Transporters present in the epithelium of the small intestine determine the efficiency by which dietary and biliary cholesterol are taken up into the body and thus control whole-body cholesterol balance. Niemann-Pick C1 Like Protein 1 (Npc1l1) transports cholesterol into the enterocyte, whereas ATP-binding cassette transporters Abca1 and Abcg5/Abcg8 are presumed to be involved in cholesterol efflux from the enterocyte toward plasma HDL and back into the intestinal lumen, respectively. Abca1, Abcg5, and Abcg8 are well-established liver X receptor (LXR) target genes. We examined the effects of a high-fat diet on expression and function of cholesterol transporters in the small intestine in mice. Npc1l1, Abca1, Abcg5, and Abcg8 were all downregulated after 2, 4, and 8 wk on a cholesterol-free, high-fat diet. The high-fat diet did not affect biliary cholesterol secretion but diminished fractional cholesterol absorption from 61 to 42% (P < 0.05). In an acute experiment in which triacylglycerols of unsaturated fatty acids were given by gavage, we found that this downregulation occurs within a 6-h time frame. Studies in LXRalpha-null mice, confirmed by in vitro data, showed that fatty acid-induced downregulation of cholesterol transporters is LXRalpha independent and associated with a posttranslational increase in 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity that reflects induction of cholesterol biosynthesis as well as with a doubling of neutral fecal sterol loss. This study highlights the induction of adaptive changes in small intestinal cholesterol metabolism during exposure to dietary fat.
This article critically reviews the design and methodology of studies aimed at evaluating relapse and recurrence prevention in major depression. A literature search in MEDLINE was performed with the medical subject headings 'depression', 'recurrence', 'relapse', 'prevention' and 'study'. This search covered the period from January 1990 to July 1999. Only long-term placebo-controlled studies that included patients with non-chronic major depression were selected. Two types of design could be distinguished: randomised withdrawal studies in responders/remitters (N = 11) and extension studies in responders without re-randomisation (N = 3). Randomised withdrawal studies are suitable for demonstrating long-term efficacy for the duration of the study period. However, this design does not permit a clear differentiation between relapse or recurrence and, therefore, is not suitable to demonstrate unequivocally relapse prevention or recurrence prevention. Extension studies in short-term responders without randomisation are not even suitable to demonstrate long-term efficacy.A novel design is proposed that overcomes the weaknesses of designs employed thus far. In essence, this design calls for a long-term randomised placebo-controlled study in patients who are free of medication for a substantial period of time and who fulfil the criteria of major depression (recurrent) in sustained remission (e.g., HDRS < 7) as a possible option.
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