Descending octopaminergic neurons modulate sensory-evoked activity of thoracic motor neurons in stick insects.

Neuromodulatory neurons located in the brain can influence activity in locomotor networks residing in the spinal cord or ventral nerve cords of invertebrates. How inputs to and outputs of neuromodulatory descending neurons affect walking activity is largely unknown. With the use of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and immunohistochemistry, we show that a population of dorsal unpaired median (DUM) neurons descending from the gnathal ganglion to thoracic ganglia of the stick insect Carausius morosus contains the neuromodulatory amine octopamine. These neurons receive excitatory input coupled to the legs' stance phases during treadmill walking. Inputs did not result from connections with thoracic central pattern-generating networks, but, instead, most are derived from leg load sensors. In excitatory and inhibitory retractor coxae motor neurons, spike activity in the descending DUM (desDUM) neurons increased depolarizing reflexlike responses to stimulation of leg load sensors. In these motor neurons, descending octopaminergic neurons apparently functioned as components of a positive feedback network mainly driven by load-detecting sense organs. Reflexlike responses in excitatory extensor tibiae motor neurons evoked by stimulations of a femur-tibia movement sensor either are increased or decreased or were not affected by the activity of the descending neurons, indicating different functions of desDUM neurons. The increase in motor neuron activity is often accompanied by a reflex reversal, which is characteristic for actively moving animals. Our findings indicate that some descending octopaminergic neurons can facilitate motor activity during walking and support a sensory-motor state necessary for active leg movements.NEW & NOTEWORTHY We investigated the role of descending octopaminergic neurons in the gnathal ganglion of stick insects. The neurons become active during walking, mainly triggered by input from load sensors in the legs rather than pattern-generating networks. This report provides novel evidence that octopamine released by descending neurons on stimulation of leg sense organs contributes to the modulation of leg sensory-evoked activity in a leg motor control system.

Effect of a Single Aspirin Dose Prior to Fecal Immunochemical Testing on Test Sensitivity for Detecting Advanced Colorectal Neoplasms: A Randomized Clinical Trial.

Importance: Fecal immunochemical tests for hemoglobin are widely used for colorectal cancer (CRC) screening. Observational studies suggested that sensitivity of fecal immunochemical tests for detecting advanced neoplasms could be increased by acetylsalicylic acid (aspirin), especially among men. Objective: To evaluate the potential to increase sensitivity of fecal immunochemical tests by administering a single 300-mg oral aspirin dose 2 days before stool sampling. Design, Setting, and Participants: A randomized, placebo-controlled, double-blind trial was conducted in 14 gastroenterology practices and 4 hospitals in Germany, and included 2422 men and women aged 40 to 80 years scheduled for colonoscopy, with no recent use of aspirin or other drugs with antithrombotic effects (enrollment from June 2013 to November 2016, and final follow-up January 27, 2017). Interventions: Administration of a single tablet containing 300 mg of aspirin (n = 1208) or placebo (n = 1214) 2 days before fecal sampling for fecal immunochemical test. Main Outcome and Measures: The primary outcome was sensitivity of a quantitative fecal immunochemical test at 2 predefined cutoffs (10.2 and 17-µg Hb/g stool) for detecting advanced neoplasms (colorectal cancer or advanced adenoma). Results: Among 2422 randomized patients (mean [SD] age, 59.6 [7.9] years; 1219, 50%, men), 2134 were included in the analysis (78% for primary screening colonoscopy, 22% for diagnostic colonoscopy). Advanced neoplasms were identified in 224 participants (10.5%), including 8 participants (0.4%) with CRC and 216 participants (10.1%) with advanced adenoma. Sensitivity was 40.2% in the aspirin group and 30.4% in the placebo group (difference 9.8%, 95% CI, -3.1% to 22.2%, P = .14) at cutoff 10.2-µg Hb/g stool and 28.6% in the aspirin and 22.5% in the placebo group (difference 6.0%, 95% CI, -5.7% to 17.5%, P = .32) at cutoff 17-µg Hb/g stool. Conclusions and Relevance: Among adults aged 40 to 80 years not using aspirin or other antithrombotic medications, administration of a single dose of oral aspirin prior to fecal immunochemical testing, compared with placebo, did not significantly increase test sensitivity for detecting advanced colorectal neoplasms at 2 predefined cutoffs of a quantitative fecal immunochemical test. Trial registration: Deutsches Register Klinischer Studien Identifier: DRKS00003252; EudraCT Identifier: 2011-005603-32/DE.

Utilization and determinants of follow-up colonoscopies within 6 years after screening colonoscopy: Prospective cohort study.

Previous studies have reported that repeat colonoscopies were often not conducted in the recommended time interval after screening colonoscopy. We prospectively followed participants of screening colonoscopy from Germany for 6 years to investigate utilization and determinants of repeat colonoscopies. In a longitudinal study on the effectiveness of screening colonoscopy in the state of Saarland (Germany), participants who had a screening colonoscopy between 2005 and 2007 were contacted by mail 6 years after screening and requested to fill in a standardized questionnaire on utilization of repeat colonoscopies. For all colonoscopies reported, colonoscopy and histology reports were requested from the physician(s). Of 6,407 screening participants, 2,212 (35%) have utilized another colonoscopy. Among participants with negative findings at screening (no adenomas), 962 (22%) had a subsequent colonoscopy within 6 years from screening, accounting for 43% of all patients with a repeat colonoscopy. Family history of CRC and detection of hyperplastic polyps were found to be determinants of higher repeat colonoscopy use. As many as 44% of the participants with low-risk adenomas (N = 509) and 39% with high-risk adenomas (N = 290) at screening did not utilize surveillance colonoscopy within 6 years. Utilization was better with higher school education, prior cancer screening participation and if high-risk adenomas were detected, lower among current smokers and lowest among participants ≥70 years. New strategies will be required considering determinants of adherence to avoid unnecessary colonoscopies and to improve utilization of surveillance according to recommended time intervals among patients at higher risk of CRC in the future.

Adherence to physician recommendations for surveillance in opportunistic colorectal cancer screening: the necessity of organized surveillance.

BACKGROUND: Limited evidence exists on the utilization of surveillance colonoscopy in colorectal cancer (CRC) screening programs. We assessed adherence to physician recommendations for surveillance in opportunistic CRC screening in Germany. METHODS: A follow-up study of screening colonoscopy participants in 2007-2009 in Saarland, Germany, was conducted using health insurance claims data. Utilization of additional colonoscopies through to 2011 was ascertained. Adherence to surveillance intervals of 3, 6, 12 and 36 months, defined as having had colonoscopy at 2.5 to 4, 5 to 8, 10.5 to 16 and 33 to 48 months, respectively (i.e., tolerating a delay of 33% of each interval) was assessed. Potential predictors of non-adherence were investigated using logistic regression analysis. RESULTS: A total of 20,058 screening colonoscopy participants were included in the study. Of those with recommended surveillance intervals of 3, 6, 12 and 36 months, 46.5% (95%-confidence interval [CI]: 37.3-55.7%), 38.5% (95%-CI: 29.6-47.3%), 25.4% (95%-CI: 21.2-29.6%) and 28.0% (95%-CI: 25.5-30.5%), respectively, had a subsequent colonoscopy within the specified margins. Old age, longer recommended surveillance interval, not having had polypectomy at screening and negative colonoscopy were statistically significant predictors of non-adherence. CONCLUSION: This study suggests frequent non-adherence to physician recommendations for surveillance colonoscopy in community practice. Increased efforts to improve adherence, including introduction of more elements of an organized screening program, seem necessary to assure a high-quality CRC screening process.

Sensitive detection of colorectal cancer in peripheral blood by septin 9 DNA methylation assay.

BACKGROUND: Colorectal cancer (CRC) is the second leading cause of cancer deaths despite the fact that detection of this cancer in early stages results in over 90% survival rate. Currently less than 45% of at-risk individuals in the US are screened regularly, exposing a need for better screening tests. We performed two case-control studies to validate a blood-based test that identifies methylated DNA in plasma from all stages of CRC. METHODOLOGY/PRINCIPAL FINDINGS: Using a PCR assay for analysis of Septin 9 (SEPT9) hypermethylation in DNA extracted from plasma, clinical performance was optimized on 354 samples (252 CRC, 102 controls) and validated in a blinded, independent study of 309 samples (126 CRC, 183 controls). 168 polyps and 411 additional disease controls were also evaluated. Based on the training study SEPT9-based classification detected 120/252 CRCs (48%) and 7/102 controls (7%). In the test study 73/126 CRCs (58%) and 18/183 control samples (10%) were positive for SEPT9 validating the training set results. Inclusion of an additional measurement replicate increased the sensitivity of the assay in the testing set to 72% (90/125 CRCs detected) while maintaining 90% specificity (19/183 for controls). Positive rates for plasmas from the other cancers (11/96) and non-cancerous conditions (41/315) were low. The rate of polyp detection (>1 cm) was approximately 20%. CONCLUSIONS/SIGNIFICANCE: Analysis of SEPT9 DNA methylation in plasma represents a straightforward, minimally invasive method to detect all stages of CRC with potential to satisfy unmet needs for increased compliance in the screening population. Further clinical testing is warranted.