Antioxidant defences and homeostasis of reactive oxygen species in different human mitochondrial DNA-depleted cell lines

Three pairs of parental (ρ+) and established mitochondrial DNA depleted (ρ0) cells, derived from bone, lung and muscle were used to verify the influence of the nuclear background and the lack of efficient mitochondrial respiratory chain on antioxidant defences and homeostasis of intracellular reactive oxygen species (ROS). Mitochondrial DNA depletion significantly lowered glutathione reductase activity, glutathione (GSH) content, and consistently altered the GSH2 : oxidized glutathione ratio in all of the ρ0 cell lines, albeit to differing extents, indicating the most oxidized redox state in bone ρ0 cells. Activity, as well as gene expression and protein content, of superoxide dismutase showed a decrease in bone and muscle ρ0 cell lines but not in lung ρ0 cells. GSH peroxidase activity was four times higher in all three ρ0 cell lines in comparison to the parental ρ+, suggesting that this may be a necessary adaptation for survival without a functional respiratory chain. Taken together, these data suggest that the lack of respiratory chain prompts the cells to reduce their need for antioxidant defences in a tissue-specific manner, exposing them to a major risk of oxidative injury. In fact bone-derived ρ0 cells displayed the highest steady-state level of intracellular ROS (measured directly by 2',7'-dichlorofluorescin, or indirectly by aconitase activity) compared to all the other ρ+ and ρ0 cells, both in the presence or absence of glucose. Analysis of mitochondrial and cytosolic/iron regulatory protein-1 aconitase indicated that most ROS of bone ρ0 cells originate from sources other than mitochondria.

Nonpharmacologic interventions need outcomes for evaluating complex interventions in rheumatic diseases

Introduction. Nonpharmacologic interventions are themselves complex and are often combined with drugs and other interventions in the treatment of rheumatic diseases. Therefore, overall strategies for treatment are complex interventions. These should be evaluated regarding their processes and outcomes.
Methods. The CARE network, an international organization of health professionals (physicians and nonphysicians) and patients conducted a survey in 2008 to identify core outcomes in the ICF perspective, completed with a second survey (2009–2010) with patients in routine practice. These surveys have provided new information about domains to investigate as a basis for evaluating complex interventions.
Results. Outcome Measures in Rheumatology Clinical Trials (OMERACT) participants in this Special Interest Group agreed that current outcomes used in pharmacological research are not sufficient if the nonpharmacologic independent or combined contributions are to be assessed; other domains need to be addressed. This is an area of interest for further development.
Conclusion. Recommendations are proposed to develop research in the area of outcome for evaluation of complex interventions in rheumatic diseases.