Adipocyte differentiation of 3T3-L1 cells under tenofovir alafenamide, tenofovir disoproxil fumarate, and integrase strand transfer inhibitors selective challenge: an in-vitro model.

OBJECTIVE: Integrase strand transfer inhibitors (INSTIs) are a class of antiretroviral therapy (ART) medications with a good tolerability profile and a high genetic barrier to HIV drug resistance. However, several studies report significant weight gain among persons receiving INSTI-based ART regimens compared with other regimens. DESIGN: In-vitro model of adipogenesis. METHODS: We used 3T3-L1 cells to investigate the effects of the nucleoside reverse transcriptase inhibitors (NRTIs) tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF), alone or in combination with INSTIs: raltegravir (RAL), elvitegravir (ELV), dolutegravir (DTG), and bictegravir (BIC) on adipose differentiation. To monitor adipocyte differentiation, expression levels of PPARÉ£ and C/EBPα and the intracellular lipid accumulation by Red Oil staining were used. Furthermore, we evaluated the immunohistochemical expression of ER-TR7, a fibroblastic marker, after INSTIs treatment. RESULTS: Compared with control, INSTIs were able to increase adipogenesis, especially RAL and ELV. TAF and TDF inhibited adipogenesis alone and in combination with INSTIs. This ability was more evident when TAF was used in combination with DTG and BIC. Finally, INSTIs increased the expression of ER-TR7 compared with control and cells treated with TAF or TDF. CONCLUSION: Our data support the evidence that in-vitro challenge of 3T3-L1 cells with INSTIs is able to increase adipocytic differentiation and to drive a number of these cells toward the expression of fibroblastic features, with a different degree according to the various drugs used whereas TAF and TDF have an antagonistic role on this phenomenon.

The precautionary principle and genetically modified organisms: A bone of contention between European institutions and member states.

This manuscript examines how the Precautionary Principle has been applied to provide a mechanism for protection of the environment and health in response to the introduction of Genetically Modified Organisms (GMOs) in Europe. It discusses how the Court of Justice of the European Union (CJEU) handled national requests across four cases in which Member States had failed in their attempt to trigger the Precautionary Principle in order to uphold a ban or suspension of the cultivation or sale of GMOs in their territory. The analysis of these judgements suggests that the court has applied a narrow interpretation to the scientific evidence emerging from risk assessments, and has thereby limited the potential for precautionary measures by Member States to be upheld by the court. This outcome reflects a `weak' application of the Precautionary Principle by the court in contrast with the `moderate' formulation and `strong' interpretation of the principle offered by the European legal framework. Moreover, the analysis highlights that the CJEU's rulings are not keeping pace with the development of the European normative framework which considers the Precautionary Principle as a key tenet and, through the 2015 Directive, enables Member States to ban GMO cultivation without referring to scientific evidence.

Are WTO Decisionmakers Regulating Technological Risks or Are Technological Risks Steering WTO Biotechnology Legal Decisions?

This article explores how technological risks and uncertainty carried by the international trade of biotechnology are regulated under the World Trade Organization (WTO) and have been governed by the WTO's judicial bodies. The article shows that the judicial evaluation of biotechnology risks is mostly justified in scientific terms and is still anchored to a quantitative approach. This, in turn, prevents WTO decisionmakers from performing a broader analysis of the societal purposes and impacts of technological innovations and, accordingly, their potential contributions to or disadvantages for the public interest. Given that, the present article investigates whether reliability can be claimed for WTO biotechnology decisions. In approaching this task, it elucidates the complex interplay between law, risks and science, and offers suggestions to enhance the reliability of biotechnology legal decisions and address the uncertainty surrounding the international trade of biotechnology.

Chronic eosinophilic ascites in a very young child.

UNLABELLED: A case of chronic eosinophilic ascites with onset in early infancy is described. An intensive diagnostic work-up ruled out other known causes of ascites in childhood. The final diagnosis was made at 2 years of age when a large number of eosinophils was detected in the ascitic fluid. The outcome was complicated by an ex vacuo intraperitoneal haemorrhage. Steroids were able to control the disease only after complete aspiration (1600 ml) of the ascitic fluid. On discontinuation of treatment, peritoneal inflammation recurred indicating steroid-dependency. CONCLUSION: eosinophilic ascites, a very rare disorder in children, should be considered in the differential diagnosis of even very young children presenting with ascites.