[Show abstract][Hide abstract] ABSTRACT: Background:
There is relevant between individual variability in paracetamol clearance in young women. In this pooled study, we focused on the population pharmacokinetic profile of intravenous paracetamol metabolism and its covariates in young women.
Population PK parameters using non-linear mixed effect modelling were estimated in a pooled dataset of plasma and urine PK studies in 69 young women [47 at delivery, 8/47 again 10-15 weeks after delivery (early postpartum), and 7/8 again 1 year after delivery (late postpartum), 22 healthy female volunteers with or without oral contraceptives].
Population PK parameters were estimated based on 815 plasma samples and 101 urine collections. Compared to healthy female volunteers (reference group) not on oral contraceptives, being at delivery was the most significant covariate for clearance to paracetamol glucuronide (Factor = 2.03), while women in early postpartum had decreased paracetamol glucuronidation clearance (Factor = 0.55). Women on contraceptives showed increased paracetamol glucuronidation clearance (Factor = 1.46). The oestradiol level did not further affect this model. Being at delivery did not prove significant for clearance to paracetamol sulphate, but was higher in pregnant women who delivered preterm (<37 weeks, Factor = 1.34) compared to term delivery and non-pregnant women. Finally, clearance of unchanged paracetamol was dependent on urine flow rate.
Compared to healthy female volunteers not on oral contraceptives, urine paracetamol glucuronidation elimination in young women is affected by pregnancy (higher), early postpartum (lower) or exposure to oral contraceptives (higher), resulting in at least a two fold variability in paracetamol clearance in young women.
[Show abstract][Hide abstract] ABSTRACT: Image guidance plays a central role in minimally invasive fetal surgery such as photocoagulation of inter-twin placental anasto-mosing vessels to treat twin-to-twin transfusion syndrome (TTTS). Fe-toscopic guidance provides insufficient sensitivity for imaging the vascu-lature that lies beneath the fetal placental surface due to strong light scattering in biological tissues. Incomplete photocoagulation of anasta-moses is associated with postoperative complications and higher perinatal mortality. In this study, we investigated the use of multi-spectral photoacoustic (PA) imaging for better visualization of the placental vas-culature. Excitation light was delivered with an optical fiber with dimensions that are compatible with the working channel of a fetoscope. Imaging was performed on an ex vivo normal term human placenta collected at Caesarean section birth. The photoacoustically-generated ultrasound signals were received by an external clinical linear array ultrasound imaging probe. A vein under illumination on the fetal placenta surface was visualized with PA imaging, and good correspondence was obtained between the measured PA spectrum and the optical absorption spectrum of deoxygenated blood. The delivery fiber had an attached fiber optic ultrasound sensor positioned directly adjacent to it, so that its spatial position could be tracked by receiving transmissions from the ultrasound imaging probe. This study provides strong indications that PA imaging in combination with ultrasonic tracking could be useful for detecting the human placental vasculature during minimally invasive fetal surgery.
[Show abstract][Hide abstract] ABSTRACT: Objective:
We first aimed to investigate in vivo thrombin generation induced by fetoscopy, and second we used term membrane explants for measurement of thrombin generation, thrombin receptor location and induction of selected matrix metalloproteinases (MMPs) in tissue culture.
Materials and methods:
In vivo study (37 cases): samples of amniotic fluid were taken at the beginning and end of fetoscopy (mean gestational age 26.7 weeks) and analyzed by ELISA for thrombin-antithrombin complexes. In vitro study: fetal membranes were put in culture and punctured for measurement of thrombin generation by calibrated automated thrombography and ELISA. Induction of MMP-9 and MMP-2 was analyzed by zymography. PAR-1 was localized by immunohistochemistry.
No significant increase in thrombin-antithrombin was measured in amniotic fluid obtained during fetoscopy. In vitro, thrombin generation induced by needle trauma of membrane cultures is correlated to the amount of plasma. Activity of MMP-9 but not MMP-2 was elevated in cultured membranes but could not be inhibited by a thrombin inhibitor. On histology, the thrombin receptor PAR-1 was located in the chorion and decidua, but not in the amnion.
Despite the influence of thrombin on punctured fetal membranes in vitro, the role of thrombin in iatrogenic preterm premature rupture of membranes is questionable.
Fetal Diagnosis and Therapy 10/2015; DOI:10.1159/000439304 · 2.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objectives:
Mesenchymal stem cells derived from human amniotic fluid (hAFSCs) are a promising source for cellular therapy, especially for renal disorders, as a subpopulation is derived from the fetal urinary tract. The purpose of this study was to evaluate if hAFSCs with a renal progenitor phenotype demonstrate a nephroprotective effect in acute ischemia reperfusion (I/R) model and prevent late stage fibrosis.
A total of 45 male 12-wk-old Wistar rats were divided into three equal groups;: rats subjected to I/R injury and treated with Chang Medium, rats subjected to I/R injury and treated with hAFSCs and sham-operated animals. In the first part of this study, hAFSCs that highly expressed CD24, CD117, SIX2 and PAX2 were isolated and characterized. In the second part, renal I/R injury was induced in male rats and cellular treatment was performed 6 hours later via arterial injection. Functional and histological analyses were performed 24 hours, 48 hours and 2 months after treatment using serum creatinine, urine protein to creatinine ratio, inflammatory and regeneration markers and histomorphometric analysis of the kidney. Statistical analysis was performed by analysis of variance followed by the Tukey's test for multiple comparisons or by nonparametric Kruskal-Wallis followed by Dunn. Statistical significance level was defined as p <0.05.
hAFSCs treatment resulted in significantly reduced serum creatinine level at 24 hours, less tubular necrosis, less hyaline cast formation, higher proliferation index, less inflammatory cell infiltration and less myofibroblasts at 48h. The treated group had less fibrosis and proteinuria at 2 months after injury.
hAFSCs contain a renal progenitor cell subpopulation that has a nephroprotective effect when delivered intra-arterially in rats with renal I/R injury, and reduces interstitial fibrosis on long term follow-up.
PLoS ONE 09/2015; 10(8). DOI:10.1371/journal.pone.0136145 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Lung hypoplasia in congenital diaphragmatic hernia (CDH) is a life-threatening birth defect. Severe cases can be offered tracheal occlusion to boost prenatal lung development, though defining those to benefit remains challenging. Metabonomics of 1H NMR spectra collected from amniotic fluid (AF) can identify general changes in diseased versus healthy fetuses. AF contains lung secretions, hence, might reflect pulmonary characteristics among general markers of disease in CDH fetuses. AF from 81 healthy and 22 CDH fetuses was collected. NMR spectroscopy was performed at 400 MHz to compare AF from fetuses with CDH against controls. Several advanced feature extraction methods based on statistical tests which explore spectral variability, similarity and dissimilarity were applied and compared. This resulted in the identification of 30 spectral regions, which accounted for 80% variability between CDH and controls. Combination with automated classification discriminates AF from CDH versus healthy fetuses with 86% accuracy. Within the identified spectral regions isoleucine, leucine, valine, pyruvate, GABA, glutamate, glutamine, citrate, creatine, creatinine, taurine and glucose were the most concentrated metabolites. As the metabolite pattern of AF changes with fetal development, we have excluded metabolites with a high age-related variability and repeated the analysis with twelve spectral regions, which has resulted in similar classification accuracy. From this analysis, it was possible to distinguish between AF from fetuses with CDH from healthy controls independent of gestational age dependent metabolic changes.
Journal of Proteome Research 09/2015; DOI:10.1021/acs.jproteome.5b00131 · 4.25 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective
Our objective was to create a semi-automated levator hiatus outlining tool to reduce inter-observer variability and speed up analysis.Methods
The proposed Automated Hiatus Segmentation algorithm (AHS) takes a C-plane image (image in the plane of minimal hiatal dimensions) and the vertical hiatal limits as inputs. The AHS then creates an initial outline by fitting pre-defined templates on an intensity invariant edge map which is further refined using the B-spline active surfaces framework.The AHS was tested using 91 representative C-plane images. Reference hiatal outlines were obtained manually and compared to the AHS outlines by three independent observers. The Mean Absolute Distance (MAD), Hausdorff distance, Dice and Jaccard Coefficients were used to quantify segmentation accuracy. Each of these metrics was calculated both for Computer-Observer Differences (COD) and Inter-Observer Difference. The Williams Index was used to test the null hypothesis that the automated method agrees with the operators at least as well as the operators agree with each other. Agreement between the two methods was studied using the Intraclass Correlation Coefficient (ICC) and Bland-Altman plots.ResultsThe AHS contours matched well with the manual ones (COD = 2.10 (1.54) mm [Median (IQR)] for MAD). The WI was greater than or close to 1 for all quality metrics indicating that the algorithm performs at least as well as the manual referees in terms of inter-rater variability. The IODs using each of the difference metrics were significantly lower when using the AHS. A higher ICC was achieved when using the AHS (0.93). The Bland Altman plots show negligible bias between two methods. Using the AHS took about 7.07(3.49) s compared to manual outlining that took 21.31(5.43)s [Median(IQR)], thus achieving a speedup of almost 3X.On an average the hiatus could be outlined completely using only three points, two for initialization, with one for manual adjustment.Conclusions
We present for the first time a method for tracing hiatal outline with minimal user input. The AHS is fast, robust, reliable and improves inter-rater agreement.
Ultrasound in Obstetrics and Gynecology 09/2015; DOI:10.1002/uog.15777 · 3.85 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The neonatal management of preterm born infants often results in damage to the developing lung and subsequent morbidity, referred to as bronchopulmonary dysplasia (BPD). Animal models may help in understanding the molecular processes involved in this condition and define therapeutic targets. Our goal was to identify molecular pathways using the earlier described preterm rabbit model of hyperoxia induced lung-injury. Transcriptome analysis by mRNA-sequencing was performed on lungs from preterm rabbit pups born at day 28 of gestation (term: 31 days) and kept in hyperoxia (95% O2) for 7 days. Controls were preterm pups kept in normoxia. Transcriptomic data were analyzed using Array Studio and Ingenuity Pathway Analysis (IPA), in order to identify the central molecules responsible for the observed transcriptional changes. We detected 2217 significantly dysregulated transcripts following hyperoxia, of which 90% could be identified. Major pathophysiological dysregulations were found in inflammation, lung development, vascular development and reactive oxygen species (ROS) metabolism. To conclude, amongst the many dysregulated transcripts, major changes were found in the inflammatory, oxidative stress and lung developmental pathways. This information may be used for the generation of new treatment hypotheses for hyperoxia-induced lung injury and BPD.
PLoS ONE 08/2015; 10(8):e0136569. DOI:10.1371/journal.pone.0136569 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Fetoscopic laser surgery for twin-twin transfusion syndrome is a procedure for which no objective tools exist to assess technical skills. To ensure that future fetal surgeons reach competence prior to performing the procedure unsupervised, we developed a performance assessment tool. The aim of this study was to validate this assessment tool for reliability and construct validity.
A procedure-specific evaluation instrument containing all essential steps of the fetoscopic laser procedure was created using Delphi methodology. Eleven experts and 13 novices from three Fetal Medicine centers performed the procedure on the same simulator. Two independent observers assessed each surgery using the instrument (maximum score: 52). Inter-observer reliability was assessed using Spearman correlation. We compared performance of novices and experts to assess construct validity.
Inter-observer reliability was high (r=0.974, p<0.001). Checklist scores for experts and novices were significantly different: median score for novices was 28/52 (54%) while for experts 42/52 (81%) (p<0.001). Procedure time and fetoscopy time were significantly shorter (p<0.001) for experts. Residual anastomoses were found in 1/11 (9%) procedures performed by experts and in 9/14 (64%) performed by novices (p=0.006). Multivariate analysis showed that the checklist score independently from age and gender predicted competence.
The procedure-specific assessment tool for fetoscopic laser surgery shows a good inter-observer reliability and discriminates experts from novices. This instrument may therefore be a useful tool in the training curriculum for starting fetal surgeons. Further intervention studies with reassessment before and after training may increase the construct validity of the tool.
This article is protected by copyright. All rights reserved.
Ultrasound in Obstetrics and Gynecology 08/2015; DOI:10.1002/uog.15734 · 3.85 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Fetal surgery has become a clinical reality, with interventions for twin-to-twin transfusion syndrome (TTTS) and spina bifida demonstrated to improve outcome. Fetal imaging is evolving, with the use of 3D ultrasound and fetal MRI becoming more common in clinical practise. Medical imaging analysis is also changing, with technology being developed to assist surgeons by creating 3D virtual models that improve understanding of complex anatomy, and prove powerful tools in surgical planning and intraoperative guidance. We introduce the concept of computer-assisted surgical planning, and present the results of a systematic review of image reconstruction for fetal surgical planning that identified six articles using such technology. Indications from other specialities suggest a benefit of surgical planning and guidance to improve outcomes. There is therefore an urgent need to develop fetal-specific technology in order to improve fetal surgical outcome.
This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: Neonates with congenital diaphragmatic hernia and large defects often require patch closure. Acellular collagen matrices (ACM) have been suggested as an alternative to synthetic durable patches as they are remodeled by the host or could also be used for tissue engineering purposes.
2.0x1.0 cm diaphragmatic defects were created in 6-weeks old New-Zealand white rabbits. We compared reconstruction with a purpose-designed cross-linked ACM (Matricel) to 4-layer non-cross-linked small intestinal submucosa (SIS) and a 1-layer synthetic Dual Mesh (Gore-Tex). Unoperated animals or animals undergoing primary closure (4/0 polyglecaprone) served as age-matched controls. 60 (n = 25) resp. 90 (n = 17) days later, animals underwent chest x-ray and obduction for gross examination of explants, scoring of adhesion and inflammatory response. Also, uniaxial tensiometry was done, comparing explants to contralateral native diaphragmatic tissue.
Overall weight nearly doubled from 1,554±242 g at surgery to 2,837±265 g at obduction (+84%). X-rays did show rare elevation of the left diaphragm (SIS = 1, Gore-Tex = 1, unoperated control = 1), but no herniation of abdominal organs. 56% of SIS and 10% of Matricel patches degraded with visceral bulging in four (SIS = 3, Matricel = 1). Adhesion scores were limited: 0.5 (Matricel) to 1 (SIS, Gore-Tex) to the left lung (p = 0.008) and 2.5 (Gore-Tex), 3 (SIS) and 4 (Matricel) to the liver (p<0.0001). Tensiometry revealed a reduced bursting strength but normal compliance for SIS. Compliance was reduced in Matricel and Gore-Tex (p<0.01). Inflammatory response was characterized by a more polymorphonuclear cell (SIS) resp. macrophage (Matricel) type of infiltrate (p<0.05). Fibrosis was similar for all groups, except there was less mature collagen deposited to Gore-Tex implants (p<0.05).
Matricel induced a macrophage-dominated inflammatory response, more adhesions, had appropriate strength but a lesser compliance compared to native tissue. The herein investigated ACM is not a viable option for CDH repair.
PLoS ONE 07/2015; 10(7):e0132021. DOI:10.1371/journal.pone.0132021 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To assess in vivo changes in lung and liver volume in fetuses with isolated congenital diaphragmatic hernia (CDH), either expectantly managed or treated in utero.
This is a secondary analysis of prospectively collected data at 2 fetal therapy centers. We used archived magnetic resonance (MR) images of fetuses taken ≥7 days apart, creating paired observations in 20 expectantly managed cases, 41 with a second MR prior to balloon reversal and 64 after balloon removal. We measured observed to expected total fetal lung volume (O/E TFLV) and liver-to-thoracic volume ratio (LiTR). We calculated changes in volume as compared to the initial measurement and its rate as a function of gestational age (GA) at occlusion.
The LiTR did not change in either group. In expectantly managed fetuses, O/E TFLV did not increase with gestation. In fetuses undergoing tracheal occlusion (TO) the measured increase in volume was 2.6-times larger with balloon in place as compared to after its removal. GA at TO was an independent predictor of the O/E TFLV. The net rate seems to initially increase and plateau at a maximum of 1.5%/week by 35-45 days after occlusion.
TO induces a net increase in volume, its magnitude essentially dependent on the GA at occlusion. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: To evaluate the effect of a newly developed training curriculum on performance of fetoscopic laser surgery for twin-twin transfusion syndrome (TTTS) using an advanced high-fidelity simulator model.
Ten novices were randomized to receive verbal instructions and skills training using the simulator (study group, n = 5) or no training (control group, n = 5). Both groups were evaluated with a pre-training test and post-training test. Assessment was performed by two independent observers and compromised a 52-item checklist for surgical performance (SP score), measurement of procedure time and number of anastomoses missed. Face validity and educational value of the simulator were assessed using a questionnaire. Eleven experts set the benchmark level of performance.
Both groups showed an improvement in SP score compared to the pre-training test. The simulator-trained group significantly outperformed the control group with a median SP score of 28 (54%) in the pre-test and 46 (88%) in the post-test versus 25 (48%) and 36 (69%) (p = 0.008). Procedure time decreased 11 min in the study group versus 1 min in the control group; to 32 min versus 38 min, respectively (p = 0.69). The number of missed anastomoses was not different between groups (1 versus none). Feedback provided by the participants indicated that training on the simulator was perceived as a useful educational activity.
Proficiency-based simulator training improves performance on surgical performance score for fetoscopic laser therapy. Despite the small sample size of this study practice on a simulator is recommended before trainees carry out laser therapy for TTTS in pregnant women.
This article is protected by copyright. All rights reserved.
Ultrasound in Obstetrics and Gynecology 06/2015; 46(3). DOI:10.1002/uog.14916 · 3.85 Impact Factor