Huntington’s disease (HD) is a fatal neurodegenerative disorder caused by an expanded polyglutamine repeat in huntingtin (Htt) protein. Current management strategies temporarily relieve disease symptoms, but fail to affect the underlying disease progression. We previously demonstrated that calorie restriction ameliorated HD pathogenesis and slowed disease progression in HD mice1. We now report that overexpression of SIRT1, a mediator of beneficial metabolic effects of calorie restriction, protects neurons against mutant Htt toxicity, whereas reduction of SIRT1 exacerbates mutant Htt toxicity. Overexpression of SIRT1 significantly improves motor function, reduces brain atrophy, and attenuates mutant Htt-mediated metabolic abnormalities in both fragment and full-length HD mouse models. Further mechanistic studies suggest that SIRT1 prevents mutant Htt-induced decline in BDNF levels and its receptor Trk-B signaling, and restores medium spiny neuronal DARPP32 levels in the striatum. SIRT1 deacetylase activity is required for SIRT1-mediated neuroprotection in HD models. Notably, we demonstrate that mutant Htt interacts with SIRT1 and inhibits SIRT1 deacetylase activity. Inhibition of SIRT1 deacetylase activity results in hyperacetylation of SIRT1 substrates such as FOXO3a thereby inhibiting its prosurvival function. Overexpression of SIRT1 counteracts mutant Htt-induced deacetylase deficit, enhances deacetylation of FOXO3a, and facilitates cell survival. These findings demonstrate a neuroprotective role of SIRT1 in mammalian HD models, indicate key mediators of this protection, and open new avenues for the development of neuroprotective strategies in HD.

AVF failure in the first year after creation is common and results in substantially higher health care costs. Compared with patients whose AVFs maintained primary patency, vascular access costs were 2 to 3 times higher for patients whose AVFs experienced primary or secondary patency loss and 4 times higher for patients who never used their AVFs. There is a need to improve AVF outcomes and reduce costs after AVF creation.

In elderly hemodialysis patients initiating hemodialysis therapy with a catheter, the optimal vascular access selection depends on tradeoffs between shorter catheter dependence and less frequent interventions to make the vascular access (AVG) functional versus longer access patency and fewer interventions after successful use of the vascular access (AVF).

BackgroundAbout half of arteriovenous fistulas (AVFs) require one or more interventions before successful dialysis use, a process called assisted maturation. Previous research suggested that AVF abandonment and interventions to maintain patency after maturation may be more frequent with assisted maturation versus unassisted maturation.MethodsUsing the US Renal Data System, we retrospectively compared patients with assisted versus unassisted AVF maturation for postmaturation AVF outcomes, including functional primary patency loss (requiring intervention after achieving AVF maturation), AVF abandonment, and frequency of interventions.ResultsWe included 7301 patients ≥67 years who initiated hemodialysis from July 2010 to June 2012 with a catheter and no prior AVF; all had an AVF created within 6 months of starting hemodialysis and used for dialysis (matured) within 6 months of creation, with 2-year postmaturation follow-up. AVFs matured without prior intervention for 56% of the patients. Assisted AVF maturation with one, two, three, or four or more prematuration interventions occurred in 23%, 12%, 5%, and 4% of patients, respectively. Patients with prematuration interventions had significantly increased risk of functional primary patency loss compared with patients who had unassisted AVF maturation, and the risk increased with the number of interventions. Although the likelihood of AVF abandonment was not higher among patients with up to three prematuration interventions compared with patients with unassisted AVF maturation, it was significantly higher among those with four or more interventions.ConclusionsFor this cohort of patients undergoing assisted AVF maturation, we observed a positive association between the number of prematuration AVF interventions and the likelihood of functional primary patency loss and frequency of postmaturation interventions.