Porcine foetal and neonatal CYP3A liver expression

Human cytochrome P450 3A7 (CYP3A7) and cytochrome P450 3A4 (CYP3A4) are hepatic metabolising enzymes which participates in the biotransformation of endo- and exogenous substances in foetuses and neonates respectively. These CYP3A enzymes display an inverse relationship: CYP3A7 is the dominant enzyme in the foetal liver, whereas the expression of CYP3A4 is low. After parturition there is a shift in the expression, thus CYP3A7 is down regulated, while the level of CYP3A4 gradually increases and becomes the dominant metabolising CYP3A enzyme in the adult. The minipig is increasingly being used as a model for humans in biomedical studies, because of its many similarities with the human physiology and anatomy. The aim of this study was to examine whether, as in humans, a shift is seen in the hepatic expression of a CYP3A7- like enzyme to cytochrome P450 3A29 (CYP3A29) (an orthologue to the human CYP3A4) in minipigs. This was elucidated by examining the hepatic mRNA expression of CYP3A7 and CYP3A29 in 39 foetuses and newborn Göttingen minipigs using quantitative real time polymerase chain reaction (qPCR). Furthermore the immunochemical level of CYP3A7-LE and CYP3A29 was measured in liver microsomes using western blotting. The expression of CYP3A29 was approximately 9- fold greater in neonates compared to foetuses, and a similar difference was reflected on the immunochemical level. It was not possible to detect a significant level of foetal CYP3A7 mRNA, but immunoblotting showed a visible difference depending on age. This study demonstrates an increase in the expression of CYP3A29, the CYP3A4 orthologue in perinatal minipigs as in humans, which suggests that the minipig could be a good model when testing for human foetal toxicity towards CYP3A4 substrates

Five things you should know about cost overrun

This paper gives an overview of good and bad practice for understanding and curbing cost overrun in large capital investment projects, with a critique of Love and Ahiaga-Dagbui (2018) as point of departure. Good practice entails: (a) Consistent definition and measurement of overrun; in contrast to mixing inconsistent baselines, price levels, etc. (b) Data collection that includes all valid and reliable data; as opposed to including idiosyncratically sampled data, data with removed outliers, non-valid data from consultancies, etc. (c) Recognition that cost overrun is systemically fat-tailed; in contrast to understanding overrun in terms of error and randomness. (d) Acknowledgment that the root cause of cost overrun is behavioral bias; in contrast to explanations in terms of scope changes, complexity, etc. (e) De-biasing cost estimates with reference class forecasting or similar methods based in behavioral science; as opposed to conventional methods of estimation, with their century-long track record of inaccuracy and systemic bias. Bad practice is characterized by violating at least one of these five points. Love and Ahiaga-Dagbui violate all five. In so doing, they produce an exceptionally useful and comprehensive catalog of the many pitfalls that exist, and must be avoided, for properly understanding and curbing cost overrun

Ny udsathed: nuancer i forståelser af psykisk mistrivsel

Mistrivslen blandt unge i Danmark og en række andre europæiske lande er over de senere år steget markant, hvilket skaber en risiko for, at man generelt kommer til at tegne et stadig mere dystert billede af ungdomslivet i dag. Men går man tættere på, er billedet noget mere broget. Der er således store forskelle på, hvordan trivsel og mistrivsel tager sig ud blandt unge. Vi dykker i denne artikel ned i nuancerne og forskellene i den trivsel, mistrivsel og udsathed, som unge oplever. Med afsæt i en repræsentativ spørgeskemaundersøgelse blandt 2.080 tilfældigt udvalgte danske unge i alderen fra 16 til 25 år har vi gennemført en latent klasseanalyse, der inddeler de unge i fem grupper på baggrund af graden og karakteren af deres trivsel og mistrivsel. Analysen viser store variationer i de unges oplevelser. For én gruppe er det presset i skole og uddannelse, der dominerer deres mistrivsel. For en anden er det psykiske udfordringer, mens en tredje gruppe oplever at trives og at have det endog rigtig godt inden for alle livsområder. Analysen giver tilsammen et mere nuanceret og mindre dramatiserende indblik i trivsel og mistrivsel i ungdomslivet end det, der tegnes i den offentlige debat og påviser vigtige forskelle i, hvad den stigende mistrivsel dækker over