ABSTRACT
The anti-inflammatory properties of essential fatty acid deficiency or n-3 polyunsaturated fatty acid supplementation have been attributed to a reduced content of arachidonic acid (AA; 20:4 n-6). An alternative, logical approach to depleting AA would be to decrease endogenous synthesis of AA by selectively inhibiting the delta5 and/or the delta6 fatty acid desaturase. High-throughput radioassays were developed for quantifying delta5, delta6, and delta9 desaturase activities in vitro and in vivo. CP-24879 (p-isopentoxyaniline), an aniline derivative, was identified as a mixed delta5/delta6 desaturase inhibitor during the screening of chemical and natural product libraries. In mouse mastocytoma ABMC-7 cells cultured chronically with CP-24879, there was a concentration-dependent inhibition of desaturase activity that correlated with the degree of depletion of AA and decreased production of leukotriene C4 (LTC4). Production of LTC4 was restored by stimulating the cells in the presence of exogenous AA, indicating that endogenous AA was limiting as substrate. In the livers of mice treated chronically with the maximally tolerated dose of CP-24879 (3 mg/kg, t.i.d.), combined delta5/delta6 desaturase activities were inhibited approximately 80% and AA was depleted nearly 50%. These results suggest that delta5 and/or delta6 desaturase inhibitors have the potential to manifest an anti-inflammatory response by decreasing the level of AA and the ensuing production of eicosanoids.
Subject(s)
Aniline Compounds/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Fatty Acid Desaturases/metabolism , Aniline Compounds/pharmacokinetics , Aniline Compounds/pharmacology , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Arachidonic Acid/metabolism , Cells, Cultured , Diet , Enzyme Inhibitors/pharmacokinetics , Fatty Acids/metabolism , In Vitro Techniques , Indicators and Reagents , Leukotriene C4/biosynthesis , Liver/drug effects , Liver/metabolism , Male , Mice , Mice, Inbred BALB C , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Rats , Rats, Sprague-Dawley , Tumor Cells, CulturedABSTRACT
In the past decade there have been increases in health care consolidations. While the literature on hospital mergers is abundant, there is little on mergers of medical staffs. In this study, we interviewed senior administrators in 22 midwestern medical institutions that had consolidated between 1987 and 1990. Our study is an exploration of topics of concern that administrators have encountered during processes of medical staff consolidation. Administrators stated that the medical staff was most concerned about relationships with nursing and support staff, "turf" issues, and a sense of loss. They recommended that increased attention be paid to specific local issues and that there be active involvement and communication between medical staff and administrators at all phases of the consolidation process.
Subject(s)
Health Facility Merger/organization & administration , Medical Staff, Hospital/organization & administration , Communication , Data Collection , Health Facility Merger/statistics & numerical data , Health Services Research , Hospital-Physician Relations , Humans , Interpersonal Relations , Medical Staff, Hospital/statistics & numerical data , Midwestern United States , Practice Patterns, Physicians' , Surveys and QuestionnairesABSTRACT
Human feces samples from a self-dosing experiment were analyzed by gas chromatography/mass spectrometry (GC/MS) for [3H]-2,3,7,8-tetrachlorodibenzo-p-dioxin (3H-2378-TCDD) to determine that 36-44% of the radioactivity was attributable to the parent compound. This method, using isotope dilution analysis, proved to be difficult due to the unexpectedly higher native 2378-TCDD background which created abnormally large precision ranges around the calculated feces concentrations of 0.1-0.2 pg/g. These results were supported by additional analyses involving the GC/MS chemical cleanup method combined with liquid scintillation counting which showed that at most, 50% of the radioactivity was due to 2378-TCDD metabolites resulting in a minimum metabolism of 50% for these samples.
Subject(s)
Dioxins/metabolism , Feces/analysis , Polychlorinated Dibenzodioxins/metabolism , Gas Chromatography-Mass Spectrometry , Humans , TritiumABSTRACT
Paired human hepatic and adipose tissues from 26 people were assayed for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). On a whole tissue weight basis, TCDD concentration in the liver was about one-tenth that in the adipose tissue. When expressed in total tissue lipid basis, the TCDD concentrations in the liver and adipose tissue were about equal. At low levels of exposure, presumably below those necessary to cause hepatic enzyme induction, TCDD appeared to be partitioning into the human liver predominantly on the basis of its lipid solubility in that tissue store. The partitioning behavior of TCDD in the livers of humans exposed to higher levels of TCDD is currently unclear.
