In vivo analysis of efavirenz metabolism in individuals with impaired CYP2A6 function

INTRODUCTION: The antiretroviral drug efavirenz (EFV) is extensively metabolized into three primary metabolites: 8-hydroxy-EFV, 7-hydroxy-EFV and N-glucuronide-EFV. There is a wide interindividual variability in EFV plasma exposure, explained to a great extent by cytochrome P450 2B6 (CYP2B6), the main isoenzyme responsible for EFV metabolism and involved in the major metabolic pathway (8-hydroxylation) and to a lesser extent in 7-hydroxylation. When CYP2B6 function is impaired, the relevance of CYP2A6, the main isoenzyme responsible for 7-hydroxylation may increase. We hypothesize that genetic variability in this gene may contribute to the particularly high, unexplained variability in EFV exposure in individuals with limited CYP2B6 function. METHODS: This study characterized CYP2A6 variation (14 alleles) in individuals (N=169) previously characterized for functional variants in CYP2B6 (18 alleles). Plasma concentrations of EFV and its primary metabolites (8-hydroxy-EFV, 7-hydroxy-EFV and N-glucuronide-EFV) were measured in different genetic backgrounds in vivo. RESULTS: The accessory metabolic pathway CYP2A6 has a critical role in limiting drug accumulation in individuals characterized as CYP2B6 slow metabolizers. CONCLUSION: Dual CYP2B6 and CYP2A6 slow metabolism occurs at significant frequency in various human populations, leading to extremely high EFV exposure.

Mutations and polymorphisms in the human argininosuccinate lyase (ASL) gene

Argininosuccinate lyase deficiency (ASLD) is caused by a defect of the urea cycle enzyme argininosuccinate lyase (ASL) encoded by the ASL gene. Patients often present early after birth with hyperammonemia but can also manifest outside the neonatal period mainly triggered by excessive protein catabolism. Clinical courses comprise asymptomatic individuals who only excrete the biochemical marker, argininosuccinic acid, in urine, and patients who succumb to their first hyperammonemic decompensation. Some patients without any hyperammonemia develop severe neurological disease. Here, we are providing an update on the molecular basis of ASLD by collecting all published (n = 67) as well as novel mutations (n = 67) of the ASL gene. We compile data on all 160 different genotypes ever identified in 223 ASLD patients, including clinical courses whenever available. Finally, we are presenting structural considerations focusing on the relevance of mutations for ASL homotetramer formation. ASLD can be considered as a panethnic disease with only single founder mutations identified in the Finnish (c.299T>C, p.Ile100Thr) and Arab (c.1060C>T, p.Gln354*) population. Most mutations are private with only few genotypes recurring in unrelated patients. The majority of mutations are missense changes including some with more frequent occurrence such as p.Arg12Gln, p.Ile100Thr, p.Val178Met, p.Arg186Trp, p.Glu189Gly, p.Gln286Arg, and p.Arg385Cys.

Agrarian learning processes in Switzerland 1918–1939

This paper examines the social impacts of weather extremes and the processes of social and communicative learning a society undertakes to find alternative ways to deal with the consequences of a crisis. In the beginning of the 20th Century hunger seemed to be expelled from Europe. Switzerland – like many other European countries – was involved in a global interdependent trade system, which provided necessary goods. But at the end of World War I very cold and wet summers in 1916/17 (causing crop failure) and the difficulties in war-trade led to malnutrition and enormous price risings of general living-standards in Switzerland, which shocked the people and caused revolutionary uprisings in 1918. The experience of malnutrition during the last two years of war made clear that the traditional ways of food supply in Switzerland lacked crisis stability. Therefore various agents in the field of food production, distribution and consumption searched for alternative ways of food supply. In that sense politicians, industrialists, consumer-groups, left-wing communitarians and farmers developed several strategies for new ways in food production. Traditionally there were political conflicts in Switzerland between farmers and consumers regarding price policies, which led mainly to the conflict in 1918. Consumers accused famers of holding back food to control extortionate prices while the farmers pointed to the bad harvest causing the price rising. The collaboration of these groups in search for new forms of food-stability made social integration possible again. In addition to other crisis-factors, weather extremes can have disastrous impacts and destroy a society’s self-confidence to its core. But even such crisis can lead to processes of substantial learning that allows a regeneration of confidence and show positive influence on political stabilization. The paper focuses on the process of learning and the alternative methods of food production that were suggested by various agents working in the field during the Interwar period. To achieve that goal documents of the various associations are analyzed and newspapers have been taken into consideration. Through the method of discourse-analysis of food-production during the Interwar period, possible solutions that crossed the minds of the agents should be brought to light.