The ancient drug salicylate directly activates AMP-activated protein kinase.

Salicylate, a plant product, has been in medicinal use since ancient times. More recently, it has been replaced by synthetic derivatives such as aspirin and salsalate, both of which are rapidly broken down to salicylate in vivo. At concentrations reached in plasma after administration of salsalate or of aspirin at high doses, salicylate activates adenosine monophosphate-activated protein kinase (AMPK), a central regulator of cell growth and metabolism. Salicylate binds at the same site as the synthetic activator A-769662 to cause allosteric activation and inhibition of dephosphorylation of the activating phosphorylation site, threonine-172. In AMPK knockout mice, effects of salicylate to increase fat utilization and to lower plasma fatty acids in vivo were lost. Our results suggest that AMPK activation could explain some beneficial effects of salsalate and aspirin in humans.

Arsenic-induced SUMO-dependent recruitment of RNF4 into PML nuclear bodies.

In acute promyelocytic leukemia (APL), the promyelocytic leukemia (PML) protein is fused to the retinoic acid receptor alpha (RAR). Arsenic is an effective treatment for this disease as it induces SUMO-dependent ubiquitin-mediated proteasomal degradation of the PML-RAR fusion protein. Here we analyze the nuclear trafficking dynamics of PML and its SUMO-dependent ubiquitin E3 ligase, RNF4 in response to arsenic. After administration of arsenic, PML immediately transits into nuclear bodies where it undergoes SUMO modification. This initial recruitment of PML into nuclear bodies is not dependent on RNF4, but RNF4 quickly follows PML into the nuclear bodies where it is responsible for ubiquitylation of SUMO-modified PML and its degradation by the proteasome. While arsenic restricts the mobility of PML, FRAP analysis indicates that RNF4 continues to rapidly shuttle into PML nuclear bodies in a SUMO-dependent manner. Under these conditions FRET studies indicate that RNF4 interacts with SUMO in PML bodies but not directly with PML. These studies indicate that arsenic induces the rapid reorganization of the cell nucleus by SUMO modification of nuclear body-associated PML and uptake of the ubiquitin E3 ligase RNF4 leading to the ubiquitin-mediated degradation of PML.

Timed Up and Go test is not useful as a discharge risk screening tool.

OBJECTIVE: To determine whether the 'Timed Up and Go' (TUG) test is a useful test for predicting re-attendance at an ED, emergency hospital admission or death within 90 days in elderly patients discharged from the ED. METHODS: This was a prospective blinded cohort study at a tertiary referral ED. Patients completed a TUG test during their Allied Health assessment prior to discharge from the department. After 90 days, patient ED attendances, emergency admissions to hospital or deaths were recorded and confirmed by phone. Data were analysed using logistic regression and reported as odds ratios (OR) or log-transformation and Pearson analysis. RESULTS: One hundred patients were enrolled: 78 (78%, 95% confidence interval [CI] 70-86%) patients remained event free, 22 (22%, 95% CI 14-30%) patients re-attended an ED and 15 (15%, 95% CI 8-22%) were admitted to hospital as an emergency admission. There was no significant difference between TUG test times and whether patients re-attended an ED (OR 1.0 [0.93-1.06] P = 0.9) or were admitted to hospital (OR 0.99 [0.91-1.07] P = 0.74). There was no significant correlation between a patient's TUG test time and the number of days to ED re-attendance (Pearson correlation coefficient 0.38 [-0.04 to 0.69] P = 0.08) or admission (Pearson correlation coefficient 0.32 [-0.23 to 0.71] P = 0.25). CONCLUSION: This study did not detect any predictive value of the TUG test for ED re-attendance or hospital admission within 90 days of discharge among aged ED patients.