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The purpose was to compare global left-ventricular (LV) function parameters measured with cine MRI with results from multiphase dual-source CT (DSCT) using 10 and 20 reconstruction phases. Twenty-eight patients with suspected or known CAD underwent DSCT coronary angiography. LV end-diastolic (EDV), end-systolic (ESV) and stroke volumes (SV), and ejection fraction (EF) were determined using LV segmentation and selection of specific phases from DSCT image sets reconstructed either at 5% or 10% steps through the R-R interval. Cine MRI served as the reference investigation. Threshold-based 3D-segmentation was feasible in all DSCT data sets. EDV and ESV were underestimated by DSCT, but showed excellent correlation (Pearson's correlation coefficient 0.95/0.97) to values obtained with MRI. Using data from 5% DSCT image reconstructions instead of 10% phase reconstructions, the position of the ED and ES phase was changed in 16 of 28 patients; ESVs were to found to be slightly smaller, whereas EDV were slightly larger, resulting in a systematic overestimation of LV EF by 1.9% (p=0.56). Threshold-based 3D segmentation enables accurate and reliable DSCT determination of global LV function with excellent correlation to cine MRI. Minor differences in LV EF indicate that both modalities are virtually interchangeable, even if the number of reconstructed phases is limited to 10% phase reconstructions. [ABSTRACT FROM AUTHOR]

1. The interindividual variation and enantioselectivity of the in vitro styrene oxidation by cytochrome P450 have been investigated in 20 human microsomal liver samples. Liver samples were genotyped for the CYP2E1*6 and CYP2E1*5B alleles. 2. Kinetic analysis indicated the presence of at least two forms of styrene-metabolizing cytochrome P450. The enzyme constants for the high-affinity component were subject to appreciable interindividual variation, i.e. V[sub max1] ranged from 0.39 to 3.20 nmol mg protein[sup -1] min[sup -1] (0.96 0.63) and K[sub m1] ranged from 0.005 to 0.03 mM (0.011±0.006). Inhibition studies with chemical inhibitors of CYP2E1, CYP1A2, CYP2C8/9 and CYP3A4 demonstrated that CYP2E1 was the primary enzyme involved in the high-affinity component of styrene oxidation. No relationship between the interindividual variation in V[sub max1] and K[sub m1] and the genetic polymorphisms of the CYP2E1 gene was found. 3. Cytochrome P450-mediated oxidation of styrene demonstrated a moderate enantioselectivity, with an enantiomeric excess (ee) of (S)-styrene oxide of 15% (range 4-27%) at low styrene concentration and an ee of (R)-styrene oxide of 7% (range -11 to +22%) at high styrene concentration. This points towards the involvement of at least two cytochrome P450, with different enantioselectivities. 4. The data indicate that cytochrome P450-mediated styrene oxidation is subject to considerable interindividual variation, but only to a moderate product enantioselectivity. [ABSTRACT FROM AUTHOR]

The long-standing use of hypotonic fluids in pediatric maintenance fluids has been challenged in recent years due to concerns over iatrogenic hyponatremia causing morbidity and mortality. Newer research has highlighted the safety of isotonic fluid alternatives. The American Academy of Pediatrics published an evidenced-based Clinical Practice Guideline in December of 2018 (Feld et al., 2018) to support the routine use of isotonic solutions in pediatric maintenance fluids. This article will also highlight relevant history, current practice, and a quality improvement project to standardize isotonic fluid use in the inpatient pediatric setting., Competing Interests: Declaration of competing interest None., (Copyright © 2021 Elsevier Inc. All rights reserved.)

In 2017 an amendment to the German transplant law concerning organ allocation and waiting list management became effective. This implies important consequences on lung transplant centers. Crucial innovations concern the transplant conference, indications for lung transplantation and waiting list management. Certain medical conditions now imply a restriction of waiting list enrollment for patients and there are new options for size-matching of donor lung and recipient. Moreover, the new amendment describes in detail how the clinical parameters, on which the lung allocation score (LAS) is based, are defined and how the essential physical examinations have to be performed. Furthermore, the current article provides a summary of the process of organ allocation by the organ exchange organization., Competing Interests: A. Kümmel: keineJ. Gottlieb: Beratung: MSD, Gilead, Therakos, Breath Therapeutics, Boehringer/Ingelheim, Janssen Vortragshonorare. Berlin Chemie, Novartis, Astellas, Chiesi, Basilea; Forschungszuwendungen: Alynylam, Gilead.R. Buhl: keineM. Wenker: Mitgliedschaften: Ständige Kommission Organtransplantation der Bundesärztekammer, Arbeitsgruppe Richtline BÄK Lunge, Berufsverband der Pneumologen, Deutsche Gesellschaft für Pneumologie und BeatmungsmedizinR. Schramm: keineC. Witt: keine, (© Georg Thieme Verlag KG Stuttgart · New York.)

Background and Objectives: Drug-drug interactions (DDIs) can occur when one drug alters the metabolism of another drug. Drug metabolism mediated by cytochrome P450 enzymes (CYPs) is responsible for the majority of metabolism of known drugs and inhibition of CYP enzymes is a well-known cause of DDIs. In the current study, the use of various human liver microsomes (HLM)-based methods to determine occurrence of CYP-mediated metabolism-dependent inhibition (MDI) and possible follow-up studies were evaluated., Methods: Human CYP inhibition was studied using the following methodologies: direct inhibition and (non-diluted) IC 50 -shift assays, a ferricyanide-based reversibility assay, a spectrophotometric metabolic intermediate complex (MIC) assay, and recording of reduced carbon monoxide (CO)-difference spectra. HLM incubations in the presence and absence of NADPH and glutathione (GSH) were performed to study the possible formation of CYP-dependent GSH adducts. HLM incubations with the radiolabeled inhibitors mifepristone and paroxetine were performed to study CYP-mediated covalent binding., Results: Dihydralazine and furafylline displayed irreversible MDI of CYP1A2. Paroxetine displayed both quasi-irreversible and irreversible MDI of CYP2D6, formation of CYP-dependent GSH adducts was observed, while CYP-mediated covalent binding occurred which was decreased in the presence of GSH. Mifepristone displayed irreversible MDI of CYP3A4, formation of CYP-dependent GSH adducts was observed, while CYP-mediated covalent binding occurred which was decreased in the presence of GSH. Troleandomycin and verapamil displayed quasi-irreversible MDI of CYP3A4; MIC formation was observed, while no formation of CYP-dependent GSH adducts occurred., Conclusions: This study gives a representative overview of current methodologies that can be used to study CYP inhibition. The here presented strategy can be applied as a tool during risk evaluation of CYP-mediated DDIs.

Drug-induced phototoxicity occurs when drugs absorb natural sunlight, leading to chemical reactions causing cellular damage. Distribution to light-exposed tissues is critical and is enhanced by binding to melanin. The International Council on Harmonization S10 guidance document on photosafety evaluation of pharmaceuticals states that although nonpigmented skin tends to be more sensitive than pigmented skin, pigmented skin models should be considered for drugs that bind significantly to melanin. In this study, an in vitro melanin-binding assay was evaluated as prescreening tool for animal model selection. Binding of various structurally diverse phototoxic drugs to synthetic melanin was investigated in vitro and the high-affinity binder sparfloxacin (SPX), moderate-affinity binder 8-methoxypsoralen (8-MOP), and low-affinity binder pirfenidone (PIF) were selected for in vivo studies. Pigmented Brown Norway (BN) rats were compared with nonpigmented Wistar Albino rats to evaluate their sensitivity for the assessment of phototoxicity and skin concentrations of the drugs were measured. For SPX, the onset of phototoxic symptoms was faster for BN rats and drug concentrations were significantly higher in skin of BN rats. For 8-MOP, both models showed comparable sensitivity and skin concentrations did not differ. For the low-affinity binder PIF, no phototoxic effects were observed and skin concentrations in both models were similar. A combined in vitro/in vivo approach was developed that can be applied for accurate photosafety evaluation of pharmaceuticals based on the assessment of possible melanin-binding effects. In view of the presented data, the pigmented model could be considered for compounds showing a high-affinity binding capacity in vitro.

Routinely in many laboratories, satellite rats are added to embryo-fetal development (EFD) studies for pharmaceuticals to assess toxicokinetic (TK) properties, because it is assumed that collection of multiple blood samples with relatively large volumes might affect the study outcome. With recent refinement of blood sampling techniques, this belief requires reevaluation. The current work showed successful implementation of jugular vein blood sampling in an EFD rat study without satellite animals, thereby reducing the number of rats in standard EFD studies for pharmaceuticals by 20%. Although not evaluated in this study, microsampling has shown to be very successful and eliminates the need of satellite animals. However, currently not all laboratories have implemented this method and regularly the bioanalytical method is already developed with a limit of quantification that is insufficiently sensitive. Therefore in those cases, a quick win to omit satellite animals can be established by using jugular vein blood sampling., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Blood sampling during juvenile rat toxicology studies is required to determine the toxicokinetic (TK) profile of compounds. Juvenile rats are too small to undergo repeated blood sampling using conventional methods, which collect 200-300 μl blood at each time point. Recently, capillary microsampling (CMS) gained interest because sample sizes are almost 10 times smaller enabling multi-sample collection from 1 rat. Here, we evaluated the use of CMS in juvenile rats in support of reduced animal usage. Juvenile rats at postnatal day (PND) 4, 10, and 17 underwent CMS via the submandibular, tail, and jugular veins. The CMS methods for pups at different ages were evaluated based on sample quality and technical practicality as well as on acute and chronic changes of toxicological parameters. The best location for CMS was the submandibular vein for PND 4 and 10 pups and the tail vein for PND 17 pups. No effects were found on clinical signs, body and organ weights and biochemistry parameters when 2 × 32 μl of blood was withdrawn from PND 4 pups or when 3 × 32 μl was taken from PND 10 and 17 pups within 24 h. Significant changes in several hematology parameters were observed 24 h after CMS due to a decrease of red blood cells and renewed production. These values had recovered to normal 7 days after CMS. CMS is feasible in juvenile rats for TK assessment. Utilizing this method could decrease the number of additional animals by 75%., (© The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Objective: The purpose of this study was to evaluate software for threshold-based 3D segmentation of the left ventricle in comparison with traditional 2D short axis-based planimetry (Simpson method) for measurement of left ventricular (LV) volume and global function with state-of-the-art dual-source CT., Subjects and Methods: Fifty patients with known or suspected coronary artery disease underwent coronary CT angiography. LV end-diastolic, end-systolic, and stroke volumes and ejection fraction were determined from axial images to which 3D segmentation had been applied and from short-axis reformations from 2D planimetry. Interobserver variability was assessed for both approaches., Results: Threshold-based 3D LV segmentation had excellent correlation with 2D short-axis results (end-diastolic volume, R = 0.99; end-systolic volume, R = 0.99; stroke volume, R = 0.90; ejection fraction, R = 0.97; p < 0.0001). Bland-Altman analyses revealed systematic underestimation of LV end-diastolic volume (-7.4 +/- 8.9 mL) and LV end-systolic volume (-7.0 +/- 4.4 mL) with the 3D segmentation approach and 2.8 +/- 3.3% overestimation of LV ejection fraction. Interobserver variation with 3D segmentation analysis was significantly (p < 0.001) less (e.g., LV ejection fraction, 0.1 +/- 1.7%) than with the 2D technique, and mean analysis time was significantly shorter (172 +/- 20 vs 248 +/- 29 seconds; p < 0.05)., Conclusion: Automated threshold-based 3D segmentation enables accurate and reproducible dual-source CT assessment of LV volume and function with excellent correlation with results of 2D short-axis analysis. Exclusion of papillary muscles from LV volume results in small systematic differences in quantitative values.

Objectives: To study the stereochemistry of styrene metabolism in volunteers, and its interindividual variability., Methods: Twenty healthy male volunteers (aged 18-37 years) were exposed to 360 mg/m3 styrene for 1 h while they performed 50 W physical exercise. Venous blood was drawn during and for up to 2 h after exposure. Urine was collected at time-intervals up to 24 h after exposure. The following parameters were determined: styrene, free and conjugated styrene glycol (SG) in blood, and conjugated SG, mandelic acid (MA) and phenylglyoxylic acid (PGA) in urine., Results: Average pulmonary retention of styrene was 62%. Excretion of the acidic metabolites MA and PGA accounted for 58% of the pulmonary uptake. The average maximum concentration (Cmax) and area under the curve (AUC) of free (R)-SG in blood were 1.3 and 1.7 times higher than those of (S)-SG respectively; the half-life of (R)-SG was longer (82 vs 62 min, P < 0.005). Cmax and AUC of the conjugated SG enantiomers in blood did not differ, but again half-life for (R)-SG was longer (72 vs 64 min, P < 0.05). Cumulative excretion and renal clearance of conjugated (S)-SG in urine were three and four times higher, respectively, than that of (R)-SG. Cumulative excretion of (S)-MA was 1.6 times higher than (R)-MA. Interindividual differences in the kinetic parameters of the metabolites were two- to threefold., Conclusions: The enantiomeric excess found was different for each metabolite under study, implying different enantioselectivity and/or enantiospecificity of the enzymes and carrier-proteins involved in the biotransformation and excretion. The use of these metabolites as biological indicators for prediction of the enantiomeric excess of the toxic metabolite styrene-7,8-oxide (SO) is therefore not justified. Interindividual differences in the stereochemical metabolism of styrene are moderate.

The aim of the present study was to assess the interindividual variation in styrene toxicokinetics and to correlate this variation with the individual metabolic capacity for cytochrome P450 (CYP), CYP2E1, CYP1A2 and CYP2D6. Twenty male volunteers were exposed on separate occasions to 104+/-3 and 360+/-20 mg/m3 of styrene for 1 h while performing 50 W physical exercise on a bicycle ergometer. Styrene concentrations in blood and mandelic (MA) and phenylglyoxylic acid (PGA) in urine were measured. The metabolic capacity was assessed by phenotyping with chlorzoxazone (CYP2E1), caffeine (CYP1A2), dextromethorphan (CYP2D6) and antipyrine (CYP450). In addition, for the main styrene-metabolising enzyme, CYP2E1, genotyping for the genetic polymorphisms of the gene was performed. The average pulmonary retention of styrene was 62 +/- 7% at both exposure concentrations, and the 24-h excretion of MA and PGA accounted for 58% of the dose at both concentrations. The interindividual variation in styrene kinetics ranged from 19% for the terminal half-life (t(1/2,beta)) of styrene to 41% for the cumulative excretion of MA and PGA. However, no correlation between the apparent blood clearance of styrene (CLapp), t(1/2,beta) of styrene or excretion of MA and PGA on one hand, and the individual metabolic capacity on the other hand was found. Although other explanations cannot be excluded, this lack of correlation might be due to the high apparent blood clearance (1.4 l/min) of styrene, indicating that styrene metabolism is liver-blood-flow-dependent.

The enantiomers of styrene-7,8-oxide (phenyloxirane, SO) were determined using a method based on base catalysed hydrolysis with sodium methoxide. The oxirane ring opening resulted in formation, without racemisation, of the enantiomeric pairs of the two regional isomers, 2-methoxy-1-phenylethanol and 2-methoxy-2-phenylethanol. The structure of these regional isomers was confirmed by gas chromatography-mass spectrometry (GC-MS) and proton nuclear magnetic resonance (1H-NMR). To improve sensitivity of determination, the formed methoxy alcohols were subsequently derivatised with pentafluoropropionic anhydride enabling electron capture detection. This derivatization proceeded also without racemisation and the formed pentafluoropropionyl derivatives were separated on two serially coupled columns, a non-chiral AT 1705 and a chiral CP Chirasil-Dex-CB. As internal standard 2S,3S-(-)-2-methyl-3-phenyloxirane was used. The limit of quantitation of the method was 0.2 microM. The repeatability of the method was assessed at two concentration levels (2.5 and 25 microM) and ranged from 6 to 9% for both enantiomers. The method was applied to the determination of the rate and enantioselectivity of the cytochrome P-450 dependent oxidation of styrene to SO enantiomers in human liver microsomes.

Styrene is an industrial solvent which is mainly oxidized by cytochrome P450 to an electrophilic, chiral epoxide metabolite: styrene-7,8-oxide (SO). SO has cytotoxic and genotoxic properties; the (R)-enantiomer is more mutagenic to Salmonella typhimurium TA 100 in the Ames test than the (S)-enantiomer. Detoxication proceeds via microsomal epoxide hydrolase (mEH). Interindividual differences in mEH activity as well as differences in mEH enantioselectivity are important factors for toxic effects of SO. To study the extent of the interindividual variation, microsomal preparations of 20 human livers were incubated with (R)- and (S)-SO separately (1-2000 microM) and Michaelis-Menten kinetics were determined. In addition, samples were genotyped for two genetic polymorphisms of the mEH gene. V(max), K(m) and V(max)/K(m) values of both enantiomers differed three- to fivefold between the livers. No association of the enzyme constants with the genetic polymorphisms of the epoxide hydrolase gene was found. Hydrolysis of the styrene oxide enantiomers proceeded in an enantioselective manner, with the (S)-enantiomer having an approximately six times higher K(m) and five times higher V(max) than the (R)-enantiomer. In vivo, both SO enantiomers are formed; therefore, time course incubations with racemic SO were carried out in vitro to investigate possible interactions between the enantiomers. When racemic SO was used as a substrate, the (R)-enantiomer acted as an inhibitor on the hydrolysis of the (S)-enantiomer. These results indicate that mEH-mediated hydrolysis of SO is subject to appreciable interindividual variation and that hydrolysis of the more toxic enantiomer is favored., (Copyright 2000 Academic Press.)

A sensitive and stereospecific GC method was developed for the analysis of R- and S-enantiomers of mandelic acid (MA) in urine, using a chiral CP Chirasil-Dex-CB column. The enantiomers of MA were derivatised with isopropanol into their corresponding isopropyl esters and determined either directly with flame ionisation detection (FID) or after subsequent derivatisation of a hydroxy group with pentafluoropropionic anhydride with electron-capture detection (ECD). Both derivatisation steps proceeded with negligible inversion of enantiomers (<1%). The limit of detection of the FID determination was 8 and 5 mg/l for R-MA and S-MA, respectively and of the ECD determination 1 mg/l for both enantiomers. Repeatability (within-day precision) and reproducibility (day-to-day precision) was for both enantiomers below 7.5% for the FID and below 5.8% for the ECD analysis. The method was applied to urine of volunteers exposed to 105 and 420 mg styrene/m3 air. In the urine of the exposed volunteers, the S-enantiomer showed higher excretion compared to that of the R-enantiomer, with marked interindividual differences in excretion of both enantiomers.

The effects of alcohol and dietary fat on spontaneous energy and macronutrient intakes were investigated in eight male subjects who participated in a protocol including four randomly assigned 2-d sessions during which they ate ad libitum. In each session they had free access to either high- or low-fat foods, with alcohol or a placebo. The high-fat diet was associated with a substantial increase in daily energy intake. Alcohol had no inhibitory effect on food intake and its energy content was thus associated with an additional increase in energy intake. The enhancing effects of alcohol and dietary fat on daily energy intake were additive so that overfeeding was maximal (2.8 MJ/d) under the high-fat diet+alcohol condition. To further examine the effects of alcohol on energy and macronutrient intakes, reported food intake was studied in 351 men and 360 women who had been tested in the Québec Family Study. The results showed that a high alcohol intake was associated with a high daily energy intake and had no inhibitory effect on lipid intake. In conclusion, a dietary regimen providing a high fraction of energy as alcohol and fat increases the risk for positive energy balance under free-living conditions.