[A Randomized Controlled Trial on the Effect of Earmuffs on Intermittent Hypoxia and Bradycardia in Preterm Infants]. / Lärm auf der Neugeborenen-Intensivstation: randomisierte Studie zum Einfluss eines Gehörschutzes auf intermittierende Hypoxien und Bradykardien.

BACKGROUND: Irregular breathing causing hypoxia and bradycardia is a common problem of preterm infants but its pathophysiology is incompletely understood. Agitation provoked by environmental noise may play a role. We wanted to know if earmuffs can at least halve the rate of intermittent hypoxia in premies. PATIENTS AND METHODS: In this randomized controlled trial 31 infants (14 male; median [min.-max.] birth weight and gestational age: 1 323 g [560-1 990] and 30(1/7) weeks [25(5/7)-33(0/7)]) had the effect of earmuffs on the frequency of pulse oximeter desaturations (SpO(2) <80%) and bradycardia events (<80 beats per minute) tested, documented via a standard home monitor. Infants were measured 2 h each with or without earmuffs; the sequence of intervention was randomised. Measurement conditions were kept constant while a noise meter recorded sound pressure levels at a 1 Hz sampling rate. RESULTS: Median sound pressure level was 46.8 dB(A). In a pre-study, ear muffs yielded a sound reduction by 7.2 dB. 19 infants had a total of 474 desaturations. The median (25.-75. percentile) number of desaturations was 1 (1-10.5) without, and 1 (1-10) with earmuffs. The amount of infants with at least one desaturation was equal in both treatment protocols. Only 7 bradycardias occurred. CONCLUSION: The earmuffs had, in a rather quiet environment, no effect on intermittent hypoxia in these infants.

Towards a European health research and innovation cloud (HRIC).

The European Union (EU) initiative on the Digital Transformation of Health and Care (Digicare) aims to provide the conditions necessary for building a secure, flexible, and decentralized digital health infrastructure. Creating a European Health Research and Innovation Cloud (HRIC) within this environment should enable data sharing and analysis for health research across the EU, in compliance with data protection legislation while preserving the full trust of the participants. Such a HRIC should learn from and build on existing data infrastructures, integrate best practices, and focus on the concrete needs of the community in terms of technologies, governance, management, regulation, and ethics requirements. Here, we describe the vision and expected benefits of digital data sharing in health research activities and present a roadmap that fosters the opportunities while answering the challenges of implementing a HRIC. For this, we put forward five specific recommendations and action points to ensure that a European HRIC: i) is built on established standards and guidelines, providing cloud technologies through an open and decentralized infrastructure; ii) is developed and certified to the highest standards of interoperability and data security that can be trusted by all stakeholders; iii) is supported by a robust ethical and legal framework that is compliant with the EU General Data Protection Regulation (GDPR); iv) establishes a proper environment for the training of new generations of data and medical scientists; and v) stimulates research and innovation in transnational collaborations through public and private initiatives and partnerships funded by the EU through Horizon 2020 and Horizon Europe.

The PH superfold: a structural scaffold for multiple functions.

Pleckstrin homology (PH) domains form a structurally conserved family that is associated with many regulatory pathways within the cell. Domains with a nearly identical fold are found in other families that share no sequence similarity, suggesting the existence of a stable PH superfold. The PH domains generally function as regulated membrane-binding modules that bind to inositol lipids and respond to upstream signals by targeting the host proteins to the correct cellular sites. The other domains with a similar fold, such as the phosphotyrosine binding domains, recognize protein ligands.

Structure of a PH domain from the C. elegans muscle protein UNC-89 suggests a novel function.

BACKGROUND: Pleckstrin homology (PH) domains constitute a structurally conserved family present in many signaling and regulatory proteins. PH domains have been shown to bind to phospholipids, and many function in membrane targeting. They generally have a strong electrostatic polarization and interact with negatively charged phospholipids via the positive pole. On the basis of electrostatic modeling, however, we have previously identified a class of PH domains with a predominantly negative charge and predicted that these domains recognize other targets. Here, we report the first experimental structure of such a PH domain. RESULTS: The structure of the PH domain from Caenorhabditis elegans muscle protein UNC-89 has been determined by heteronuclear NMR. The domain adopts the classic PH fold, but has an unusual closed conformation of the "inositol binding loops. This creates a small opening to a deep hydrophobic pocket lined with negative charges on one side, and provides a molecular explanation for the lack of association with inositol-1,4,5-triphosphate. As predicted, the PH domain of UNC-89 has a strongly negative overall electrostatic potential. Modeling the Dbl homology (DH)-linked PH domains from the C. elegans genome shows that a large proportion of these modules are negatively charged. CONCLUSIONS: We present the first structure of a PH domain with a strong negative overall electrostatic potential. The presence of a deep pocket lined with negative charges suggests that the domain binds to ligands other than acidic phospholipids. The abundance of this class of PH domain in the C. elegans genome suggests a prominent role in mediating protein-protein interactions.

Structure of the PPARalpha and -gamma ligand binding domain in complex with AZ 242; ligand selectivity and agonist activation in the PPAR family.

BACKGROUND: The peroxisome proliferator-activated receptors (PPAR) are ligand-activated transcription factors belonging to the nuclear receptor family. The roles of PPARalpha in fatty acid oxidation and PPARgamma in adipocyte differentiation and lipid storage have been characterized extensively. PPARs are activated by fatty acids and eicosanoids and are also targets for antidyslipidemic drugs, but the molecular interactions governing ligand selectivity for specific subtypes are unclear due to the lack of a PPARalpha ligand binding domain structure. RESULTS: We have solved the crystal structure of the PPARalpha ligand binding domain (LBD) in complex with the combined PPARalpha and -gamma agonist AZ 242, a novel dihydro cinnamate derivative that is structurally different from thiazolidinediones. In addition, we present the crystal structure of the PPARgamma_LBD/AZ 242 complex and provide a rationale for ligand selectivity toward the PPARalpha and -gamma subtypes. Heteronuclear NMR data on PPARalpha in both the apo form and in complex with AZ 242 shows an overall stabilization of the LBD upon agonist binding. A comparison of the novel PPARalpha/AZ 242 complex with the PPARgamma/AZ 242 complex and previously solved PPARgamma structures reveals a conserved hydrogen bonding network between agonists and the AF2 helix. CONCLUSIONS: The complex of PPARalpha and PPARgamma with the dual specificity agonist AZ 242 highlights the conserved interactions required for receptor activation. Together with the NMR data, this suggests a general model for ligand activation in the PPAR family. A comparison of the ligand binding sites reveals a molecular explanation for subtype selectivity and provides a basis for rational drug design.

Functional diversity of PH domains: an exhaustive modelling study.

BACKGROUND: Pleckstrin homology (PH) domains are found in many proteins involved in signal transduction or cytoskeletal organization. The general function for the domain is still unclear; phospholipid binding of some PH domains and a strong electrostatic polarization in the experimental structures suggest a role in localization on membranes. We have analyzed the electrostatic properties and the spatial amino acid distribution from homology models of the entire PH domain family. RESULTS: Despite the sequence divergence, the quality of the models is sufficient for our study. Most PH domains have an electrostatic polarization similar to the experimental structures. but roughly half of the PH domains linked to a Dbl homology domain have very different electrostatic properties. We also found a striking electrostatic complementarity in some internal PH domain repeats. The analysis of the spatial distribution of amino acids identified residues in the phospholipid-binding site of the spectrin and dynamin PH domains as specific for these domains. CONCLUSIONS: The mostly conserved electrostatic polarization supports a general function in binding to phospholipid membranes. But the presence of PH domains with opposite polarity suggests that ligands and functions have diverged during evolution. We also demonstrate homology modelling as a general sequence analysis tool that can yield significantly more information than conventional analysis.

A new approach for applying residual dipolar couplings as restraints in structure elucidation.

Residual dipolar couplings are useful global structural restraints. The dipolar couplings define the orientation of a vector with respect to the alignment tensor. Although the size of the alignment tensor can be derived from the distribution of the experimental dipolar couplings, its orientation with respect to the coordinate system of the molecule is unknown at the beginning of structure determination. This causes convergence problems in the simulated annealing process. We therefore propose a protocol that translates dipolar couplings into intervector projection angles, which are independent of the orientation of the alignment tensor with respect to the molecule. These restraints can be used during the whole simulated annealing protocol.

Preterm birth and maternal smoking: risks related to gestational age and onset of delivery.

OBJECTIVE: The object was to examine the effects of smoking on spontaneous and induced very and moderately preterm birth (< or = 32 and 33-36 completed weeks' gestation, respectively). STUDY DESIGN: Live singleton births in Sweden, 1991-1993 (n = 311,977), were examined. RESULTS: Risk of preterm birth consistently increased with amount smoked. Smoking was most heavily associated with increased risks of very preterm birth and spontaneous preterm birth. The highest impact of smoking was seen on risk of spontaneous very preterm birth among women who smoked at least 10 cigarettes/d (odds ratio 1.7). The smoking-related risks of preterm birth remained essentially unchanged after excluding pregnancies with smoking-associated pregnancy complications. CONCLUSIONS: There is a dose-related impact of smoking on risk of preterm birth. The fact that the smoking-related risk of spontaneous preterm birth is more pronounced than that of induced preterm birth suggests that smoking is associated with spontaneous preterm labor.

Classification of protein sequences by homology modeling and quantitative analysis of electrostatic similarity.

Protein electrostatics plays a key role in ligand binding and protein-protein interactions. Therefore, similarities or dissimilarities in electrostatic potentials can be used as indicators of similarities or dissimilarities in protein function. We here describe a method to compare the electrostatic properties within protein families objectively and quantitatively. Three-dimensional structures are built from database sequences by comparative modeling. Molecular potentials are then computed for these with a continuum solvation model by finite difference solution of the Poisson-Boltzmann equation or analytically as a multipole expansion that permits rapid comparison of very large datasets. This approach is applied to 104 members of the Pleckstrin homology (PH) domain family. The deviation of the potentials of the homology models from those of the corresponding experimental structures is comparable to the variation of the potential in an ensemble of structures from nuclear magnetic resonance data or between snapshots from a molecular dynamics simulation. For this dataset, the results for analysis of the full electrostatic potential and the analysis using only monopole and dipole terms are very similar. The electrostatic properties of the PH domains are generally conserved despite the extreme sequence divergence in this family. Notable exceptions from this conservation are seen for PH domains linked to a Db1 homology (DH) domain and in proteins with internal PH domain repeats.

Placental abruption and perinatal death.

Studies of risk factors for abruptio placentae (AP) are partly conflicting and studies of risk factors for perinatal death in these pregnancies are scarce. Using the population-based Swedish Birth Registry from 1987 to 1993, we were able to study these risks in 795,459 singleton pregnancies. Logistic regression analysis was used to estimate odds ratios (OR) for risk of AP and risk of perinatal death in pregnancies with and without AP. Risk factors for AP were: age, primiparity, high parity, not cohabiting with infant's father, low education, smoking, infertility, pregestational diabetes, essential hypertension, pregnancy-induced hypertensive diseases, preterm premature rupture of membranes, preterm birth and small-for-gestational-age (SGA) births. Risk factors for perinatal death in pregnancies with placental abruption were smoking (1--9 and > or =10 cigarettes/day; OR 1.4 and 1.7 respectively), severe pre-eclampsia (OR 2.0) and SGA (OR 1.9), whereas in pregnancies without abruption, risks were also increased in maternal age > or =35 years, primiparity, infertility, essential hypertension and pregestational diabetes. These findings support the theory that, in cases of AP, a general impairment of the placenta and/or a defect placentation may be fatal.