Relationship of oxidative damage to the hepatocarcinogenicity of the peroxisome proliferators di(2-ethylhexyl)phthalate and Wy-14,643

Quantitative comparisons of the time course of biochemical andmorphological changes induced by peroxisome proliferators resultingin low and high incidences of hepatic cancer have not been conductedpreviously under bioassay conditions. [4-Chloro-6-(2,3 xylidino)-2-pyrimidyl-thio]aceticacid (Wy-14,643) at 0.1% in the diet produced a much higherincidence of hepatic cancer in male rats than 1.2% di(2-ethylhexyl)phthalate(DEHP) in the diet. Both diets, however, caused similar degreesof peroxisome proliferation. To investigate this differencein carcinogenicity, H₂O₂-detoxification mechanisms and indicesof oxidative damage were evaluated in male F-344 rats fed 1.2%DEHP or 0.1% Wy-14,643 for up to one year. DEHP or Wy-14,643treatment increased hepatic catalase activity 25% from 8 to365 days. DEHP or Wy-14,643 treatment decreased hepatic glutathioneperoxidase activity by 50% from 8 to 365 days. Glutathione concentrationswere not affected by 151 days of DEHP or Wy-14,643 feeding.The similar effects of DEHP and Wy on H₂O₂ detoxification enzymesand glutathione concentrations suggests that these factors arenot responsible for the widely different carcinogenicities ofWy-14,643 and DEHP. Hepatic vitamin E concentrations were 50%lower in rats receiving Wy-14,643 for 151 days as compared torats fed DEHP or control diets. Lipofuscin, which was containedwithin lysosomes, was increased 3-fold after 39 days of DEHPand remained at this level up to 365 days of treatment. In comparison,lipofuscin was increased 4-fold after 18 days of Wy-14,643 andcontinued to accumulate in a linear manner reaching values 30-foldover controls after 365 days of treatment. DEHP treatment for39–365 days increased the activities of the lysosomalenzymes -fucosidase, ß-galactosidase and N-acetylglucosaminidase50–100%. The same enzyme activities were increased 4-foldafter 39–365 days of Wy-14,643. Lysosomal cathepsin Bactivity was unchanged by DEHP but doubled by 151 and 365 daysof Wy-14,643. Acid phosphatase activity was unchanged by DEHPbut increased by 50% after 151 and 365 days of Wy-14, 643. Inaddition, conjugated dienes were increased (45%) only in ratsreceiving Wy-14,643 for 151 and 365 days. These data show forthe first time that the magnitude and time course of lipofuscindeposition, induction of lysosomal enzymes and conjugated dieneaccumulation, is correlated closely with the degree of carcinogenicity.Wy-14,643-induced decreases in hepatic vitamin E concentrationscould contribute to the observed accumulation of conjugateddienes at later time points. The data suggest that lipofuscinaccumulation is an early biomarker that is quantitatively predictiveof the carcinogenicity of the peroxisome proliferators DEHPand Wy-14,643.     

Quantitative study of the immunoglobulin-containing cells in trephine samples of bone marrow

Immunoglobulin (Ig) was demonstrated in paraffin sections of 12 trephine bone marrow biopsies by means of the unlabelled antibody peroxidase-antiperoxidase (PAP) method. The Ig-containing cells, which were counted with the Reichert-Jung (Kontron) MOP-AMO₃ user-controlled image-analyser, were found to constitute approximately 4·2% of all the nucleated cells in the marrow, a figure significantly higher than those reported by previous workers.     

Consensus guidelines on analgesia and sedation in dying intensive care unit patients

Background

Intensivists must provide enough analgesia and sedation to ensure dying patients receive good palliative care. However, if it is perceived that too much is given, they risk prosecution for committing euthanasia. The goal of this study is to develop consensus guidelines on analgesia and sedation in dying intensive care unit patients that help distinguish palliative care from euthanasia.

Methods

Using the Delphi technique, panelists rated levels of agreement with statements describing how analgesics and sedatives should be given to dying ICU patients and how palliative care should be distinguished from euthanasia. Participants were drawn from 3 panels: 1) Canadian Academic Adult Intensive Care Fellowship program directors and Intensive Care division chiefs (N = 9); 2) Deputy chief provincial coroners (N = 5); 3) Validation panel of Intensivists attending the Canadian Critical Care Trials Group meeting (N = 12).

Results

After three Delphi rounds, consensus was achieved on 16 statements encompassing the role of palliative care in the intensive care unit, the management of pain and suffering, current areas of controversy, and ways of improving palliative care in the ICU.

Conclusion

Consensus guidelines were developed to guide the administration of analgesics and sedatives to dying ICU patients and to help distinguish palliative care from euthanasia.