtained from analysis of fetal heart rate variability (HRV). However, uterine contractions can strongly influence fetal HRV. The aim of this study is therefore to investigate whether HRV analysis for detection of fetal distress can be improved by distinguishing contractions from rest periods. Our results from feature selection indicate that HRV features calculated separately during contractions or during rest periods are more informative on fetal distress than HRV features that are calculated over the entire fetal heart rate. Furthermore, classification performance improved from a geometric mean of 69.0% to 79.6% when including the contraction-dependent HRV features, in addition to HRV features calculated over the entire fetal heart rate.

Reliability of spectral analysis of fetal heart rate variability.

Spectral analysis of fetal heart rate variability could provide information on fetal wellbeing. Unfortunately, fetal heart rate recordings are often contaminated by artifacts. Correction of these artifacts affects the outcome of spectral analysis, but it is currently unclear what level of artifact correction facilitates reliable spectral analysis. In this study, a method is presented that estimates the error in spectral powers due to artifact correction, based on the properties of the Continuous Wavelet Transformation. The results show that it is possible to estimate the error in spectral powers. The information about this error makes it possible for clinicians to assess the reliability of spectral analysis of fetal heart rate recordings that are contaminated by artifacts.

QRS classification and spatial combination for robust heart rate detection in low-quality fetal ECG recordings.

Non-invasive fetal electrocardiography (ECG) can be used for prolonged monitoring of the fetal heart rate (FHR). However, the signal-to-noise-ratio (SNR) of non-invasive ECG recordings is often insufficient for reliable detection of the FHR. To overcome this problem, source separation techniques can be used to enhance the fetal ECG. This study uses a physiology-based source separation (PBSS) technique that has already been demonstrated to outperform widely used blind source separation techniques. Despite the relatively good performance of PBSS in enhancing the fetal ECG, PBSS is still susceptible to artifacts. In this study an augmented PBSS technique is developed to reduce the influence of artifacts. The performance of the developed method is compared to PBSS on multi-channel non-invasive fetal ECG recordings. Based on this comparison, the developed method is shown to outperform PBSS for the enhancement of the fetal ECG.

Treatment options for active removal of renal stones.

This study provides an update on the technological aspects of the methods for active removal of renal stones. Currently, extracorporeal shock wave lithotripsy (ESWL), ureteroscopy (URS) and percutaneous nephrolithotomy (PCNL) are the available options. Findings are based upon recent literature from the PubMed database and the European Association of Urology (EAU) guidelines. ESWL remains the option of choice for stones with diameter ≤ 20 mm due to its low invasive character, whereas PCNL is the standard for stones with diameter > 20 mm because of its high stone-free rates. Although ESWL treatment has become more patient friendly, its efficacy has not improved. On the other hand, URS has gained renewed interest due to new technological developments and improved treatment methods.

Enthalpic and entropic contributions to the mutational changes in the reduction potential of azurin.

The changes in the reduction potential of Pseudomonas aeruginosa and Alcaligenes denitrificans azurins following point mutations and residue ionizations were factorized into the enthalpic and entropic contributions through variable temperature direct electrochemistry experiments. The effects on the reduction enthalpy due to changes in the first coordination sphere of the copper ion, as in the Met121Gln and Met121His variants of A. denitrificans azurin, insertion of a net charge and alteration in the solvation properties and electrostatic potential in proximity of the metal site, as in the Met44Lys and His35Leu variants of P. aeruginosa azurin, respectively, and proton uptake/release in wild-type and mutated species could invariably be accounted for on the basis of simple coordination chemistry and/or electrostatic considerations. The concomitant changes in reduction entropy were found in general to contribute to the E degrees ' variation to a lesser extent as compared to the enthalpy changes. However, their effects were by no means negligible and in some instances were found to heavily contribute to (or even become the main determinant of) the observed change in reduction potential. Several lines of evidence indicate that the entropic effects are notably influenced by reduction-induced solvent reorganization effects. In particular, protein reduction tends to be favored on entropic grounds with increasing exposure of the copper site to the solvent. Moreover, enthalpy-entropy compensation phenomena are invariably observed when residue mutation or pH-induced conformational changes modify the solvent accessibility of the metal site or alter the H-bonding network in the hydration shell of the molecule. Therefore, in these cases, caution must be used in making predictions of E degrees ' changes simply based on Coulombic or coordination chemistry arguments.

Understanding the electronic properties of the CuA site from the soluble domain of cytochrome c oxidase through paramagnetic 1H NMR.

The soluble domain of the subunit II of cytochrome c oxidase from Paracoccus versutus was cloned, expressed, and studied by 1H NMR at 600 MHz. The properties of the redox-active dinuclear CuA site in the paramagnetic mixed-valence Cu(I)-Cu(II) state were investigated in detail. A group of relatively sharp signals found between 30 and 15 ppm in the 1H NMR spectrum correspond to the imidazole protons of the coordinated histidines (H181 and H224). A second group of broader and farther shifted signals between 50 and 300 ppm are assigned to Hbeta protons of the bridging cysteines (C216 and C220); the protons from the weak M227 and E218 ligands do not shift outside of the diamagnetic envelope. About 40% of the total spin density appears delocalized over the cysteine-bridging ligands while a much smaller amount is delocalized on the two ligand histidines. The latter have similar spin density distributions. Analysis of the pattern of the hyperfine shifts of the Cys H beta protons shows that the ground state bears 2B3u character, in which the sulfur lobes in the singly occupied molecular orbital are aligned with the Cu-Cu axis. Analysis of the temperature dependence of the shifts of the Cys H beta signals leads to the conclusion that the 2B2u excited state is thermally accessible at room temperature (Delta E approximately kT).

The influence of the peptide chain on the kinetics and stability of microperoxidases.

Microperoxidases with increasing lengths of the peptide attached to the heme moiety have been isolated after proteolytic digestion of horse-heart cytochrome c (microperoxidases 6, 8, and 11) and of cytochrome c550 from Thiobacillus versutus (microperoxidase 17). The different microperoxidases catalyze the H2O2-dependent para-hydroxylation of aniline relatively efficiently but are rapidly inactivated under turnover conditions. The horse-heart cytochrome-c-derived microperoxidases have identical values for Vmax but show a decrease of the K(m) for aniline and a higher stability when the attached peptide is longer. The kinetic constants obtained for microperoxidase 17, differ markedly from the microperoxidases derived from horse-heart cytochrome c. Possible factors underlying the observed differences are discussed.

Paramagnetic cobalt and nickel derivatives of Alcaligenes denitrificans azurin and its M121Q mutant. A 1H NMR study.

Using cobalt or nickel to replace copper in native azurin allows one to fingerprint the metal coordination site of the protein. The metal sites of wild type Alcaligenes denitrificans azurin and its M121Q mutant are clearly distinguishable through the paramagnetic 1H NMR spectra of the Ni(II) and Co(II) derivatives. In the wild type azurin, Gly45 coordinates to nickel or cobalt, while Met121 appears as a weak metal ligand. On the contrary, in the M121Q azurin mutant, the metal exhibits a clear preference for the Gln121, which coordinates through the side chain carbonyl oxygen, and Gly45 is not a ligand. Changes in the isotropic shifts and relaxation properties of signals from the Cys112, His46, and His117 metal ligands suggest a movement of the metal ion out of the equatorial plane, indicating that the metal site is tetrahedral. These effects are less pronounced in the Ni(II) M121Q azurin than in the Co(II) metalloderivative. The similarity between the NMR spectra of the Co(II) derivatives of stellacyanin and the M121Q azurin is in agreement with a very similar metal site in both proteins and supports the existence of a coordinated Gln in stellacyanin.

Cloning and characterization of the bovine polymeric immunoglobulin receptor-encoding cDNA.

Trans-epithelial transport of polymeric immunoglobulins (pIg) into mucosal and glandular secretions is carried out by the pIg receptor (pIgR). Therefore, expression of the pIgR gene in epithelial cells of mucosal and glandular tissues is an absolute requirement for achieving mucosal immunity. We report the cloning and characterization of the bovine pIgR cDNA. Three overlapping cDNA clones with a total length of 3608 bp yielded an open reading frame encoding a 757-amino-acid (aa) transmembrane (TM) glycoprotein. Although polymorphism was found in two separate clones, Northern blot analysis showed a single pIgR mRNA (approx. 3.8 kb) to be present in the mammary gland, liver, lung, kidney and intestine of a lactating cow. There was no detectable expression of pIgR in the spleen of the same animal. Comparison of the deduced bovine pIgR as sequence with those of rat, mouse, man and rabbit shows that this receptor is highly conserved both in aa sequence and structural organization. The degree of conservation in the TM sequence and the C-terminal cytoplasmic tail, which contains the various signals for intracellular trafficking of the receptor, is 65-73%. We also find a high degree of conservation (61-66%) in the ectoplasmic part of the receptor, known as the secretory component (SC), with an exception for that of the rabbit SC, which is much lower (47%). Among the five Ig-like domains in the SC, the N-terminal domain I, where the primary pIg-binding site is located, showed the highest (72-83%) aa sequence conservation.

The role of lysine 99 of Thiobacillus versutus cytochrome c-550 in the alkaline transition.

The methionine ligand of the heme iron in ferricytochrome c-550 from Thiobacillus versutus is replaced by another residue at high pH. This transition is similar to the alkaline transition in mitochondrial cytochrome c. To investigate the possible role of lysine 99 in this process, this residue has been mutated to a glutamate. The mutation causes the apparent pKa of the transition to decrease from 11.2 in wild type to 10.8 in Lys99Glu cytochrome c-550. This destabilization of the native form is ascribed to the absence of the hydrogen bond between the epsilon-amine group of Lys99 and the carbonyl of Lys54 in the mutant protein. The 1H-NMR spectrum of Lys99Glu ferricytochrome c-550 at alkaline pH still shows resonance positions of the heme methyl peaks that are characteristic of the alkaline form. These results strongly suggest that Lys99 does not act as a ligand in the high-pH form, contrary to the case of yeast iso-1-cytochrome c. Evidence has been presented that in the latter protein the homologous Lys79 can act as a ligand in the alkaline form [1993, J. Am. Chem. Soc. 115, 7507-7508]. In the EPR spectrum of Lys99Glu cytochrome c-550 the species with Met-His coordination (gz = 3.27) is replaced by two forms with gz = 3.45 and 3.20 in the alkaline form (pH > or = 10.6). At pH > 11 yet another form is observed with g-values 2.87, 2.18 and 1.60, tentatively identified as a species with a lysine-histidinate coordination of the heme iron.