Mixed-mode oscillations and interspike interval statistics in the stochastic FitzHugh-Nagumo model

We study the stochastic FitzHugh-Nagumo equations, modelling the dynamics of neuronal action potentials, in parameter regimes characterised by mixed-mode oscillations. The interspike time interval is related to the random number of small-amplitude oscillations separating consecutive spikes. We prove that this number has an asymptotically geometric distribution, whose parameter is related to the principal eigenvalue of a substochastic Markov chain. We provide rigorous bounds on this eigenvalue in the small-noise regime, and derive an approximation of its dependence on the system's parameters for a large range of noise intensities. This yields a precise description of the probability distribution of observed mixed-mode patterns and interspike intervals.Comment: 36 page

Effects of NSAIDs and paracetamol (acetaminophen) on protein kinase C epsilon translocation and on substance P synthesis and release in cultured sensory neurons.

Celecoxib, diclofenac, ibuprofen, and nimesulide are nonsteroidal anti-inflammatory drugs (NSAIDs) very commonly used for the treatment of moderate to mild pain, together with paracetamol (acetaminophen), a very widely used analgesic with a lesser anti-inflammatory effect. In the study reported here, we tested the efficacy of celecoxib, diclofenac, and ibuprofen on preprotachykinin mRNA synthesis, substance P (SP) release, prostaglandin E(2) (PGE(2)) release, and protein kinase C epsilon (PKC\u25b) translocation in rat cultured sensory neurons from dorsal root ganglia (DRGs). The efficacy of these NSAIDs was compared with the efficacy of paracetamol and nimesulide in in vitro models of hyperalgesia (investigated previously). While nimesulide and paracetamol, as in previous experiments, decreased the percentage of cultured DRG neurons showing translocation of PKC\u25b caused by 100 nM thrombin or 1 \u3bcM bradykinin in a dose-dependent manner, the other NSAIDs tested did not have a significant effect. The amount of SP released by peptidergic neurons and the expression level of preprotachykinin mRNA were assessed in basal conditions and after 70 minutes or 36 hours of stimulation with an inflammatory soup (IS) containing potassium chloride, thrombin, bradykinin, and endothelin-1. The release of SP at 70 minutes was inhibited only by nimesulide, while celecoxib and diclofenac were effective at 36 hours. The mRNA basal level of the SP precursor preprotachykinin expressed in DRG neurons was reduced only by nimesulide, while the increased levels expressed during treatment with the IS were significantly reduced by all drugs tested, with the exception of ibuprofen. All drugs were able to decrease basal and IS-stimulated PGE(2) release. Our study demonstrates novel mechanisms of action of commonly used NSAIDS

Epigenome-wide association study reveals decreased average methylation levels years before breast cancer diagnosis

Interest in the potential of DNA methylation in peripheral blood as a biomarker of cancer risk is increasing. We aimed to assess whether epigenome-wide DNA methylation measured in peripheral blood samples obtained before onset of the disease is associated with increased risk of breast cancer. We report on three independent prospective nested case-control studies from the European Prospective Investigation into Cancer and Nutrition (EPIC-Italy; n = 162 matched case-control pairs), the Norwegian Women and Cancer study (NOWAC; n = 168 matched pairs), and the Breakthrough Generations Study (BGS; n = 548 matched pairs). We used the Illumina 450k array to measure methylation in the EPIC and NOWAC cohorts. Whole-genome bisulphite sequencing (WGBS) was performed on the BGS cohort using pooled DNA samples, combined to reach 50× coverage across ~16 million CpG sites in the genome including 450k array CpG sites. Mean β values over all probes were calculated as a measurement for epigenome-wide methylation

Hospital factors and patient characteristics in the treatment of colorectal cancer: a population based study

BACKGROUND: The present study focuses on the analysis of social, clinical and hospital characteristics that can lead to disparities in the management and outcome of care. To that end, indicators of the quality of initial treatment delivered to newly-diagnosed colorectal cancer patients in a North-Western Region of Italy, were investigated using administrative data. METHODS: The cohort includes all incident colorectal cancer patients (N = 24,187) selected by a validated algorithm from the Piedmont Hospital Discharge Record system over an 8-year period (2000–2007). Three indicators of quality of care in this population-based cohort were evaluated: the proportion of preoperative radiotherapy (RT) and of abdominoperineal (AP) resection in rectal cancer patients, and the proportion of postoperative in-hospital mortality in colorectal cancer patients. RESULTS: Among rectal cancers, older patients were less likely to have preoperative RT, and more likely to receive an AP resection compared to younger patients. The probability of undergoing preoperative RT and AP resection was reduced in females compared to males (odds ratio (OR) 0.77, 95% confidence interval (CI) 0.64-0.93 and OR 0.78, 95%CI 0.69-0.89, respectively). However, there was a trend of increasing RT over time (p for trend <0.01). The probability of undergoing AP resection was increased in less-educated patients and in hospitals with a low caseload. A higher risk of postoperative in-hospital mortality was found among colorectal cancer patients who were older, male, (female versus male OR 0.71, 95%CI 0.60-0.84), unmarried (OR 1.32, 95%CI 1.09-1.59) or with unknown marital status. CONCLUSIONS: The study provides evidence of the importance of social, clinical and hospital characteristics on the equity and quality of care in a Southern European country with an open-access public health care system