Explore the vast range of titles available.

Molecular dynamics (MD) simulations represent an essential tool in the toolbox of modern chemistry, enabling the prediction of experimental observables for a variety of chemical systems and processes and majorly impacting the study of biological membranes. However, the chemical diversity of complex lipids beyond phospholipids brings new challenges to well-established protocols used in MD simulations of soft matter and requires continuous assessment to ensure simulation reproducibility and minimize unphysical behavior. Lipopolysaccharides (LPS) are highly charged glycolipids whose aggregation in a lamellar arrangement requires the binding of numerous cations to oppositely charged groups deep inside the membrane. The delicate balance between the fully hydrated carbohydrate region and the smaller hydrophobic core makes LPS membranes very sensitive to the choice of equilibration protocol. In this work, we show that the protocol successfully used to equilibrate phospholipid bilayers when applied to complex lipopolysaccharide membranes occasionally leads to a small expansion of the simulation box very early in the equilibration phase. Although the use of a barostat algorithm controls the system dimension and particle distances according to the target pressure, fluctuation in the fleeting pressure occasionally enables a few water molecules to trickle into the hydrophobic region of the membrane, with spurious solvent buildup. We show that this effect stems from the initial steps of NPT equilibration, where initial pressure can be fairly high. This can be solved with the use of a stepwise-thermalization NVT/NPT protocol, as demonstrated for atomistic MD simulations of LPS/DPPE and lipid-A membranes in the presence of different salts using an extension of the GROMOS forcefield within the GROMACS software. This equilibration protocol should be standard procedure for the generation of consistent structural ensembles of charged glycolipids starting from atomic coordinates not previously pre-equilibrated. Although different ways to deal with this issue can be envisioned, we investigated one alternative that could be readily available in major MD engines with general users in mind.

Background Chronic megacolon is a rare disease of the colonic motor function characterized by a permanent increase in colonic diameter. Methods We reviewed electronic medical records of all patients diagnosed with chronic megacolon from 1999 to 2014 at Mayo Clinic. Our aim was to summarize clinical and motility features, including colonic compliance and tone measured by colonic barostat-controlled 10-cm-long infinitely compliant balloon. Colonic compliance curves were compared to healthy control (40) and disease (47) control groups. Results Among 24 identified patients, the mean maximal colonic diameter on abdominal radiograph was 12.7 ± 0.8 cm. The cause of megacolon was idiopathic in 16 of 24 and secondary in 8 of 24. A relatively high prevalence (10/24) of comorbid pelvic floor dyssynergia was identified. At the time of this report, 16 patients had undergone colectomy. In general, megacolon presented high fasting colonic volume at relatively low pressures (16–20 mmHg), suggesting high colonic compliance; similarly, volumes at operating pressures that ensured apposition of the balloon to the colonic wall suggested low colonic tone. Median balloon volume at 44 mmHg distension was 584 mL (IQR 556.5–600) in patients with megacolon compared to 251 mL (212–281) in healthy, 240 mL (207–286) in functional constipation, and 241 mL (210.8–277.5) in diarrhea-predominant irritable bowel syndrome controls. Colon’s tonic response to feeding was generally intact, and there was frequently maintained phasic contractile response to feeding. Conclusions Chronic megacolon is a severe colonic dysmotility, manifesting radiologically with increased colonic diameter; it can be proven by measuring colonic compliance and typically requires colectomy because of failed medical therapy.

Signals arising from the upper part of the gut are essential for the regulation of food intake, particularly satiation. This information is supplied to the brain partly by vagal nervous afferents. The porcine model, because of its sizeable gyrencephalic brain, omnivorous regimen, and comparative anatomy of the proximal part of the gut to that of humans, has provided several important insights relating to the relevance of vagally mediated gut-brain relationships to the regulation of food intake. Furthermore, its large size combined with the capacity to become obese while overeating a western diet makes it a pivotal addition to existing murine models, especially for translational studies relating to obesity. How gastric, proximal intestinal, and portal information relating to meal arrival and transit are encoded by vagal afferents and their further processing by primary and secondary brain projections are reviewed. Their peripheral and central plasticities in the context of obesity are emphasized. We also present recent insights derived from chronic stimulation of the abdominal vagi with specific reference to the modulation of mesolimbic structures and their role in the restoration of insulin sensitivity in the obese miniature pig model.

Abnormal visceral perception and motor function are often observed in patients with fecal incontinence, evacuation disorders and irritable bowel syndrome. The international anorectal physiology working group has proposed a standardization for anorectal function assessment, where rectal sensitivity testing is performed using an elastic balloon attached to a high-resolution anorectal manometry (HRAM) catheter. Rectal compliance, another component of rectal function evaluation, is a pressure–volume relationship that refers to the rectum’s ability to stretch and expand as it receives and holds fecal matter. There are no data available regarding the possibility of compliance testing using HRAM, although this is theoretically possible by correcting for the elastic balloon’s intrinsic properties. The gold standard for measurement of visceral sensitivity and compliance is the rectal barostat, according to the procedure described by the European COST action GENIEUR group. Data on the agreement between the two different procedures are scarce. Hence, we performed a comparative study of the HRAM and barostat investigations in 26 healthy individuals. We hypothesized that by inflating the balloon before the examination, rectal compliance can be measured with HRAM investigations, and we examined correlations and levels of agreement between the methods. Our results demonstrate that assessing rectal compliance with HRAM is technically possible; however, a strong correlation with the rectal barostat was only observed at the maximum tolerable volume (Spearman’s rho = 0.7, p = 0.02). We only found moderate correlations (Spearman’s rho = 0.562, p = 0.019) for compliance according to the barostat methodology and for rectal sensibility testing (Spearman’s rho = 0.57, p = 0.03 for maximum tolerable volume). Bland–Altman plots showed poor levels of agreement between the methods. We conclude that HRAM and the rectal barostat cannot be used interchangeably for compliance or sensitivity assessments. We suggest the development of a non-elastic balloon with a fixed size and shape to assess rectal sensory function and compliance in HRAM testing.

Background Irritable bowel syndrome with diarrhoea (IBS-D) affects up to 4% of the general population. Symptoms include frequent, loose, or watery stools with associated urgency, resulting in marked reduction of quality of life and loss of work productivity. Ondansetron, a 5HT 3 receptor antagonist, has had an excellent safety record for over 20 years as an antiemetic, yet is not widely used in the treatment of IBS-D. It has, however, been shown to slow colonic transit and in a small randomised, placebo-controlled, cross-over pilot study, benefited patients with IBS-D. Methods This trial is a phase III, parallel group, randomised, double-blind, multi-centre, placebo-controlled trial, with embedded mechanistic studies. Participants ( n = 400) meeting Rome IV criteria for IBS-D will be recruited from outpatient and primary care clinics and by social media to receive either ondansetron (dose titrated up to 24 mg daily) or placebo for 12 weeks. Throughout the trial, participants will record their worst abdominal pain, worst urgency, stool frequency, and stool consistency on a daily basis. The primary endpoint is the proportion of “responders” in each group, using Food and Drug Administration (FDA) recommendations. Secondary endpoints include pain intensity, stool consistency, frequency, and urgency. Mood and quality of life will also be assessed. Mechanistic assessments will include whole gut transit, faecal tryptase and faecal bile acid concentrations at baseline and between weeks 8 and 11. A subgroup of participants will also undergo assessment of sensitivity ( n  = 80) using the barostat, and/or high-resolution colonic manometry ( n  = 40) to assess motor patterns in the left colon and the impact of ondansetron. Discussion The TRITON trial aims to assess the effect of ondansetron across multiple centres. By defining ondansetron’s mechanisms of action we hope to better identify patients with IBS-D who are likely to respond. Trial registration ISRCTN, ISRCTN17508514 , Registered on 2 October 2017.

Luminal capsaicin induces local and distant reflexes in the upper gastrointestinal tract and stimulates lower gastrointestinal symptoms in susceptible persons. We aimed to evaluate the effect of gastric capsaicin on rectal motor function and sensation. Methods Eighteen healthy volunteers participated twice, at least 1 week apart, in this double-blind, placebo-controlled crossover study. Participants swallowed a gastric tube for capsaicin or saline infusion. A barostat tube was placed in the rectum to measure rectal tone before and during gastric capsaicin (40 µg/ml, 2.5 ml/min) or placebo infusion and to conduct distension experiments before and after gastric infusions. Gastric infusions were terminated after 60 min or when epigastric discomfort occurred. Differences in rectal tone, compliance, and sensitivity between gastric placebo and gastric capsaicin were determined. Results On both study days, basal rectal volumes, compliance, and sensitivity parameters were comparable (NS) before gastric infusions. Gastric capsaicin infusion induced epigastric discomfort that necessitated termination of infusion after 29.6 ± 12.3 min (saline: 54.7 ± 8.9 min; p  < 0.01). Rectal tone, aggregate perception scores, and rectal compliance did not differ between placebo and capsaicin trials ( p  > 0.05). Rectal tone increased significantly only when capsaicin induced epigastric discomfort ( p  < 0.05). The reproducibility of the barostat trial was acceptable with significant correlations of volumes, pressures (< 0.05; r 2 from 0.41 to 0.55), rectal compliance ( p  < 0.01; r 2  = 0.44), and aggregate perception scores ( p values all < 0.05; r 2 from 0.44 to 0.0.65) between the two barostat trials. Conclusion Gastric perfusion with capsaicin does not directly influence rectal physiology through a reflex arc.

Background Increased esophagogastric junction distensibility occurs with esophageal reflux. The EndoFLIP ® is now available as a clinical tool to measure this. Control data for patients without reflux has to date only been available for a handful of patients evaluated under sedation during endoscopy. This study explores the baseline data for patients who undergo laparoscopy using general anesthesia with pneumoperitoneum. Methods Patients who require surgery in the absence of a history of esophageal reflux underwent EndoFLIP ® evaluation of pressure, cross-sectional area, and distensibility with bag fills of 30 and 40 ml. This was performed after induction of anesthesia, during pneumoperitoneum, and just before extubation. Results Baseline levels were established and were noted to be significantly affected by the impact of pneumoperitoneum, with negligible effects from general anesthesia, patient gender, age, body mass index, or muscle relaxation. Conclusions These data provide a guide for more accurate intraoperative EndoFLIP ® calibration of crural hiatal repair during surgery.

Adaptation and implementation of the Generalized Shadow Hybrid Monte Carlo (GSHMC) method for molecular simulation at constant pressure in the NPT ensemble are discussed. The resulting method, termed NPT-GSHMC, combines Andersen barostat with GSHMC to enable molecular simulations in the environment natural for biological applications, namely, at constant pressure and constant temperature. Generalized Hybrid Monte Carlo methods are designed to maintain constant temperature and volume and extending their functionality to preserving pressure is not trivial. The theoretical formulation of NPT-GSHMC was previously introduced. Our main contribution is the implementation of this methodology in the GROMACS molecular simulation package and the evaluation of properties of NPT-GSHMC, such as accuracy, performance, effectiveness for real physical systems in comparison with well-established molecular simulation techniques. Benchmarking tests are presented and the obtained preliminary results are promising. For the first time, the generalized hybrid Monte Carlo simulations at constant pressure are available within the popular open source molecular dynamics software package.

Irritable pouch syndrome (IPS) is a functional disorder in patients with ileal pouch–anal anastomosis (IPAA), which presents with symptoms in the absence of structural abnormalities of the pouch. Thus, it resembles other functional disorders, such as irritable bowel syndrome characterized by visceral hypersensitivity in the presence of normal rectal biomechanics. The aim was to assess pouch biomechanics and perception of balloon distension in different groups of subjects with IPAA and to correlate the findings with clinical features.MethodsPouch tone, compliance, and sensation to balloon distension were measured in 18 patients with IPS, 11 patients with active pouch inflammation (pouchitis or Crohn's disease of the pouch), and 12 asymptomatic subjects with normal pouches. All patients were recruited from a subspecialty Pouchitis Clinic.ResultsScores of sensation of gas, urge to defecate, and pain measured by visual analog scales at various distension pressures were significantly higher in IPS than pouchitis and normal pouch patients. Pouch tone was comparable among the groups and compliance was reduced in the pouchitis group. The visual analog scale showed a trend of correlation with the Pouchitis Disease Activity Index symptom scores in IPS.ConclusionsIPS, like other gut functional disorders, is characterized by visceral hypersensitivity, with normal pouch biomechanics. (Inflamm Bowel Dis 2011)

Molecular dynamics simulations of solids are often performed using anisotropic barostats that allow the shape and volume of the periodic cell to change during the simulation. Most existing schemes are based on a second-order differential equation that might lead to undesired oscillatory behaviors and should not be used in the equilibration phase. We recently introduced stochastic cell rescaling, a first-order stochastic barostat that can be used for both the equilibration and production phases. Only the isotropic and semi-isotropic variants have been formulated and implemented so far. In this paper, we develop and implement the equations of motion of the fully anisotropic variant and test them on Lennard-Jones solids, ice, gypsum, and gold. The algorithm has a single parameter that controls the relaxation time of the volume, results in the exponential decay of correlation functions, and can be effectively applied to a wide range of systems.