Transient Relaxation Research Articles

The effects of a novel metabotropic glutamate receptor 5 antagonist (AZD2066) on transient lower oesophageal sphincter relaxations and reflux episodes in healthy volunteers

Selective metabotropic glutamate receptor 5 (mGluR5) antagonists inhibit transient lower oesophageal sphincter relaxations (TLESRs) in animals and acid reflux in humans. To assess the effect of single doses of the mGluR5 antagonist AZD2066 on TLESRs and reflux in humans. Healthy male volunteers received AZD2066 13 mg and placebo (part A), or AZD2066 2 mg and AZD2066 6 mg and placebo (part B), in a randomised crossover study. Postprandial manometry/pH-impedance measurements were taken after each dose. A total of 13 individuals completed part A of the study and 19 individuals completed part B. There was a significant reduction in the geometric mean number of TLESRs (27%; P = 0.02) and the geometric mean number of reflux episodes (51%; P = 0.01) in subjects receiving AZD2066 13 mg compared with placebo. Adverse events in participants receiving AZD2066 13 mg were mostly related to the nervous system [dizziness (3/13); disturbance in attention (3/13)]. Adverse events were reversible and of mild intensity. There were no serious adverse events. The effects of AZD2066 appeared dose-dependent, with smaller reductions in TLESRs and reflux episodes (relative to placebo) and fewer adverse events observed for AZD2066 2 mg and AZD2066 6 mg compared with AZD2066 13 mg. The mGluR5-mediated inhibition of TLESRs may be a useful approach for inhibiting gastro-oesophageal reflux.

Therapeutic options for refractory gastroesophageal reflux disease

Refractory gastroesophageal reflux disease may affect up to one-third of the patients that consume proton pump inhibitor (PPI) once daily. Treatment in clinical practice has been primarily focused on doubling the PPI dose, despite lack of evidence of its value. In patients who failed PPI twice daily, medical treatment has been primarily focused on reducing transient lower esophageal sphincter relaxation rate or attenuating esophageal pain perception using visceral analgesics. In patients with evidence of reflux as the direct trigger of their symptoms, endoscopic treatment or antireflux surgery may be helpful in remitting symptoms. The role of psychological interventions, as well as non-traditional therapeutic strategies remains to be further elucidated.

AMP-activated protein kinase phosphorylates cardiac troponin I and alters contractility of murine ventricular myocytes.

AMP-activated protein kinase (AMPK) is an important regulator of energy balance and signaling in the heart. Mutations affecting the regulatory γ2 subunit have been shown to cause an essentially cardiac-restricted phenotype of hypertrophy and conduction disease, suggesting a specific role for this subunit in the heart. The γ isoforms are highly conserved at their C-termini but have unique N-terminal sequences, and we hypothesized that the N-terminus of γ2 may be involved in conferring substrate specificity or in determining intracellular localization. A yeast 2-hybrid screen of a human heart cDNA library using the N-terminal 273 residues of γ2 as bait identified cardiac troponin I (cTnI) as a putative interactor. In vitro studies showed that cTnI is a good AMPK substrate and that Ser150 is the principal residue phosphorylated. Furthermore, on AMPK activation during ischemia, Ser150 is phosphorylated in whole hearts. Using phosphomimics, measurements of actomyosin ATPase in vitro and force generation in demembraneated trabeculae showed that modification at Ser150 resulted in increased Ca(2+) sensitivity of contractile regulation. Treatment of cardiomyocytes with the AMPK activator 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) resulted in increased myocyte contractility without changing the amplitude of Ca(2+) transient and prolonged relaxation despite shortening the time constant of Ca(2+) transient decay (tau). Compound C prevented the effect of AICAR on myocyte function. These results suggest that AMPK activation increases myocyte contraction and prolongs relaxation by increasing myofilament Ca(2+) sensitivity. We conclude that cTnI phosphorylation by AMPK may represent a novel mechanism of regulation of cardiac function.

Randomised clinical trial: the effect of baclofen in patients with gastro‐oesophageal reflux ‐ a randomised prospective study

Baclofen, a GABA(B) agonist, has been shown to reduce transient lower oesophageal sphincter relaxations (TLESRs), a major cause of gastro-oesophageal reflux disease (GERD). To examine the effect and tolerability of baclofen in GERD patients over a 2-week period. Forty-three GERD patients with abnormal 24-h pH tests were prospectively randomised to receive baclofen or placebo in a double-blind fashion for 2 weeks. Oesophageal manometry, 24-h pH monitoring, and a standard questionnaire was administered, before and after treatment. Thirty-four patients completed the study. In the baclofen group there were significant decreases in 24-h pH score (P = 0.020), percent of upright reflux episodes (P = 0.016), percent total time pH <4 (P = 0.003), number of reflux episodes (P = 0.018), number of reflux episodes longer than 5 min (P = 0.016), number of postprandial reflux episodes (P = 0.045), and percentage of time pH <4 (P = 0.003). No significant changes in reflux parameters were noted in the placebo group. Patients receiving baclofen had significantly less belching (P = 0.038), regurgitation (P = 0.036) and overall symptom score (P = 0.004) whereas placebo patients had less heartburn (P = 0.001), chest pain (P = 0.002), regurgitation (P = 0.017) and overall symptom score (P = 0.000). However, there were no significant differences in changes of reflux parameters or symptoms when comparing the two groups. Drowsiness did not limit baclofen use. Baclofen was associated with a significant decrease in percent upright reflux by 24-h pH monitoring and a significant improvement in belching, regurgitation and overall symptom score. Baclofen may be more effective in patients with predominantly upright reflux and belching.

Transient postseismic mantle relaxation following 2004 Sumatra earthquake: implications of seismic vulnerability in the Andaman-Nicobar region

Abstract. Throughout the world, the tsunami generation potential of some large under-sea earthquakes significantly contributes to regional seismic hazard, which gives rise to significant risk in the near-shore provinces where human settlements are in sizeable population, often referred to as coastal seismic risk. In this context, we show from the pertinent GPS data that the transient stresses generated by the viscoelastic relaxation process taking place in the mantle is capable of rupturing major faults by stress transfer from the mantle through the lower crust including triggering additional rupture on the other major faults. We also infer that postseismic relaxation at relatively large depths can push some of the fault segments to reactivation causing failure sequences. As an illustration to these effects, we consider in detail the earthquake sequence comprising six events, starting from the main event of Mw = 7.5, on 10 August 2009 and tapering off to a small earthquake of Mw = 4.5 on 2 February 2011 over a period of eighteen months in the intensely seismic Andaman Islands between India and Myanmar. The persisting transient stresses, spatio-temporal seismic pattern, modeled Coulomb stress changes, and the southward migration of earthquake activity has increased the probability of moderate earthquakes recurring in the northern Andaman region, particularly closer to or somewhat south of Diglipur.

Increased frequency and enhanced perception of reflux in non-erosive reflux disease patients non-responders to proton pump inhibitors

BackgroundThe unsatisfactory response to medical treatment in non-erosive patients is becoming a real challenge for gastroenterologists. Non-responder patients, evaluated under treatment, present symptoms which are related to non-acidic, mixed and proximal reflux episodes. MethodsTo elucidate the reflux pattern and mechanisms related to persistence of symptoms despite treatment, oesophageal pH-impedance was performed in 55 non-erosive responder and 24 non-responder patients, studied off therapy. Ten responder and 10 non-responder patients underwent a repeated study during proton pump inhibitor treatment. ResultsNon-responders were characterised by a higher overall number and larger proportion of symptomatic reflux episodes. Non-responders were also characterised by an enhanced sensitivity to acidic, mixed and proximal refluxes. Weakly acidic reflux accounted for 29% of symptomatic refluxes in non-responders and 34% in responders. Proportions of acidic and weakly acidic reflux episodes were comparable both in responders and non-responders when analysed off and on treatment. ConclusionsAn increased overall number of reflux episodes and enhanced sensitivity to reflux are strongly associated with treatment failure. Treatment strategies aimed at decreasing transient lower oesophageal sphincter relaxations, pain modulators or anti-reflux surgery should be considered in non-responders in whom a significant relationship between symptoms and reflux has been confirmed.

Thermal rounding exponent of the depinning transition of an elastic string in a random medium

We study numerically thermal effects at the depinning transition of an elastic string driven in a two-dimensional uncorrelated disorder potential. The velocity of the string exactly at the sample critical force is shown to behave as V~T(ψ), with ψ the thermal rounding exponent. We show that the computed value of the thermal rounding exponent, ψ=0.15, is robust and accounts for the different scaling properties of several observables both in the steady state and in the transient relaxation to the steady state. In particular, we show the compatibility of the thermal rounding exponent with the scaling properties of the steady-state structure factor, the universal short-time dynamics of the transient velocity at the sample critical force, and the velocity scaling function describing the joint dependence of the steady-state velocity on the external drive and temperature.

Different in vitro and in vivo profiles of substituted 3‐aminopropylphosphinate and 3‐aminopropyl(methyl)phosphinate GABAB receptor agonists as inhibitors of transient lower oesophageal sphincter relaxation

Gastro-oesophageal reflux is predominantly caused by transient lower oesophageal sphincter relaxation (TLOSR) and GABA(B) receptor stimulation inhibits TLOSR. Lesogaberan produces fewer CNS side effects than baclofen, which has been attributed to its affinity for the GABA transporter (GAT), the action of which limits stimulation of central GABA(B) receptors. To understand the structure-activity relationship for analogues of lesogaberan (3-aminopropylphosphinic acids), and corresponding 3-aminopropyl(methyl)phosphinic acids, we have compared representatives of these classes in different in vitro and in vivo models. The compounds were characterized in terms of GABA(B) agonism in vitro. Binding to GATs and cellular uptake was done using rat brain membranes and slices respectively. TLOSR was measured in dogs, and CNS side effects were evaluated as hypothermia in mice and rats. 3-Aminopropylphosphinic acids inhibited TLOSR with a superior therapeutic index compared to 3-aminopropyl(methyl)phosphinic acids. This difference was most likely due to differential GAT-mediated uptake into brain cells of the former but not latter. In agreement, 3-aminopropyl(methyl)phosphinic acids were much more potent in producing hypothermia in rats even when administered i.c.v. An enhanced therapeutic window for 3-aminopropylphosphinic acids compared with 3-aminopropyl(methyl)phosphinic acids with respect to inhibition of TLOSR was observed and is probably mechanistically linked to neural cell uptake of the former but not latter group of compounds. These findings offer a platform for discovery of new GABA(B) receptor agonists for the treatment of reflux disease and other conditions where selective peripheral GABA(B) receptor agonism may afford therapeutic effects.

Effect of nitrite delivered in saliva on postprandial gastro-esophageal function

Objective.Acid reflux produces troublesome symptoms (heartburn) and complications including esophagitis, Barrett's esophagus, and adenocarcinoma. Reflux occurs due to excessive and inappropriate relaxation of the lower esophageal sphincter. An important mediator of this is nitric oxide, high concentrations of which are generated within the lumen when swallowed saliva meets gastric acid. Saliva contains nitrite, derived from the enterosalivary recirculation of dietary nitrate, which is reduced to nitric oxide by gastric acid. The aim of this study was to investigate whether salivary nitrite contributes to dysfunction of the lower esophageal sphincter. Materials and methods.In 20 volunteers, studies of gastro-esophageal function were performed on four separate days, following consumption of a standardized meal, with saliva nitrite concentrations modified differently each day by intra-oral nitrite infusion. Results.The infusions produced an appropriate range in saliva nitrite concentrations, from below to well above the physiological range. The standardized meal induced expected physiological changes in gastro-esophageal function confirming the recordings were sensitive and robust. Esophageal acid exposure (primary outcome) was similar on each study day. Secondary outcomes, including number and duration of reflux events, rate of transient lower esophageal sphincter relaxations, lower esophageal sphincter pressure and rate of gastric emptying were also unaffected by variations in saliva nitrite concentration. Conclusions.Nitrite in swallowed saliva does not modify gastro-esophageal junction function or predispose to gastro-esophageal reflux. The wide range in saliva nitrite concentrations, the sensitivity of the physiological recordings and the number of subjects studied make it very unlikely that an effect has been missed.

Step-by-step management of refractory gastresophageal reflux disease

Up to a third of the patients who receive proton pump inhibitor (PPI) once daily will demonstrate lack or partial response to treatment. There are various mechanisms that contribute to PPI failure and they include residual acid reflux, weakly acidic and weakly alkaline reflux, esophageal hypersensitivity, and psychological comorbidity, among others. Some of these underlying mechanisms may coincide in the same patient. Evaluation for proper compliance and adequate dosing time of PPIs should be the first management step before ordering invasive diagnostic tests. Doubling the PPI dose or switching to another PPI is the second step of management. Upper endoscopy and pH testing appear to have limited diagnostic value in patients who failed PPI treatment. In contrast, esophageal impedance with pH testing (multichannel intraluminal impedance MII-pH) on therapy appears to provide the most insightful information about the subsequent management of these patients (step 3). In step 4, treatment should be tailored to the specific underlying mechanism of patient's PPI failure. For those who demonstrate weakly acidic or weakly alkaline reflux as the underlying cause of their residual symptoms, transient lower esophageal sphincter relaxation reducers, endoscopic treatment, antireflux surgery and pain modulators should be considered. In those with functional heartburn, pain modulators are the cornerstone of therapy.

Localization of mGluR5, GABAB, GABAA, and cannabinoid receptors on the vago‐vagal reflex pathway responsible for transient lower esophageal sphincter relaxation in humans: an immunohistochemical study

Transient lower esophageal sphincter relaxations (TLESRs) are the predominant mechanisms underlying gastro-esophageal reflux. TLESRs are mediated by a vago-vagal reflex, which can be blocked by interaction with metabotropic Glutamate Receptor 5 (mGluR5), γ-aminobutyric acid type B (GABA(B)), γ-aminobutyric acid type A (GABA(A)), and cannabinoid (CB) receptors. However, the distribution of these receptors in the neural pathway underlying the triggering of TLESRs has not been evaluated in humans. Using immunohistochemistry, we investigated the distribution of mGluR5, GABA(A), GABA(B), CB1, and CB2 receptors in the human nodose ganglion, the brain stem, and the myenteric plexus of the esophagus. MGluR5, GABA(B), CB1, and CB2 receptors are abundantly expressed in neurons of the myenteric plexus of the LES, nodose ganglion cell bodies and nerve fibers, the dorsal motor nucleus, and nucleus of the solitary tract in the brain stem. GABA(A) receptors are expressed in the same regions except in the nodose ganglion and myenteric plexus of the LES. Human mGluR5, GABA(A,B), and CB(1,2) receptors are abundantly expressed along the vago-vagal neural pathway and involved in the triggering of TLESRs. These findings are not only in line with the central side effects observed during treatment with reflux inhibitors such as GABA(B) receptor agonists and mGluR5 antagonists, but also suggest that peripherally acting compounds may be effective.

Na+ Access Kinetics in the Na+/K+-Atpase Pump

In exchanging three Na+ for two K+, Na+/K+ pumps move net charge through the membrane's electric field. Most charge moves during transitions that release Na+ to the exterior, as Na+ traverse a fraction of the membrane field along an access channel connecting their binding sites deep inside the pump with the extracellular space. We separate the resulting electrical signals from others in the pump cycle by withholding K+ and intracellular ADP, thereby constraining pumps to steps that release and rebind external Na+. Under these conditions, at a given external Na+ concentration ([Na+]o) and membrane potential, the pumps distribute among conformations with zero, one, two, or three bound Na+. After a sudden jump to a new potential, as pumps redistribute to a new steady-state arrangement, transient currents are generated upon Na+-ion release or binding. By rapidly changing the squid giant axon membrane potential, we previously identified three distinct components in these transient current relaxations: fast (comparable to the voltage-jump time course), medium-speed (τm ∼0.2-0.5 ms), and slow (τs ∼1-10 ms). Technical advances now allow us to simultaneously follow the charge amounts in all three phases, with unprecedented temporal resolution. We find that, over a broad range of [Na+]o and potential, the charge amount contained in the fast component is dictated by how far the medium-speed component has progressed towards equilibrium at that time, which is itself determined by how far the slow component has progressed. Thus, under all conditions examined, as Na+-bound and -unbound pump populations redistribute, the amounts and time courses of the three charge movements are closely correlated. These strict correlations reveal the dynamics of the conformational changes by which Na+ are released from (or sequestered into) their binding sites one at a time, in an obligatorily sequential manner. HL36783, U54-GM087519.

Antitussive effects of the peripherally restricted GABAB receptor agonist lesogaberan in guinea pigs: Comparison to baclofen and other GABAB receptor-selective agonists

BackgroundGastroesophageal reflux disease (GERD) is a common cause of chronic cough. Both acid and nonacid reflux is thought to play a role in the initiation of coughing and cough hypersensitivity. The GABAB receptor agonist lesogaberan was developed as a peripherally restricted anti-reflux therapy that reduces the frequency of transient lower esophageal sphincter relaxations (TLESR; the major cause of reflux) in animals and in patients with GERD. GABAB receptor agonists have also been shown to possess antitussive effects in patients and in animals independent of their effects on TLESR, suggesting that lesogaberan may be a promising treatment for chronic cough.MethodsWe have assessed the direct antitussive effects of lesogaberan (AZD3355). The effects of other GABAB receptor agonists were also determined. Coughing was evoked in awake guinea pigs using aerosol challenges with citric acid.ResultsLesogaberan dose-dependently inhibited citric acid evoked coughing in guinea pigs. Comparable effects of the GABAB receptor agonists baclofen and 3-aminopropylphosphinic acid (3-APPiA) on cough were also observed. Baclofen produced obvious signs of sedation and respiratory depression. By contrast, both lesogaberan and 3-APPiA (both inactivated centrally by GABA transporters) were devoid of sedative effects and did not alter respiratory rate.ConclusionsTogether, the data suggest that lesogaberan and related GABAB receptor agonists may hold promise as safe and effective antitussive agents largely devoid of CNS side effects.

Sub-Nanomolar Sensitivity of Nitric Oxide Mediated Regulation of cGMP and Vasomotor Reactivity in Vascular Smooth Muscle

Nitric oxide (NO) is a potent dilator of vascular smooth muscle (VSM) by modulating intracellular cGMP ([cGMP]i) through the binding and activation of receptor guanylyl cylases (sGC). The kinetic relationship of NO and sGC, as well as the subsequent regulation of [cGMP]i and its effects on blood vessel vasodilation, is largely unknown. In isolated VSM cells exposed to both pulsed and clamped NO we observed transient and sustained increases in [cGMP]i, with sub-nanomolar sensitivity to NO (EC50 = 0.28 nM). Through the use of pharmacological inhibitors of sGC, PDE5, and PKG, a comprehensive VSM-specific modeling algorithm was constructed to elucidate the concerted activity profiles of sGC, PDE5, phosphorylated PDE5, and PDE1 in the maintenance of [cGMP]i. In small pressure-constricted arteries of the resistance vasculature we again observed both transient and sustained relaxations upon delivery of pulsed and clamped NO, while maintaining a similarly high sensitivity to NO (EC50 = 0.42 nM). Our results propose an intricate dependency of the messengers and enzymes involved in cGMP homeostasis, and vasodilation in VSM. Particularly, the high sensitivity of sGC to NO in primary tissue indicates how small changes in the concentrations of NO, irrespective of the form of NO delivery, can have significant effects on the dynamic regulation of vascular tone.

Transient Lower Esophageal Sphincter Relaxation and the Related Esophageal Motor Activities

Transient lower esophageal sphincter (LES) relaxation (TLESR) is defined as LES relaxation without a swallow. TLESRs are observed in both of the normal individuals and the patients with gastroesophageal reflux disorder (GERD). However, TLESR is widely considered as the major mechanism of the GERD. The new equipments such as high resolution manometry and impedance pH study is helped to understand of TLESR and the related esophageal motor activities. The strong longitudinal muscle contraction was observed during development of TLESR. Most of TLESRs are terminated by TLESR related motor events such as primary peristalsis and secondary contractions. The majority of TLESRs are associated with gastroesophageal reflux. Upper esophageal sphincter (UES) contraction is mainly associated with liquid reflux during recumbent position and UES relaxation predominantly related with air reflux during upright position. The frequency of TLESR in GERD patients seems to be not different compared to normal individuals, but the refluxate of GERD patients tend to be more acidic during TLESR.

Mixed-Mode Oscillations in a Multiple Time Scale Phantom Bursting System

In this work we study mixed mode oscillations in a model of secretion of GnRH (Gonadotropin Releasing Hormone). The model is a phantom burster consisting of two feedforward coupled FitzHugh-Nagumo systems, with three time scales. The forcing system (Regulator) evolves on the slowest scale and acts by moving the slow nullcline of the forced system (Secretor). There are three modes of dynamics: pulsatility (transient relaxation oscillation), surge (quasi steady state) and small oscillations related to the passage of the slow nullcline through a fold point of the fast nullcline. We derive a variety of reductions, taking advantage of the mentioned features of the system. We obtain two results; one on the local dynamics near the fold in the parameter regime corresponding to the presence of small oscillations and the other on the global dynamics, more specifically on the existence of an attracting limit cycle. Our local result is a rigorous characterization of small canards and sectors of rotation in the case of folded node with an additional time scale, a feature allowing for a clear geometric argument. The global result gives the existence of an attracting unique limit cycle, which, in some parameter regimes, remains attracting and unique even during passages through a canard explosion.

Amplified NO/cGMP‐mediated relaxation and ryanodine receptor‐to‐BKCa channel signalling in corpus cavernosum smooth muscle from phospholamban knockout mice

Relaxation of corpus cavernosum smooth muscle (CCSM) is induced by NO. NO promotes the formation of cGMP, which activates cGMP-dependent protein kinase I (PKGI). The large conductance calcium-activated potassium (BK(Ca) ) channel is regarded as a major target of NO/cGMP signalling; however, the mechanism of BK(Ca) activation remains unclear. The aim of the present study was to determine whether sarcoplasmic reticulum (SR) Ca(2+) load and Ca(2+) release from the SR via ryanodine receptors (RyRs) is important for BK(Ca) channel activation in response to NO/cGMP. In vitro myography was performed on CCSM strips from wild-type and PLB knockout (PLB(-/-)) mice to evaluate contraction and relaxation in response to pharmacological agents and electrical field stimulation (EFS). In CCSM strips from PLB(-/-) mice, a model of increased SR Ca(2+) load, contractile force in response to EFS or phenylephrine (PE) was increased by nearly 100%. EFS of strips precontracted with PE induced transient relaxation in CCSM, an effect that was significantly larger in PLB(-/-) strips. Likewise, the relaxation of PE-induced contraction in response to SNP and cGMP was greater in PLB(-/-) , as demonstrated by a shift in the concentration-response curve towards lower concentrations. Blocking RyRs and BK(Ca) channels diminished the induced relaxations and eliminated the difference between wild-type and PLB(-/-). NO/cGMP activates BK(Ca) channels through RyR-mediated Ca(2+) release. This signalling pathway is responsible for approximately 40% of the NO/cGMP effects and is amplified by increased SR Ca(2+) concentrations.

Study of an initial transient relaxation in XLPE cable insulation by TSDC and PEA

Space charge profiles in electrets of cable XLPE insulation have been determined by pulsed electroacustic method (PEA). A single positive peak close to the cathode, which decreases with annealing time, is observed. Typically, thermally stimulated depolarization currents (TSDC) of those electrets show heteropolar peaks initially. A new transient homopolar peak emerges in TSDC profiles at 99°C with annealing at high temperatures. No direct correlation can be established between PEA and TSDC results, since the case of the largest value of the maximum of this TSDC peak corresponds to the smallest charge peak observed in PEA profile. The transient behavior is explained by means of charge trapped on crystals surfaces due to the differences between the conductivities of amorphous and crystalline phases. The homoplar peak is associated with dipolar contaminants located in the interlamellar amorphous phase, which are reoriented by the field produced by charge trapped on crystal surfaces, during the TSDC discharges. Detrapping of charge trapped on crystal surfaces occurs when lamellae melt, which contributes homopolarly to the current. Both contributions result in the peaks observed in the TSDC discharge.

Gastroesophageal reflux disease—from reflux episodes to mucosal inflammation

Gastroesophageal reflux disease (GERD) affects 20-30% of the population in Western countries, and is one of the most common clinical problems in daily practice. GERD-associated functional and structural abnormalities are caused by recurrent exposure of the esophagus to acidic and nonacidic refluxate of gastric contents (containing duodenal and intestinal proteases as well as acid and gastric pepsin) from the stomach. Major progress has been made in the understanding of the molecular pathogenesis of GERD-associated mucosal inflammation, suggesting a complex and multifactorial pathogenesis and immune-mediated effects. This Review summarizes the complexity of mucosal pathogenesis, including microscopic changes, mucosal inflammation and GERD-specific molecular mediators, in the context of the clinical features and pathophysiological characteristics of GERD. The abnormal exposure of the esophagus to luminal contents leads to chronic mucosal inflammation that is characterized by the release of IL-8 specifically, as well as other proinflammatory mediators, from the esophageal mucosa. Evidence from animal studies indicates a stepwise inflammatory response by the epithelium, which attracts immune effector cells to infiltrate the mucosa. From bench to bedside, these novel molecular findings might provide new treatment options beyond current acid-suppressive therapy and the principle of inhibition of transient lower esophageal sphincter relaxation.

Objective definition and detection of transient lower esophageal sphincter relaxation revisited: is there room for improvement?

AbstractBackground The advent of drugs that inhibit transient lower esophageal sphincter relaxation (TLESR) necessitates accurate identification and scoring. We assessed the intra‐ and inter‐assessor variability of the existing objective criteria for TLESR, improving them where necessary.Methods Two 3‐h postprandial esophageal manometric and pH recordings were performed in 20 healthy volunteers. Each recording was duplicated. The recordings were analyzed by five experienced observers for TLESRs based on their expert opinion. TLESRs were also analyzed for the presence of the original four criteria as well as inhibition of the crural diaphragm (ID), a prominent after‐contraction (AC), acid reflux and an esophageal common cavity.Key Results The overall inter‐ and intra‐observer agreements for TLESRs scored, according to observer’s expert opinion, were 59% (range 56–67%) and 74% (60–89%), respectively. When TLESRs were restricted to those fulfilling the original criteria, these agreements fell to 46% (40–53%) and 60% (44–67%), respectively. Cleaning the recordings by removal of technically flawed sections improved agreements by 5%. Inclusion of additional criteria (ID and AC) resulted in inter‐ and intra‐observer agreements of 62% (52–70%) and 69% (53–79%), respectively. A consensus analysis performed collectively by three observers and based on the new criteria (original ± ID and AC) resulted in 84% agreement between the paired recordings.Conclusions &amp; Inferences The original criteria for the definition of TLESRs allows for substantial inter‐ and intra‐observer variability, which can be reduced by incorporation of additional objective criteria. However, the highest level of intra‐observer agreement can be achieved by consensus analysis.