Desynchronizing effect of high-frequency stimulation in a generic cortical network model

Transcranial Electrical Stimulation (TCES) and Deep Brain Stimulation (DBS) are two different applications of electrical current to the brain used in different areas of medicine. Both have a similar frequency dependence of their efficiency, with the most pronounced effects around 100Hz. We apply superthreshold electrical stimulation, specifically depolarizing DC current, interrupted at different frequencies, to a simple model of a population of cortical neurons which uses phenomenological descriptions of neurons by Izhikevich and synaptic connections on a similar level of sophistication. With this model, we are able to reproduce the optimal desynchronization around 100Hz, as well as to predict the full frequency dependence of the efficiency of desynchronization, and thereby to give a possible explanation for the action mechanism of TCES.Comment: 9 pages, figs included. Accepted for publication in Cognitive Neurodynamic

Endotoxaemia in Haemodialysis: A Novel Factor in Erythropoetin Resistance?

Background/Objectives Translocated endotoxin derived from intestinal bacteria is a driver of systemic inflammation and oxidative stress. Severe endotoxaemia is an underappreciated, but characteristic finding in haemodialysis (HD) patients, and appears to be driven by acute repetitive dialysis induced circulatory stress. Resistance to erythropoietin (EPO) has been identified as a predictor of mortality risk, and associated with inflammation and malnutrition. This study aims to explore the potential link between previously unrecognised endotoxaemia and EPO Resistance Index (ERI) in HD patients. Methodology/Principal Findings 50 established HD patients were studied at a routine dialysis session. Data collection included weight, BMI, ultrafiltration volume, weekly EPO dose, and blood sampling pre and post HD. ERI was calculated as ratio of total weekly EPO dose to body weight (U/kg) to haemoglobin level (g/dL). Mean haemoglobin (Hb) was 11.3±1.3 g/dL with a median EPO dose of 10,000 [IQR 7,500–20,000] u/wk and ERI of 13.7 [IQR 6.9–23.3] ((U/Kg)/(g/dL)). Mean pre-HD serum ET levels were significantly elevated at 0.69±0.30 EU/ml. Natural logarithm (Ln) of ERI correlated to predialysis ET levels (r = 0.324, p = 0.03) with a trend towards association with hsCRP (r = 0.280, p = 0.07). Ln ERI correlated with ultrafiltration volume, a driver of circulatory stress (r = 0.295, p = 0.046), previously identified to be associated with increased intradialytic endotoxin translocation. Both serum ET and ultrafiltration volume corrected for body weight were independently associated with Ln ERI in multivariable analysis. Conclusions This study suggests that endotoxaemia is a significant factor in setting levels of EPO requirement. It raises the possibility that elevated EPO doses may in part merely be identifying patients subjected to significant circulatory stress and suffering the myriad of negative biological consequences arising from sustained systemic exposure to endotoxin

High-throughput spheroid screens using volume, resazurin reduction and acid phosphatase activity

Mainstream adoption of physiologically-relevant three-dimensional models has been slow in the last 50 years due to long, manual protocols with poor reproducibility, high price and closed commercial platforms. This chapter describes high-throughput, low-cost, open methods for spheroid viability assessment which use readily-available reagents and open-source software to analyse spheroid volume, metabolism and enzymatic activity. We provide two ImageJ macros for automated spheroid size determination - for both single images and for images in stacks. We also share an Excel template spreadsheet allowing users to rapidly process spheroid size data, analyse plate uniformity (such as edge effects and systematic seeding errors), detect outliers and calculate dose-response. The methods would be useful to researchers in preclinical and translational research planning to move away from simplistic monolayer studies and explore 3D spheroid screens for drug safety and efficacy without substantial investment in money or time

A Miniaturized Ultra-Focal Magnetic Stimulator and Its Preliminary Application to the Peripheral Nervous System

AbstractTranscranial magnetic stimulation (TMS) is a noninvasive brain stimulation technique used in the clinic to treat several neurological disorders and psychiatric diseases. One of TMS's significant limitations is its low spatial resolution, which often results in a mismatch between the target area in the brain and the stimulation site on the scalp. To enhance its spatial resolution, we designed and built a complete stimulation system complete with a millimetric-diameter coil and microscopic traces (μCoil). The first tests conducted on healthy volunteers showed that the μCoil stimulation of the radial nerve in the wrist could indeed evoke somatosensory nerve action potentials (SNAPs). In this chapter, we study this nerve stimulation system with electromagnetic and neuron simulators on a neurofunctionalized model from the Virtual Population (ViP v.4) and a μCoil figure-8 geometry. In particular, we study how changes in the μCoil geometry, such as the number of layers, shape, and length of an iron or air core, may help to promote the generation of somatosensory nerve action potentials

Retained Surgical Items and Minimally Invasive Surgery

A retained surgical item is a surgical patient safety problem. Early reports have focused on the epidemiology of retained-item cases and the identification of patient risk factors for retention. We now know that retention has very little to do with patient characteristics and everything to do with operating room culture. It is a perception that minimally invasive procedures are safer with regard to the risk of retention. Minimally invasive surgery is still an operation where an incision is made and surgical tools are placed inside of patients, so these cases are not immune to the problem of inadvertent retention. Retained surgical items occur because of problems with multi-stakeholder operating room practices and problems in communication. The prevention of retained surgical items will therefore require practice change, knowledge, and shared information between all perioperative personnel

New Measurement of Parity Violation in Elastic Electron-Proton Scattering and Implications for Strange Form Factors

We have measured the parity-violating electroweak asymmetry in the elastic scattering of polarized electrons from the proton. The result is A = -15.05 +- 0.98(stat) +- 0.56(syst) ppm at the kinematic point theta_lab = 12.3 degrees and Q^2 = 0.477 (GeV/c)^2. The measurement implies that the value for the strange form factor (G_E^s + 0.392 G_M^s) = 0.025 +- 0.020 +- 0.014, where the first error is experimental and the second arises from the uncertainties in electromagnetic form factors. This measurement is the first fixed-target parity violation experiment that used either a `strained' GaAs photocathode to produce highly polarized electrons or a Compton polarimeter to continuously monitor the electron beam polarization.Comment: 8 pages, 4 figures, Tex, elsart.cls; revised version as accepted for Phys. Lett.

Oral vitamin B(12 )therapy in the primary care setting: a qualitative and quantitative study of patient perspectives

BACKGROUND: Although oral replacement with high doses of vitamin B(12 )is both effective and safe for the treatment of B(12 )deficiency, little is known about patients' views concerning the acceptability and effectiveness of oral B(12). We investigated patient perspectives on switching from injection to oral B(12 )therapy. METHODS: This study involved a quantitative arm using questionnaires and a qualitative arm using semi-structured interviews, both to assess patient views on injection and oral therapy. Patients were also offered a six-month trial of oral B(12 )therapy. One hundred and thirty-three patients who receive regular B(12 )injections were included from three family practice units (two hospital-based academic clinics and one community health centre clinic) in Toronto. RESULTS: Seventy-three percent (63/86) of respondents were willing to try oral B(12). In a multivariate analysis, patient factors associated with a "willingness to switch" to oral B(12 )included being able to get to the clinic in less than 30 minutes (OR 9.3, 95% CI 2.2–40.0), and believing that frequent visits to the health care provider (OR 5.4, 95% CI 1.1–26.6) or the increased costs to the health care system (OR 16.7, 95% CI 1.5–184.2) were disadvantages of injection B(12). Fifty-five patients attempted oral therapy and 52 patients returned the final questionnaire. Of those who tried oral therapy, 76% (39/51) were satisfied and 71% (39/55) wished to permanently switch. Factors associated with permanently switching to oral therapy included believing that the frequent visits to the health care provider (OR 35.4, 95% CI 2.9–432.7) and travel/parking costs (OR 8.7, 95% CI 1.2–65.3) were disadvantages of injection B(12). Interview participants consistently cited convenience as an advantage of oral therapy. CONCLUSION: Switching patients from injection to oral B(12 )is both feasible and acceptable to patients. Oral B(12 )supplementation is well received largely due to increased convenience. Clinicians should offer oral B(12 )therapy to their patients who are currently receiving injections, and newly diagnosed B(12)-deficient patients who can tolerate and are compliant with oral medications should be offered oral supplementation

Generalized shrinkage F-like statistics for testing an interaction term in gene expression analysis in the presence of heteroscedasticity

<p>Abstract</p> <p>Background</p> <p>Many analyses of gene expression data involve hypothesis tests of an interaction term between two fixed effects, typically tested using a residual variance. In expression studies, the issue of variance heteroscedasticity has received much attention, and previous work has focused on either between-gene or within-gene heteroscedasticity. However, in a single experiment, heteroscedasticity may exist both within and between genes. Here we develop flexible shrinkage error estimators considering both between-gene and within-gene heteroscedasticity and use them to construct <it>F</it>-like test statistics for testing interactions, with cutoff values obtained by permutation. These permutation tests are complicated, and several permutation tests are investigated here.</p> <p>Results</p> <p>Our proposed test statistics are compared with other existing shrinkage-type test statistics through extensive simulation studies and a real data example. The results show that the choice of permutation procedures has dramatically more influence on detection power than the choice of <it>F </it>or <it>F</it>-like test statistics. When both types of gene heteroscedasticity exist, our proposed test statistics can control preselected type-I errors and are more powerful. Raw data permutation is not valid in this setting. Whether unrestricted or restricted residual permutation should be used depends on the specific type of test statistic.</p> <p>Conclusions</p> <p>The <it>F</it>-like test statistic that uses the proposed flexible shrinkage error estimator considering both types of gene heteroscedasticity and unrestricted residual permutation can provide a statistically valid and powerful test. Therefore, we recommended that it should always applied in the analysis of real gene expression data analysis to test an interaction term.</p

Display of probability densities for data from a continuous distribution

Based on cumulative distribution functions, Fourier series expansion and Kolmogorov tests, we present a simple method to display probability densities for data drawn from a continuous distribution. It is often more efficient than using histograms.Comment: 5 pages, 4 figures, presented at Computer Simulation Studies XXIV, Athens, GA, 201

Real-Time CARS Imaging Reveals a Calpain-Dependent Pathway for Paranodal Myelin Retraction during High-Frequency Stimulation

High-frequency electrical stimulation is becoming a promising therapy for neurological disorders, however the response of the central nervous system to stimulation remains poorly understood. The current work investigates the response of myelin to electrical stimulation by laser-scanning coherent anti-Stokes Raman scattering (CARS) imaging of myelin in live spinal tissues in real time. Paranodal myelin retraction at the nodes of Ranvier was observed during 200 Hz electrical stimulation. Retraction was seen to begin minutes after the onset of stimulation and continue for up to 10 min after stimulation was ceased, but was found to reverse after a 2 h recovery period. The myelin retraction resulted in exposure of Kv 1.2 potassium channels visualized by immunofluorescence. Accordingly, treating the stimulated tissue with a potassium channel blocker, 4-aminopyridine, led to the appearance of a shoulder peak in the compound action potential curve. Label-free CARS imaging of myelin coupled with multiphoton fluorescence imaging of immuno-labeled proteins at the nodes of Ranvier revealed that high-frequency stimulation induced paranodal myelin retraction via pathologic calcium influx into axons, calpain activation, and cytoskeleton degradation through spectrin break-down