Mast cell–nerve axis with a focus on the human gut

AbstractThis paper summarizes the current knowledge on the interactions between intestinal mast cells, enteric neurons and visceral afferents which are part of the gut brain axis. The focus of this review is on the relevance of the mast cell–nerve axis in the human intestine. Similarities and important differences in the organization of the mast cell–nerve axis between human and rodents are discussed. Functionally important human mast cell mediators with neural actions in the human ENS are histamine (H1-4 receptors), proteases (PAR1 receptors), several cytokines and chemokines and probably also serotonin (5-HT3 receptors). On the other hand, mediator release from human intestinal mast cells is modulated by neuropeptides released from enteric and visceral afferent nerves. This article is part of a Special Issue entitled: Mast Cells in Inflammation

Low-Complexity Feedback Data Compression for Closed-Loop Digital Predistortion

This paper proposes sample combining as a low-complex and effective feedback data compression technique that allows to significantly reduce the computational effort and buffering needs for parameter adaptation in a closed-loop digital predistortion (DPD) system. Compression is achieved by applying an integrate & dump operation to an undersampled feedback signal. The proposed method is experimentally validated for RF measurement based behavioral modeling as well as closed-loop DPD of a 3.5 GHz GaN Doherty PA, taking also quantization effects of the feedback path into account. Our results demonstrate that the proposed technique is as capable as state-of-the-art histogram-based sample selection, however, at a much lower complexity.Peer reviewe

Replication of an emergency department-based recovery coaching intervention and pilot testing of pragmatic trial protocols within the context of Indiana's Opioid State Targeted Response plan

Solving the opioid crisis requires immediate, innovative, and sustainable solutions. A number of promising strategies are being carried out by U.S. states and territories as part of their Opioid State Targeted Response (STR) plans funded through the 21st Century Cures Act, and they provide an opportunity for researchers to assess effectiveness of these interventions using pragmatic approaches. This paper describes a pilot study of Project Planned Outreach, Intervention, Naloxone, and Treatment (POINT), the intervention that served as the basis for Indiana's STR-funded, emergency department (ED)-based peer specialist expansion that was conducted in preparation for a larger, multisite pragmatic trial. Through the pilot, we identified, documented, and corrected for challenges encountered while implementing planned study protocols. Per the project's funding mechanism, the ability to move to the larger trial was determined by the achievement of 3 milestones: (1) successful replication of the intervention; (2) demonstrated ability to obtain the necessary sample size; and (3) observe a higher level of engagement in medication for addiction treatment in the POINT group compared to standard care. Overall implementation of the study protocols was successful, with only minor refinements to proposed procedures being required in light of challenges with (1) data access, (2) recruitment, and (3) identification of the expansion hospitals. All three milestones were reached. Challenges in implementing protocols and reaching milestones resulted in refinements that improved the study design overall. The subsequent trial will add to the limited but growing evidence on ED-based peer supports. Capitalizing on STR efforts to study an already scaling and promising intervention is likely to lead to faster and more sustainable results with greater generalizability than traditional, efficacy-focused clinical research

NANOPARTICLE-MODIFICATION OF NICU-BASED ALLOY 400 FOR LASER POWDER BED FUSION

NiCu-based Alloy 400 is a material being frequently used in corrosive environments wherefore it is applied in several industries like the maritime sector or chemical processing [1]. Numerous functional parts made of this alloy, like heat exchangers or liquid-carrying tubes for instance, may withstand harsh environments to a certain extend but still, at high temperatures and especially in carbon-rich atmospheres, component failure occurs due to poor metal dusting and creep resistance [2–5]. Reinforcing the base alloy system with nanoparticles using gas atomization and subsequent laser powder bed fusion (LPBF) can counteract such material failure [6]. Hence, in this work, titanium was added to Alloy 400 and atomized under nitrogen atmosphere in order to cause TiN nanoparticle formation in the microstructure of printed components.Mechanical Engineerin

The Mast Cell Degranulator Compound 48/80 Directly Activates Neurons

Background Compound 48/80 is widely used in animal and tissue models as a “selective” mast cell activator. With this study we demonstrate that compound 48/80 also directly activates enteric neurons and visceral afferents. Methodology/Principal Findings We used in vivo recordings from extrinsic intestinal afferents together with Ca++ imaging from primary cultures of DRG and nodose neurons. Enteric neuronal activation was examined by Ca++ and voltage sensitive dye imaging in isolated gut preparations and primary cultures of enteric neurons. Intraluminal application of compound 48/80 evoked marked afferent firing which desensitized on subsequent administration. In egg albumen-sensitized animals, intraluminal antigen evoked a similar pattern of afferent activation which also desensitized on subsequent exposure to antigen. In cross-desensitization experiments prior administration of compound 48/80 failed to influence the mast cell mediated response. Application of 1 and 10 µg/ml compound 48/80 evoked spike discharge and Ca++ transients in enteric neurons. The same nerve activating effect was observed in primary cultures of DRG and nodose ganglion cells. Enteric neuron cultures were devoid of mast cells confirmed by negative staining for c-kit or toluidine blue. In addition, in cultured enteric neurons the excitatory action of compound 48/80 was preserved in the presence of histamine H1 and H2 antagonists. The mast cell stabilizer cromolyn attenuated compound 48/80 and nicotine evoked Ca++ transients in mast cell-free enteric neuron cultures. Conclusions/Significance The results showed direct excitatory action of compound 48/80 on enteric neurons and visceral afferents. Therefore, functional changes measured in tissue or animal models may involve a mast cell independent effect of compound 48/80 and cromolyn

Antimicrobial resistance and synergy in herbal medicine

Antimicrobial resistance (AMR) is a serious and growing threat to human health. The development of new antibiotics is limited and slow. The tradition of synergy in herbal medicine is being used as a source of research ideas. A literature review of antimicrobial research and plant synergy published in a five year period was carried out using online databases. The in vitro findings were that most of the research reported synergy both within plants and between plants and antibiotics. Whole plant extracts and combinations of compounds were shown to be more effective antimicrobials than isolated constituents. The discussion highlights that the in vitro herbal research findings are difficult to apply to practice and aren’t progressing to clinical trials. Collaborative, innovative, inter-disciplinary clinical research is recommended

Characterisation of faecal protease activity in irritable bowel syndrome with diarrhoea: origin and effect of gut transit

OBJECTIVES: Faecal serine proteases (FSPs) may play a role in irritable bowel syndrome with diarrhoea (IBS-D), but their origin is unclear. We aimed to structurally characterise them and define the impact of colonic cleansing and transit time. DESIGN: Faecal samples were obtained from 30 healthy volunteers (HV) and 79 patients with IBS-D participating in a trial of ondansetron versus placebo. Colonic transit was measured using radio-opaque markers. Samples were also obtained from 24 HV before and after colonic cleansing with the osmotic laxative MoviPrep. FSPs were purified from faecal extracts using benzamidine-Sepharose affinity chromatography. SDS-PAGE profiled components were identified using trypsinolysis and tandem mass spectrometry. Functional protease activity in faecal extracts was measured using a colorimetric assay based on the proteolysis of azo-casein. RESULTS: Protein analysis identified the most abundant FSPs as being of human origin and probably derived from pancreatic juice. Functional assays showed increased faecal protease (FP) and amylase in patients with IBS-D compared with HV. Those with higher amylase had significantly higher FP and greater anxiety. FP activity correlated negatively with whole gut transit in patients with IBS-D (Spearman r=−0.32, p=0.005) and HV (r=−0.55, p=0.014). Colon cleansing caused a significant rise in FP activity in HV from a baseline of median (IQR) 253 (140–426) to 1031 (435–2296), levels similar to those seen in patients with IBS-D. FSP activity correlated positively with days/week with urgency. CONCLUSIONS: The most abundant FSPs are of human origin. Rapid transit through the colon and/or decreased (possibly bacterial) proteolytic degradation increases their faecal concentration and could contribute to visceral hypersensitivity in patients with IBS-D. CLINICALTRIALS.GOV: NCT00745004

Effect of biased noise fluctuations on the output radiation of coherent beat laser

Effect of biased noise fluctuations on the degree of squeezing as well as the intensity of a radiation generated by a one-photon coherent beat laser is presented. It turns out that the radiation exhibits squeezing inside and outside the cavity under certain conditions. The degree of squeezing is enhanced by the biased noise input significantly in both regions. Despite the presence of the biased environment modes outside the cavity, the degree of squeezing outside the cavity can be greater than or equal to or even less than the cavity radiation depending on the initial preparation of the atomic superposition and amplitude of the external driving radiation. But the intensity of the radiation is found to be lesser outside the cavity regardless of these parameters.Comment: 18 pages, 7 figure

A mechanistic multi-centre, parallel group, randomised placebo controlled trial of Mesalazine for treatment of irritable bowel syndrome with diarrhoea (IBS-D)

Introduction: Immune activation has been reported in the mucosa of irritable bowel syndrome patients with diarrhoea (IBS-D) and some small studies have suggested that Mesalazine may reduce symptoms. We performed a double blind, randomised placebo controlled trial of 2g Mesalazine twice daily versus placebo for 3 months in Rome III criteria IBS-D patients. Primary outcome was daily average stool frequency during weeks 11-12; secondary outcomes were abdominal pain, stool consistency, urgency and satisfactory relief of IBS symptoms. Methods: Participants were randomised after a 2-week baseline stool diary. All participants completed a 12-week stool diary and at the end of each week recorded the presence of “satisfactory relief of IBS symptoms”. Results: 136 patients with IBS-D (82 F, 54 M) were randomised, 10 patients withdrew from each group. Analysis by intention to treat showed the daily average stool frequency during weeks 11 and 12 were mean (SD), 2.8 (1.2) in Mesalazine and 2.7 (1.9) in placebo group with no significant group difference (95% confidence interval) 0.1 (-0.33,0.53); p=0.66. Mesalazine did not improve abdominal pain, stool consistency nor percentage with satisfactory relief compared to placebo during the last 2 weeks follow up. Conclusion: This study does not support any clinically meaningful benefit or harm of Mesalazine compared with placebo in unselected IBS with diarrhoea. More precise subtyping based on underlying disease mechanisms is needed to allow more effective targeting of treatment in IBS. (ClinicalTrials.gov number NCT01316718