Differential Role of Liver X Receptor (LXR) α and LXRß in the Regulation of UDP-Glucuronosyltransferase 1A1 in Humanized UGT1 Mice.

Liver X receptors (LXRs), LXRα and LXRß, are nuclear receptors that regulate the metabolism of cholesterol and bile acids and are activated by oxysterols. Humanized UGT1 (hUGT1) mice express the 9-human UGT1A genes associated with the UGT1 locus in a Ugt1-null background. The expression of UGT1A1 is developmentally delayed in the liver and intestines, resulting in the accumulation of serum bilirubin during the neonatal period. Induction of UGT1A1 in newborn hUGT1 mice leads to rapid reduction in total serum bilirubin (TSB) levels, a phenotype measurement that allows for an accurate prediction on UGT1A1 expression. When neonatal hUGT1 mice were treated by oral gavage with the LXR agonist T0901317, TSB levels were dramatically reduced. To determine the LXR contribution to the induction of UGT1A1 and the lowering of TSB levels, experiments were conducted in neonatal hUGT1/Lxrα -/- , hUGT1/Lxrß -/- , and hUGT1/Lxrαß -/- mice treated with T0901317. Induction of liver UGT1A1 was dependent upon LXRα, with the induction pattern paralleling induction of LXRα-specific stearoyl CoA desaturase 1. However, the actions of T0901317 were also shown to display a lack of specificity for LXR, with the induction of liver UGT1A1 in hUGT1/Lxrαß -/- mice, a result associated with activation of both pregnane X receptor and constitutive androstane receptor. However, the LXR agonist GW3965 was highly selective toward LXRα, showing no impact on lowering TSB values or inducing UGT1A1 in hUGT1/Lxrα -/- mice. An LXR-specific enhancer site on the UGT1A1 gene was identified, along with convincing evidence that LXRα is crucial in maintaining constitutive expression of UGT1A1 in adult hUGT1 mice. SIGNIFICANCE STATEMENT: It has been established that activation of LXRα, and not LXRß, is responsible for the induction of liver UGT1A1 and metabolism of serum bilirubin in neonatal hUGT1 mice. Although induction of the human UGT1A1 gene is initiated at a newly characterized LXR enhancer site, allelic deletion of the Lxrα gene drastically reduces the constitutive expression of liver UGT1A1 in adult hUGT1 mice. Combined, these findings indicate that LXRα is critical for the developmental expression of UGT1A1.

[Legal aspects of quality assurance : Example of operative intravitreal injection therapy]. / Rechtliche Aspekte der Qualitätssicherung : Beispiel der intravitrealen operativen Injektionstherapie.

BACKGROUND: In the legal evaluation of medical treatments it is important to know which legal and contractual regulations apply. OBJECTIVE: This article discusses in which context treatment errors play a role and are identified as such. MATERIAL AND METHODS: Relevant German legal framework conditions are discussed and examples with reference to intravitreal injection therapy are given. RESULTS: The civil law treatment contract between physician and patient results in the medical obligations of a service contract. As a consequence, the physician is obliged to provide the patient with treatment according to the current generally accepted professional standard, including information obligations, the certainty of a diagnosis, the execution of treatment and aftercare. Before claims for compensation and damages for pain and suffering can be enforced, proof of a treatment error and the causal connection must be provided. In court, mostly expert opinions are used to assess what the professional standard is and whether the physician was sufficiently qualified, whether informed consent and documentation met the legal requirements and whether a (gross) treatment error must be assumed. The Patients' Rights Act emphasizes the importance of an open error culture by requiring a practitioner to inform patients of third party/own treatment errors on request or in order to avert health risks, if circumstances are discernible to the practitioner that justify the assumption of a treatment error. CONCLUSION: Although ophthalmologists cannot guarantee healing or success but only the treatment, there are many medical obligations for intravitreal therapy. Increased standards of quality assurance can be implemented within the framework of selective contracts.