Development of a pig mammary epithelial cell culture model as a non‐clinical tool for studying epithelial barrier— a contribution from the imi‐conception project

The ConcePTION project aims at generating further knowledge about the risks related to the use of medication during breastfeeding, as this information is lacking for most commonly used drugs. Taking into consideration multiple aspects, the pig model has been considered by the consortium as the most appropriate choice. The present research was planned to develop an efficient method for the isolation and culture of porcine Mammary Epithelial Cells (pMECs) to study the mammary epithelial barrier in vitro. Mammary gland tissues were collected at a local slaughterhouse, dissociated and the selected cellular population was cultured, expanded and characterized by morphology, cell cycle analysis and immunophenotyping. Their ability to create a barrier was tested by TEER measurement and sodium fluorescein transport activity. Expression of 84 genes related to drug transporters was evaluated by a PCR array. Our results show that primary cells express epithelial cell markers: CKs, CK18, E‐Cad and tight junctions molecules ZO‐1 and OCL. All the three pMEC cellular lines were able to create a tight barrier, although with different strengths and kinetics, and express the main ABC and SLC drug transporters. In conclusion, in the present paper we have reported an efficient method to obtain primary pMEC lines to study epithelial barrier function in the pig model

Series resistance effects in submicron MOS transistors operated from 300 K down to 4.2 K

In this paper low temperature electrical characterisation (LTEC) of submicron MOS transistors is proposed as an optional tool to investigate second-order effects. The LTEC allows to prove the link between the carrier multiplication at the source side and the series resistance effects. This link cannot be distinguished when the MOS transistor is operated at room temperature. This way one is able to do a further research on the series resistance effects and their impact on the extraction of the electrical parameters of submicron MOS transistors

Soft tissue-based registration of intraoral scan with cone beam computed tomography scan

The aim of this study was to evaluate a novel soft tissue-based method to register an intraoral scan (IOS) with a cone beam computed tomography (CBCT) scan. IOS and CBCT data were obtained from eight dentate patients (mean age 21 ± 2 years; three male, five female) and 14 fully edentulous patients (mean age 56 ± 9 years; eight male, six female). An algorithm was developed to create a soft tissue model of the CBCT scan, which allowed a soft tissue-based registration to be performed with the IOS. First, validation was performed on dentate jaws with registration of the palatal mucosal surface and accuracy evaluation at the level of the teeth. Second, fully edentulous jaws were registered using both the palatal and alveolar crest mucosal surfaces. Distance maps were created to measure the method accuracy. The mean registration error was 0.49 ± 0.26 mm for the dentate jaws. Registration of the fully edentulous jaws had a mean error of 0.16 ± 0.08 mm at the palate and 0.16 ± 0.05 mm at the alveolar crest. In conclusion, the high accuracy of this registration method may allow the digital workflow to be optimized when no teeth are available to perform a regular registration procedure

Glomerular Filtration Rate in Asphyxiated Neonates Under Therapeutic Whole-Body Hypothermia, Quantified by Mannitol Clearance

BACKGROUND Therapeutic hypothermia (TH) is an established intervention to improve the outcome of neonates with moderate-to-severe hypoxic-ischemic encephalopathy resulting from perinatal asphyxia. Despite this beneficial effect, TH may further affect drug elimination pathways such as the glomerular filtration rate. OBJECTIVES The objective of this study was to quantify the effect of TH in addition to asphyxia on mannitol clearance as a surrogate for the glomerular filtration rate. METHODS The effect of asphyxia and TH (mild vs moderate/severe) on mannitol clearance was assessed using a population approach, based on mannitol observations collected in the ALBINO (ALlopurinol in addition to TH for hypoxic-ischemic Brain Injury on Neurocognitive Outcome) trial, as some were exposed to a second dose of 10 mg/kg intravenous mannitol as placebo to ensure blinding. Pharmacokinetic analysis and model development were conducted using NONMEM version 7.4. RESULTS Based on 77 observations from 17 neonates (TH = 13), a one-compartment model with first-order linear elimination best described the observed data. To account for prenatal glomerular filtration rate maturation, both birthweight and gestational age were implemented as clearance covariates using an earlier published three-quarters power function and a sigmoid hyperbolic function. Our final model predicted a mannitol clearance of 0.15 L/h for a typical asphyxia neonate (39.5 weeks, birthweight 3.25 kg, no TH), lower than the reported value of 0.33 L/h for a healthy neonate of similar age and weight. By introducing TH as a binary covariate on clearance, the additional impact of TH on mannitol clearance was quantified (60% decrease). CONCLUSIONS Mannitol clearance was decreased by approximately 60% in neonates undergoing TH, although this is likely confounded with asphyxia severity. TRIAL REGISTRATION ClinicalTrials.gov identifier NCT03162653