Analgesic effect of a cholinergic agonist (carbachol) in a sural nerve ligation-induced hypersensitivity mouse model

Neuropathic pain is characterized by long-lasting, intractable pain. Sciatic nerve ligation is often used as an animal model of neuropathic pain, and the spared nerve injury (SNI) model, in which the common peroneal nerve (CPN) and tibial nerve (TN) are ligated, is widely used. In the present study, we evaluated the analgesic effect of a cholinergic agonist, carbachol, on a neuropathic pain model prepared by sural nerve (SN) ligation in mice. The SN was tightly ligated as a branch of the sciatic nerve. Mechanical and thermal allodynia, and hyperalgesia were assessed using von Frey filaments and heat from a hot plate. The analgesic effects of intracerebroventricularly-administered morphine and carbachol were compared. SN ligation resulted in a significant decrease in pain threshold for mechanical stimulation 1 day after ligation. In response to thermal stimulation, allodynia was observed at 50°C and hyperalgesia at 53 and 56°C 3 days after ligation. Content of thiobarbituric acid reactive substances (TBARS) in the spinal cord increased significantly at 6 and 12 h after ligation. Acetylcholine content of the spinal cord also increased at 5 and 7 days after ligation. Intracerebroventricular administration of carbachol at 7 days after ligation produced a marked analgesic effect against mechanical and thermal stimuli, which was stronger and longer-lasting than morphine at all experimental time points. These findings suggest that cholinergic nerves are involved in allodynia and hyperalgesia of the SN ligation neuropathic pain model.</p

Additional file 1: Table S1. of Edoxaban versus enoxaparin for the prevention of venous thromboembolism after total knee or hip arthroplasty: pooled analysis of coagulation biomarkers and primary efficacy and safety endpoints from two phase 3 trials

Median and range of plasma concentrations of coagulation biomarkers at various time points after total knee or total hip arthroplasty. (DOCX 14 kb

A noninferiority confirmatory trial of prasugrel versus clopidogrel in Japanese patients with non-cardioembolic stroke: rationale and study design for a randomized controlled trial – PRASTRO-I trial

<p><b>Background</b>: This comparison of PRAsugrel and clopidogrel in Japanese patients with ischemic STROke (PRASTRO)-I trial investigates the noninferiority of prasugrel to clopidogrel sulfate in the prevention of recurrence of primary events (ischemic stroke, myocardial infarction, and death from other vascular causes), and the long-term safety of prasugrel in Japanese patients with non-cardioembolic stroke.</p> <p><b>Research design and methods</b>: This was an active-controlled, randomized, double-blind, double-dummy, parallel-group study conducted between July 2011 and March 2016 at multiple centers around Japan. Patients had to meet eligibility criteria before receiving 3.75 mg prasugrel or 75 mg clopidogrel orally once daily for a period of 96–104 weeks.</p> <p><b>Results</b>: A total of 3747 patients were included in this trial; 1598 in the 3.75 mg prasugrel group and 1551 in the 75 mg clopidogrel group completed the study. During the study period, 287 (15.2%) patients in the prasugrel group and 311 (16.7%) in the clopidogrel group discontinued treatment. Baseline characteristics, safety, and efficacy results are forthcoming and will be published separately.</p> <p><b>Conclusions</b>: This article presents the study design and rationale for a trial investigating the noninferiority of prasugrel to clopidogrel sulfate with regards to the inhibitory effect on primary events in patients with non-cardioembolic stroke.</p

Multiple HCV infections among 8 drug users.

<p>*Genotyping 6a with core region can not differentiate clusters, because of the high similarity of the nucleotides.</p>¶<p>Not classifiable into clusters. this isolate was close to a reference.</p

HCV genotype distribution.

<p>HCV genotype distribution.</p

Positive rates of anti-HCV and HCV RNA among drug users.

<p>Positive rates of anti-HCV and HCV RNA among drug users.</p

Subtype 6a phylogenies estimated from (A) E1 and (B) NS5B region sequences, corresponding to H77 nucleotide positions of 869–1289 and 8276–8615, respectively.

<p>Subtype 6b sequence D84262 was used as an outgroup. Green pies label sequences from our previous studies <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0028006#pone.0028006-Lu1" target="_blank">[8]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0028006#pone.0028006-Fu1" target="_blank">[9]</a>. Red and yellow pies label sequences from this study, in which yellow pies mark isolates from IDUs with multiple HCV infections. Sequences without pies were retrieved from Genbank. In each tree, five rectangles highlight the further classification of 6a isolates into I, II, III, VI, and VII clusters. Scale bar represents 0.02 nucleotide substitutions per site.</p

The overlapped BSPs.

<p>Three indicated solid lines represent the estimated effective population sizes through time under three combination models: BSP + Uncorrected Exponential, BSP + Uncorrected Lognormal, and BSP + Strict Clock, respectively. The colored areas (pink = Exponential, blue = Lognormal, and yellow = Strict) around the solid lines represent the 95% highest posterior density confidence intervals for these estimates. The vertical ruler on the left scales the effective population size while the horizontal ruler on the bottom measures time.</p

MCC tree estimated under the model of BSP + Uncorrelated Exponential (see <b>Table 4</b>).

<p>In addition to the isolates presented in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0028006#pone-0028006-g001" target="_blank">Figure 1A</a>, sequences determined among 21 blood donors from Vietnam, 22 blood donors from the 12 provinces of China, and 36 IDUs from Liuzhou City in the Guangxi Province <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0028006#pone.0028006-Tan1" target="_blank">[3]</a> were also included. Branches were colored according to their respective geographic origins. Posterior probabilities greater than 0.9 were shown at the respective nodes, while the estimated time points of the origin for the nodes were parenthesized. Below the tree is a time scale from 1960–2010, which measures 6a origin and evolution.</p

Map of HCV 6a migration in China.

<p>With origin from Vietnam, 6a was spread to the neighboring Guangxi and Yunnan Provinces for circulation (shown in pink arrows). From Guangxi, 6a was further spread to the Guangdong, Hainan, Yunnan, and Hubei provinces (shown in green arrows), while from Yunnan, 6a was brought by IDUs to the central part of China (shown in a blue arrow). For unknown reasons, 6a has become a local epidemic in Guangdong and caused infections not only among IDUs, but also among blood donors and patients. As the prevalence is increasing, Guangdong has become the second source region to radiate 6a to other regions (shown in red arrows).</p