Postural Hypotension and Cognitive Function in Older Adults.

Background: Cognitive decline in the elderly is associated with chronic cerebral hypoperfusion. While many forms of exercise can slow or reverse cognitive decline, compliance in unsupervised exercise programs is poor. Objective: We address whether passive exercise, that is, muscle stimulation, is capable of reversing postural hypotension in an older adult population sufficiently to significantly improve cognitive function as measured by executive function tests. Subjects and Methods: In this study, 50- to 80-year-old women underwent cognitive testing, long-duration cardiac hemodynamic recordings during quiet sitting, and 60 min of soleus muscle stimulation with continued hemodynamic recording. Results: Two thirds of our subjects were hypotensive (diastolic blood pressure [DBP] < 70 mmHg) after 30 min of quiet sitting. Cognitive performance was significantly better in individuals with higher DBPs (0.79 s per 1-mmHg increase in DBP). Soleus muscle stimulation resulted in an average increase in DBP of 6.1 mmHg, which could translate into a 30% or greater improvement in cognitive performance. Conclusions: Incongruent Stroop testing provides high statistical power for distinguishing differential cognitive responses to resting DBP levels. These results set the stage to investigate whether regular use of calf muscle pump stimulation could effectively reverse age-related cognitive impairment.

Biodistribution and pharmacokinetics of a telodendrimer micellar paclitaxel nanoformulation in a mouse xenograft model of ovarian cancer.

BACKGROUND: A multifunctional telodendrimer-based micelle system was characterized for delivery of imaging and chemotherapy agents to mouse tumor xenografts. Previous optical imaging studies demonstrated qualitatively that these classes of nanoparticles, called nanomicelles, preferentially accumulate at tumor sites in mice. The research reported herein describes the detailed quantitative imaging and biodistribution profiling of nanomicelles loaded with a cargo of paclitaxel. METHODS: The telodendrimer was covalently labeled with ¹²5I and the nanomicelles were loaded with ¹4C-paclitaxel, which allowed measurement of pharmacokinetics and biodistribution in the mice using microSPECT/CT imaging and liquid scintillation counting, respectively. RESULTS: The radio imaging data showed preferential accumulation of nanomicelles at the tumor site along with a slower clearance rate than paclitaxel formulated in Cremophor EL (Taxol®). Liquid scintillation counting confirmed that ¹4C-labeled paclitaxel sequestered in nanomicelles had increased uptake by tumor tissue and slower pharmacokinetics than Taxol. CONCLUSION: Overall, the results indicate that nanomicelle-formulated paclitaxel is a potentially superior formulation compared with Taxol in terms of water solubility, pharmacokinetics, and tumor accumulation, and may be clinically useful for both tumor imaging and improved chemotherapy applications.

A functional type I topoisomerase from Pseudomonas aeruginosa.

BACKGROUND: Pseudomonas aeruginosa encodes a putative topoisomerase with sequence similarity to the eukaryotic type IB topoisomerase from Vaccinia virus. Residues in the active site are conserved, notably Tyr292 which would be predicted to form the transient covalent bond to DNA. RESULTS: The gene encoding the P. aeruginosa topoisomerase I was cloned and expressed in E. coli. The enzyme relaxes supercoiled DNA, while a mutant containing a Tyr292 to Phe substitution at the active site was found to be catalytically inert. This is consistent with the role of Tyr in forming the covalent intermediate. Like Vaccinia topoisomerase, the P. aeruginosa topoisomerase relaxes DNA in the absence of ATP, but unlike Vaccinia topoisomerase, P. aeruginosa topoisomerase does not relax supercoiled DNA without MgCl2 present. In addition, high concentration of NaCl is not able to substitute for MgCl2 as seen for Vaccinia topoisomerase. A truncated derivative of the topoisomerase lacking residues 1-98 relaxes DNA, with both full length and truncated enzyme exhibiting equivalent requirements for divalent cations and the ability to relax DNA to completion, suggesting a shared domain organization. DNA-binding assays suggest an only modest preference for the CCCTT pentameric sequence required for transesterification by Vaccinia topoisomerase IB. CONCLUSION: P. aeruginosa encodes a functional topoisomerase with significant similarity to the type IB enzyme encoded by poxviruses. In contrast to the Vaccinia-encoded homolog, the P. aeruginosa-encoded enzyme requires divalent cations for catalytic activity, relaxes DNA to completion, and does not exhibit a strong preference for the pentameric sequence stringently required by the Vaccinia-encoded homolog. A comparison with the structure of poxviral topoisomerase in complex with DNA suggests that bacterial homologs of the eukaryotic type IB topoisomerase may exhibit a relaxed sequence preference due to the lack of conservation of certain residues involved in sequence-specific DNA contacts, and that interaction with an only modestly preferred sequence may result in suboptimal positioning of catalytic residues.