Localized Delivery of Amifostine Enhances Salivary Gland Radioprotection.

Radiotherapy for head and neck cancers commonly causes damage to salivary gland tissue, resulting in xerostomia (dry mouth) and numerous adverse medical and quality-of-life issues. Amifostine is the only Food and Drug Administration-approved radioprotective drug used clinically to prevent xerostomia. However, systemic administration of amifostine is limited by severe side effects, including rapid decrease in blood pressure (hypotension), nausea, and a narrow therapeutic window. In this study, we demonstrate that retroductal delivery of amifostine and its active metabolite, WR-1065, to murine submandibular glands prior to a single radiation dose of 15 Gy maintained gland function and significantly increased acinar cell survival. Furthermore, in vivo stimulated saliva secretion was maintained in retrograde-treated groups at levels significantly higher than irradiated-only and systemically treated groups. In contrast to intravenous injections, retroductal delivery of WR-1065 or amifostine significantly attenuated hypotension. We conclude that localized delivery to salivary glands markedly improves radioprotection at the cellular level, as well as mitigates the adverse side effects associated with systemic administration. These results support the further development of a localized delivery system that would be compatible with the fractionated dose regimen used clinically.

Analysis of the non-Markov parameter in continuous-time signal processing.

The use of statistical complexity metrics has yielded a number of successful methodologies to differentiate and identify signals from complex systems where the underlying dynamics cannot be calculated. The Mori-Zwanzig framework from statistical mechanics forms the basis for the generalized non-Markov parameter (NMP). The NMP has been used to successfully analyze signals in a diverse set of complex systems. In this paper we show that the Mori-Zwanzig framework masks an elegantly simple closed form of the first NMP, which, for C(1) smooth autocorrelation functions, is solely a function of the second moment (spread) and amplitude envelope of the measured power spectrum. We then show that the higher-order NMPs can be constructed in closed form in a modular fashion from the lower-order NMPs. These results provide an alternative, signal processing-based perspective to analyze the NMP, which does not require an understanding of the Mori-Zwanzig generating equations. We analyze the parametric sensitivity of the zero-frequency value of the first NMP, which has been used as a metric to discriminate between states in complex systems. Specifically, we develop closed-form expressions for three instructive systems: band-limited white noise, the output of white noise input to an idealized all-pole filter,f and a simple harmonic oscillator driven by white noise. Analysis of these systems shows a primary sensitivity to the decay rate of the tail of the power spectrum.

Renin-sensitive microRNAs correlate with atherosclerosis plaque progression.

Recent trials with inhibition of the renin-angiotensin-aldosterone system (RAAS) in patients with established atherosclerosis have been equivocal. MicroRNAs (miRs) are known to affect multiple pathways relevant to atherosclerosis, including RAAS. We postulated that the use of a direct renin antagonist would result in differential regulation of miRs. We examined monocyte miR expression before and after treatment with renin antagonist, Aliskiren, in patients with established cardiovascular disease as part of a prospective, single-center, randomized, double-blind and placebo-controlled clinical trial (NCT01417104). After screening, patients (mean age 62±3 years) were randomized to placebo or Aliskiren. Three-dimensional dark-blood magnetic resonance imaging assessment of atherosclerosis in the thoracic and abdominal aorta was conducted at baseline and at study completion (19-36 weeks). MiR expression arrays were performed on RNA from peripheral blood mononuclear cells collected at baseline and 12 weeks following randomization to placebo or Aliskiren and showed that hsa-miR-106b-5p, 27a-3p and 18b-5p were significantly downregulated with Aliskiren. Baseline expression of these miRs positively correlated with normalized total wall volume in subjects taking Aliskiren (miR-106b, R=0.62; miR-27a, R=0.63; miR-18b, R=0.77; P<0.05). Hsa-miR-106b-5p, 27a-3p and 18b-5p may represent pathway-specific adaptations to renin inhibition relevant to atherosclerosis.

Theoretical & experimental analysis of the Non Markov Parameter to detect low frequency synchronisation in time series analysis.

A theoretical investigation into the behaviour of the Non-Markov Parameter is performed from a signal processing perspective in contrast to previous methodologies based on stochastic processes theory. The results indicate that the NMP can be regarded as an informational metric which is indicative of the degree of low frequency synchronisation in a complex system. These results have deep implications for physiological analysis of biological systems where the presence of sychronisation is often a marker of pathological functioning. The NMP measure is then applied to in vivo micro-electrode recordings from the subthalamic nucleus.