Health utilities for children and adults with type 1 diabetes.

OBJECTIVE: We studied health utilities in patients with type 1 diabetes to understand potential differences in health utilities as function of age, type of respondent (self report vs. proxy report), and method of assessment (direct vs. indirect). RESEARCH DESIGN AND METHODS: We elicited self-reported health utilities for adults (n=213) and children (n=238) with type 1 diabetes, and by parent proxy report (n=223) for overall quality of life [Health Utilities Index (HUI) Mark 3 and experienced time-trade-off (TTO) questions] and hypothetical complication states (TTO questions). RESULTS: Mean health utilities for overall quality of life (QOL) ranged from 0.81 to 0.91. Children had significantly higher overall QOL compared with adults (0.89 vs. 0.85, P<0.01) by HUI, but had no significant difference in QOL by TTO. There were no significant differences in QOL between child self report and parent proxy report. Utilities were higher for HUI versus TTO for parent proxy report (P<0.01) but not for adult or child self report. Utilities for hypothetical complication states were lower than for current QOL. Values were lower for stroke (0.34 to 0.53), end stage renal disease (0.47 to 0.55), and blindness (0.52 to 0.69) than for amputation (0.73 to 0.82) and angina (0.74 to 0.80). Complication utilities for parent proxy report were higher compared with adult self report for most hypothetical complication states. CONCLUSIONS: Individuals with type 1 diabetes with few complications report a relatively high QOL; however, future end stage complications are rated as having a significant impact on QOL. Differences in utilities by age, self report versus proxy report, and method raise important questions about whose utilities should be used in economic analyses.

Fast kinase domain-containing protein 3 is a mitochondrial protein essential for cellular respiration.

Fas-activated serine/threonine phosphoprotein (FAST) is the founding member of the FAST kinase domain-containing protein (FASTKD) family that includes FASTKD1-5. FAST is a sensor of mitochondrial stress that modulates protein translation to promote the survival of cells exposed to adverse conditions. Mutations in FASTKD2 have been linked to a mitochondrial encephalomyopathy that is associated with reduced cytochrome c oxidase activity, an essential component of the mitochondrial electron transport chain. We have confirmed the mitochondrial localization of FASTKD2 and shown that all FASTKD family members are found in mitochondria. Although human and mouse FASTKD1-5 genes are expressed ubiquitously, some of them are most abundantly expressed in mitochondria-enriched tissues. We have found that RNA interference-mediated knockdown of FASTKD3 severely blunts basal and stress-induced mitochondrial oxygen consumption without disrupting the assembly of respiratory chain complexes. Tandem affinity purification reveals that FASTKD3 interacts with components of mitochondrial respiratory and translation machineries. Our results introduce FASTKD3 as an essential component of mitochondrial respiration that may modulate energy balance in cells exposed to adverse conditions by functionally coupling mitochondrial protein synthesis to respiration.

Fas-activated serine/threonine phosphoprotein (FAST) is a regulator of alternative splicing.

Fas-activated serine/threonine phosphoprotein (FAST) is a survival protein that is tethered to the outer mitochondrial membrane. In cells subjected to environmental stress, FAST moves to stress granules, where it interacts with TIA1 to modulate the process of stress-induced translational silencing. Both FAST and TIA1 are also found in the nucleus, where TIA1 promotes the inclusion of exons flanked by weak splice recognition sites such as exon IIIb of the fibroblast growth factor receptor 2 (FGFR2) mRNA. Two-hybrid interaction screens and biochemical analysis reveal that FAST binds to several alternative and constitutive splicing regulators, suggesting that FAST might participate in this process. The finding that FAST is concentrated at nuclear speckles also supports this contention. We show that FAST, like TIA1, promotes the inclusion of exon IIIb of the FGFR2 mRNA. Both FAST and TIA1 target a U-rich intronic sequence (IAS1) adjacent the 5' splice site of exon IIIb. However, unlike TIA1, FAST does not bind to the IAS1 sequence. Surprisingly, knockdown experiments reveal that FAST and TIA1 act independently of one another to promote the inclusion of exon IIIb. Mutational analysis reveals that FAST-mediated alternative splicing is separable from the survival effects of FAST. Our data reveal that nuclear FAST can regulate the splicing of FGFR2 transcripts.