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Background A majority of patients with gastroesophageal reflux disease (GERD) have normal endoscopy. We aimed to investigate whether esophageal primary and secondary peristalsis influence esophageal reflux parameters in patients with normal endoscopy. Methods We enrolled consecutive patients with typical reflux symptoms and normal endoscopy. All patients underwent High resolution manometry (HRM) and 24-h impedance-pH studies off therapy. During HRM, secondary peristalsis was evaluated using ten 20-mL rapid air infusions into the esophagus, while primary peristalsis was evaluated using ten 5-mL water swallows. Results A total of 43 patients completed the study; 13 patients had normal motility, 20 had ineffective esophageal motility (IEM), and 10 had absent contractility. Acid exposure time (AET) (total, supine, and upright) was significantly higher in those with absent primary peristalsis (absent contractility) compared to normal motility (P = 0.001; 0.01; 0.007) and IEM (P = 0.002; 0.02; 0.03). Supine AET was significantly higher in patients without secondary peristalsis compared to those with secondary peristalsis (P = 0.04). Conclusion In the setting of normal endoscopy, acid reflux burden is more profound in patients with absent primary peristalsis, as well as in patients lacking a secondary peristaltic response to esophageal air distension.

Background and aim Opioid receptors agonists have been demonstrated to impair lower esophageal sphincter (LES) relaxation and induce spastic esophageal dysmotility, but little was known for their impact on distension-induced secondary peristalsis. The aim of the study was to investigate the hypothesis whether acute administration of codeine can influence physiological characteristics of primary and secondary peristalsis in healthy adults. Methods Eighteen healthy volunteers (13 men, mean age 27.5 years, aged 20-43 years) underwent high resolution manometry (HRM) with a catheter containing an injection port in mid-esophagus. Secondary peristalsis was performed with 10 and 20 mL rapid air injections. Two different sessions including acute administration of codeine (60 mg) or the placebo were randomly performed. Results Codeine significantly increased 4-second integrated relaxation pressure (IRP-4s) (P = 0.003) and shortens distal latency (DL) (P = 0.003) of primary peristalsis. The IRP-4s of secondary peristalsis was also significantly higher after codeine than the placebo during air injections with 10 mL (P = 0.048) and 20 mL (P = 0.047). Codeine significantly increased the frequency of secondary peristalsis during air injections with 10 mL than the placebo (P = 0.007), but not for air injection with 20 mL (P = 0.305). Conclusions In addition to impair LES relaxation and reduce distal latency of primary peristalsis, codeine impairs LES relaxation of secondary peristalsis and increases secondary peristaltic frequency. Our study supports the notion in human esophagus that the impact of opioids on peristaltic physiology appears to be present in both primary and secondary peristalsis.

Sleep quality and sleep disorders affect symptom manifestation and the pathogenesis of digestive diseases. Sleep is largely regulated by the light-dark cycle and associated circadian rhythms. These occurrences are closely regulated through several mechanisms with direct effects on the gastrointestinal tract. Misalignment of the circadian system is a common cause of sleep complaints, which play an important role in the presentation of many gastrointestinal disorders. This Review will focus on sleep disorders and how these alterations in sleep play an important role in many commonly encountered digestive diseases, such as gastro-oesophageal reflux disease, irritable bowel syndrome, inflammatory bowel disease, and non-alcoholic fatty liver disease. Therapeutic interventions focusing on resolving sleep disorders could optimise treatment and improve quality of life in these patients.

Background/aim The cold receptor, transient receptor potential melastatin 8 (TRPM8), has been reported to be expressed in esophageal vagal afferents. Esophageal infusion of menthol modulates esophageal perception in reflux patients via TRPM8, but the effects of menthol on esophageal motility are not well investigated. This study aimed to test the hypothesis whether the infusion of menthol into the esophagus could affect esophageal peristaltic characteristics. Methods Eighteen healthy adults (men 13, mean age 27) underwent high-resolution manometry (HRM) using a catheter with the injection port located in mid-esophagus. Primary peristalsis was performed with ten wet swallows, while secondary peristalsis was generated by 10 rapid air injections. Two different sessions were randomly performed including acute administration of menthol (3 mM) and the placebo. Results Menthol significantly decreased upper esophageal (UES) pressure of primary peristalsis than the placebo (p = 0.019). There was no difference in distal contractile integral (p = 0.33), distal latency (p = 0.86), basal lower esophageal sphincter pressure (p = 0.19), or 4-second integrated relaxation pressure (p = 0.75) between menthol and placebo. Menthol significantly decreased the frequency of secondary peristalsis subsequent to the administration of menthol during rapid injections with 20 mL air (p = 0.04). Conclusions Intraluminal infusion of menthol reduces UES basal pressure and inhibits peristaltic frequency of secondary peristalsis. The data suggest that the triggering of secondary peristalsis is probably modulated by TRPM8-sensitive mechanoreceptors; however, the activation of TRPM8 from menthol does not alter esophageal motility following deglutition or distension-induced secondary peristalsis.

Background: Patients with gastroesophageal reflux disease (GERD) frequently report symptoms like dyspepsia or/and irritable bowel syndrome (IBS). The aim of the study was to investigate the impact of symptom overlap on GERD symptom burden. We also investigate whether GERD overlapping dyspepsia or/and IBS would have different clinical and psychological features as compared with GERD alone. Methods: A total of 2752 subjects were screened from a health check-up population. We compared the clinical and psychological factors among subjects with GERD alone and with overlap of two or all three diseases. All participants underwent an evaluation with questionnaires including Reflux Disease Questionnaire score, Pittsburgh Sleep Quality Index, Taiwanese Depression Questionnaire, and State-Trait Anxiety Inventory before receiving endoscopic exam. Results: Among the GERD population, we identified 26 with IBS (GERD-IBS), 60 with dyspepsia (GERD-D), and 25 subjects with overlap of all three conditions (GERD-D-IBS). GERD-D and GERD-D-IBS subjects had more severe GERD symptoms as compared subjects with GERD alone (p

Recent research has documented the substantial and important alterations in gastrointestinal functioning which occurs during sleep. Since the autonomic nervous system (ANS) is integrally involved in the control of gastrointestinal (GI) function, it is essential to understand the role of the ANS to allow a more complete understanding of the pathogenesis and optimal treatment of GI disease. Esophageal sensory and motor functions are largely regulated by the vagus nerve. Assessment of autonomic function has been largely done via spectral analysis of heart rate variability (HRV). These results are quite variable, but there appears to be some evidence for increased sympathetic dominance in the gastroesophageal reflux disease (GERD) group. The authors speculate that these changes could result in a decrease in intrinsic inhibitory control and thereby facilitate an increase in spontaneous relaxations of the lower esophageal sphincter (LES). The majority of studies have been accomplished in irritable bowel syndrome (IBS) patients with HRV analysis during sleep. Increased sympathetic dominance in IBS patients has been noted, and this is particularly noted during REM sleep. It was observed by the authors that these data could support the hypothesis of an enhanced sympathetic activity contributing to increased waking susceptibility to pain. IBS patients frequently have comorbid symptoms of sleep disturbance and psychological issues such as anxiety and depression. IBS patients with depression revealed a significant increase in GI symptom severity, but HRV analysis did not reveal significant differences between the study groups. Results of studies with IBS do seem to suggest some sympathetic dominance during sleep in IBS patients.

Mitochondrial dysfunction often leads to neurodegeneration and is considered one of the main causes of neurological disorders, such as Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and other age-related diseases. Mitochondrial dysfunction is tightly linked to oxidative stress and accumulating evidence suggests the association between oxidative stress and neurological disorders. However, there is insufficient knowledge about the role of pro-oxidative shift in cellular redox and impairment of redox-sensitive signaling in the development of neurodegenerative pathological conditions. To gain a more complete understanding of the relationship between mitochondria, redox status, and neurodegenerative disorders, we investigated the effect of mitochondrial thiol-dependent peroxidases, peroxiredoxins (Prxs), on the physiological characteristics of flies, which change with pathologies such as PD, ALS and during aging. We previously found that through their ability to sense changes in redox and regulate redox-sensitive signaling, Prxs play a critical role in maintaining global thiol homeostasis, preventing age-related apoptosis and chronic activation of the immune response. We also found that the phenotype of flies under-expressing Prxs in mitochondria shares many characteristics with the phenotype of Drosophila models of neurological disorders such as ALS, including impaired locomotor activity and compromised redox balance. Here, we expanded the study and found that under-expression of mitochondrial Prxs leads to behavioral changes associated with neural function, including locomotor ability, sleep-wake behavior, and temperature-sensitive paralysis. We also found that under-expression of mitochondrial Prxs with a motor-neuron-specific driver, D42-GAL4, was a determining factor in the development of the phenotype of shortened lifespan and impaired motor activity in flies. The results of the study suggest a causal link between mitochondrial Prx activity and the development of neurological disorders and pre-mature aging.

Background and aim Prucalopride, a high-affinity 5-hydroxytryptamine 4 receptor agonist, promotes esophageal peristalsis, while phosphodiesterase type 5 inhibitor sildenafil inhibits esophageal peristalsis. The present study was aimed to evaluate whether prucalopride would augment esophageal peristalsis subsequent to the application of sildenafil. Methods Seventeen healthy adults underwent high-resolution manometry by a catheter with one injection port located in the mid-esophagus. Secondary peristalsis was assessed by rapid air injections after water swallows. Two sessions were randomly performed including acute administration of sildenafil 50 mg after pretreatment with prucalopride or the placebo. Results The frequency of primary peristalsis subsequent to the administration of sildenafil was significantly increased by prucalopride (P = 0.02). Prucalopride also significantly increased distal contractile integral of primary peristalsis subsequent to the administration of sildenafil (P = 0.03). No difference in the frequency of secondary peristalsis subsequent to the administration of sildenafil for air injects of 10 mL (P = 0.14) or 20 mL (P = 0.21) was found between prucalopride and placebo. Prucalopride did not change distal contractile integral of secondary peristalsis subsequent to the administration of sildenafil for air injections of 10 mL (P = 0.09) or 20 mL (P = 0.12). Conclusions Prucalopride modulates sildenafil-induced inhibition of primary peristalsis by increasing its effectiveness and peristaltic wave amplitude. Our findings suggest that activation of 5-hydroxytryptamine 4 receptors plays a role in mediating sildenafil-induced inhibition of esophageal primary peristalsis rather than secondary peristalsis.

Study objectives Insomnia is a common medical complaint. Current pharmacologic treatments have modest efficacy and numerous side effects. Baclofen is a gamma-aminobutyric acid (GABA)b receptor agonist used to treat spasticity in various medical conditions. Several studies noted that baclofen, when used to treat sleep related disorders, resulted in improvement in sleep parameters. Measures of insomnia, however, were not assessed in those studies. To date, baclofen has not been assessed for efficacy in the treatment of insomnia. Methods We randomized 20 healthy subjects to baclofen or placebo in a cross over design. All subjects underwent two polysomnograms (PSG) assessing sleep parameters. Baclofen or placebo was given 90 min prior to lights out in random order for each subject. Lights out occurred two hours earlier than the subject's median habitual bedtime. Results Baclofen resulted in significantly less objective wake after sleep onset and stage 1 sleep, and significantly increased total sleep time (TST), sleep efficiency, and stage 3/4 sleep. There was no effect on sleep onset latency (SOL). Self-report variables indicated significantly less subjective awakenings from sleep and increased subjective sleep quality. There was no effect on subjective TST or subjective SOL. Conclusions This study showed that baclofen was superior to placebo with regard to several objective and subjective measures used to assess sleep quality. These data support the notion that baclofen shows promise as an effective hypnotic drug.

The catalytic activity of peroxiredoxins (Prx) is determined by the conserved peroxidatic cysteine (CysP), which reacts with peroxides to form sulfenic acid (Cys-SOH). Under conditions of oxidative stress, CysP is oxidized to catalytically inactive sulfinic (Cys-SO2) and sulfonic (Cys-SO3) forms. The Cys-SO2 form can be reduced in a reaction catalyzed by sulfiredoxin (Srx). To explore the physiological significance of peroxiredoxin overoxidation, we investigated daily variations in the oxidation state of 2-Cys peroxiredoxins in flies of different ages, or under conditions when the pro-oxidative load is high. We found no statistically significant changes in the 2-Cys Prxs monomer:dimer ratio, which indirectly reflects changes in the Prx catalytic activity. However, we found daily variations in Prx-SO2/3 that were more pronounced in older flies as well as in flies lacking Srx. Unexpectedly, the srx mutant flies did not exhibit a diminished survivorship under normal or oxidative stress conditions. Moreover, the srx mutant was characterized by a higher physiological activity. In conclusion, catalytically inactive forms of Prx-SO2/3 serve not only as a marker of cellular oxidative burden, but may also play a role in an adaptive response, leading to a positive effect on the physiology of Drosophila melanogaster.

Background and aim Esophageal infusion of capsaicin-containing red pepper sauce induced heartburn symptoms in patients with gastroesophageal reflux disease (GERD). We aimed to test the hypothesis whether sleep disturbance modulates esophageal sensitivity to capsaicin infusion in patients with GERD. Methods We enrolled 40 patients with their sleep quality measured by the Pittsburg Sleep Quality Index with > 5 indicating sleep disturbance. Esophageal sensation to capsaicin infusion was documented via measures of lag time to initial heartburn perception, heartburn intensity rating, and sensitivity score by esophageal infusion of capsaicin-containing red pepper sauce. Objective sleep measures were assessed by ambulatory actigraphy. Results We found 22 patients with sleep disturbance. The patients with sleep disturbance had shorter lag time to initial heartburn perception (P = 0.03) and greater sensory intensity rating (P = 0.02). The sensitivity score for capsaicin infusion was greater in patients with sleep disturbance when compared with those without sleep disturbance (P = 0.04). Actigraphy measures revealed that patients with sleep disturbance also had poor sleep efficiency (P = 0.04), longer average awakening time (P = 0.03), and greater total activity account (P = 0.04). The lag time for perceiving capsaicin infusion was positively correlated with total sleep time (r = 0.43, P = 0.03). Conclusions We have shown that GERD patients with sleep disturbance have significantly enhanced heartburn perception to capsaicin infusion as compared with those with normal sleep. Our findings suggest that sleep disturbance is associated with esophageal hypersensitivity to capsaicin infusion in patients with GERD.

In prior studies, we determined that the moderate overexpression of the Drosophila endoplasmic reticulum (ER)-localized peroxiredoxin (Prx), dPrx4, reduced oxidative damage and conferred beneficial effects on life span, while a high-level expression increased the incidence of tissue-specific apoptosis and dramatically shortened longevity. The detrimental pro-apoptotic and life-shortening effects were attributed to aberrant localization of dPrx4 and the apparent ER stress elicited by dPrx4 overexpression. In addition, the activation of both the NF-κB- and the JAK/STAT-mediated stress responses was detected, although it was not clear whether these served as functional alarm signals. Here we extend these findings to show that the activation of the NF-κB-dependent immunity-related/inflammatory genes, associated with life span shortening effects, is dependent on the activity of a Drosophila NF-κB ortholog, Relish. In the absence of Relish, the pro-inflammatory effects typically elicited by dPrx4 overexpression were not detected. The absence of Relish not only prevented the hyperactivation of the immunity-related genes but also significantly rescued the severe shortening of life span normally observed in dPrx4 overexpressors. The overactivation of the immune/inflammatory responses was also lessened by JAK/STAT signaling. In addition, we found that cellular immune/pro-inflammatory responses provoked by the oxidant paraquat but not bacteria are mediated via dPrx4 activity in the ER, as the upregulation of the immune-related genes was eliminated in flies underexpressing dPrx4, whereas immune responses triggered by bacteria were unaffected. Finally, efforts to reveal critical tissues where dPrx4 modulates longevity showed that broad targeting of dPrx4 to neuronal tissue had strong beneficial effects, while targeting expression to the fat body had deleterious effects.

BACKGROUND/AIM Esophageal instillation of capsaicin or hydrochloric acid enhances secondary peristalsis. Our aim was to investigate whether intra-esophageal capsaicin infusion can influence symptom perception and physiological alteration of secondary peristalsis subsequent to acid infusion. METHODS Secondary peristalsis was induced by mid-esophagus injections of air in 18 healthy subjects. Two different sessions including esophageal infusion of hydrochloric acid (0.1 N) following pretreatment with saline or capsaicin-containing red pepper sauce were randomly performed at least one week apart. Symptoms of heartburn and secondary peristalsis were determined and compared between each study session. RESULTS The intensity of heartburn symptom subsequent to acid infusion was significantly reduced after capsaicin infusion as compared with saline infusion (54 ± 3 vs 61 ± 3; P = 0.03). Capsaicin infusion significantly increased the threshold volume of secondary peristalsis to rapid air injections subsequent to esophageal acid infusion (8.0 ± 0.5 mL vs 4.4 ± 0.3 mL; P

This is the first study to compare reflux events during wake and sleep in obese and non-obese individuals with obstructive sleep apnea (OSA) and obese individuals without OSA. The primary aim of the study was to investigate any additive effect of OSA on gastroesophageal reflux (GER) above that of obesity.Twenty obese individuals (body mass index, BMI30 kg/m(2)), 9 non-obese individuals (BMI30 kg/m(2)) with moderate-to-severe OSA, and 17 obese control subjects (BMI30 kg/m(2)) underwent high-resolution esophageal manometry, 24-h esophageal pH-impedance monitoring, and in-laboratory polysomnography.Mean body mass index was 40 ± 6 and 27 ± 4 kg/m(2) for the obese and non-obese OSA groups, respectively, and 34 ± 5 kg/m(2) for the obese control group. Apnea-hypopnea index (AHI) was 50 ± 30 and 30 ± 25 per hour for the obese and non-obese OSA groups (p0.05), significantly higher than that of the obese control group (3 ± 3 per hour, p0.05). The two obese groups did not show any significant differences in the total number of acidic reflux events (41 ± 20 vs 28 ± 16); however, the obese OSA group had a greater number of acidic reflux events compared to the non-obese OSA group (22 ± 12 events, p0.05). In multivariate analysis, BMI significantly predicted number of acidic reflux events (r(2) = 0.16, p = 0.01) during the 24-h period; however, AHI showed no significant association with any measure of GER severity.This study confirms an important role for obesity, rather than OSA per se in the relationship between OSA and GER.

Significance: Peroxiredoxins (Prxs), a family of thiol-associated peroxidases, are purported to play a major role in sensing and managing hydrogen peroxide concentrations and transducing peroxide-derived signals. Recent Advances: Prxs can act as detoxifying factors and impart effects to cells that can be either sparing or suicidal. Advances have been made to address the qualitative changes in Prx function in response to quantitative changes in the signal level and to understand how Prx activity could be affected by their own substrates. Here we rationalize the basis for both positive and negative effects on signaling pathways and cell physiology, summarizing data from model organisms, including invertebrates. Critical Issues: Resolving the relationship between the promiscuous behavior of reactive oxygen species and the specificity of Prxs toward different targets in redox-sensitive signaling pathways is a key area of research. Attempts to understand Prx function and underlying mechanisms were conducted in vitro or in vivo under nonphysiological conditions, leaving the physiological relevance yet to be defined. Other issues: Why despite the high degree of homology and similarities in subcellular and tissue distribution between Prxs do they display differential effects on signaling? How is the specificity of post-translational protein modifications determined? Other than chaperone-like activity, how do hyperoxidized Prxs function? Future Directions: Genetic models with mutated catalytic and resolving cysteines should be further exploited to dissect the functional significance of individual Prxs in their different states together with their alternative reducing partners. Such an analysis may then be extended to help identify Prx-specific targets.

The innate immune response tends to become hyperactive and pro-inflammatory in older organisms. We investigated connections between activity of the immune-related genes and aging using the Drosophila model. A hallmark of Drosophila immunity is the production of antimicrobial peptides (AMP), whose expression is triggered via activation of the Toll and Imd immune pathways and regulated by NF-κB-like transcription factors, Dif/Dorsal and Relish. It was previously shown that overexpression of the upstream component of the immune pathways shortens life span via activation of the Relish-dependent immune response. Here we show that direct overexpression of the Relish target AMP genes broadly at high levels or in the fat body induced apoptosis, elicited depolarization of the mitochondria and significantly shortened life span. Under-expression of Relish in the fat body beginning in the second half of life span prevented over-activation of AMPs and extended longevity. Unlike infection-induced responses, the age-related increase in AMPs does not require the upstream recognition/transduction module of the Imd pathway. It does however require downstream elements, including Relish and Ird5, a component of the downstream IKK complex. Together, these results established causal links between high-level production of antimicrobial peptides and longevity.

Concurrent clinical presentation of insomnia and anxiety is frequent in clinical practice. The onset and course of anxiety and insomnia are intimately related; traditional conceptualizations of insomnia as secondary to anxiety are no longer clinically viable. Evolving evidence suggests a relationship between these 2 conditions that is complex and reciprocal and that evolves over time. In terms of diagnosis and management, unless initial assessment and intervention are initiated in the earliest stages of illness, emerging opinion supports recognition of cooccurring anxiety and insomnia as independent comorbid conditions with each condition likely requiring targeted therapeutic attention to achieve optimal therapeutic outcomes.

Sleep is associated with substantial changes in gastrointestinal functioning that have considerable clinical relevance Symptoms of sleep-related dysfunction are common and are primarily related to sleep-related heartburn and regurgitation. Sleep disturbances accompany several other gastrointestinal disorders, such as irritable bowel syndrome (IBS). Sleep-related gastroesophageal reflux (GER) has been shown to plan a major role in the pathogenesis of more complicated gastroesophageal reflux disease (GERD), notably via a prolongation of acid contact. Mucosal damage has been shown to be more closely associated with this pattern of reflux in comparison with waking reflux, which is associated with more frequent but very short reflux events. Sleep disturbance is also associated with a visceral hyperalgesia that enhances pain responses associated with acid–mucosal contact. Sleep does influence intestinal motility, but further research is needed to confirm the details of exactly how intestinal motility is modulated by sleep.

With an estimated 70 million Americans suffering, sleep disorders have become a global issue, and discovering their causes and consequences are the focus of many clinical research studies. Sleep is now also considered to be an important environmental and behavioral factor associated with the process of inflammation and the immune system. Increased sleepiness is considered part of the acute phase of response to tissue injury, and sleep loss activates inflammatory cytokines such as interleukin (IL)-1 and tumor necrosis factor (TNF)-α. Clinical studies in many immune-mediated diseases, such as systemic lupus erythematosus, rheumatoid arthritis, and ankylosing spondylitis, have revealed an association of sleep disturbances with disease activity. Recent research suggests that individuals with sleep abnormalities are also at greater risk of serious adverse health, economic consequences, and most importantly increased all-cause mortality. The importance of sleep in inflammatory bowel disease has recently gained attention with some published studies demonstrating the association of sleep disturbances with disease activity, subclinical inflammation, and risk of disease relapse. A comprehensive review of sleep physiology and its association with the immune system is provided here. Experimental and clinical studies exploring this relationship in inflammatory bowel disease are reviewed, and the clinical implications of this relationship and future directions for research are also discussed.

Identify factors that predict improvement versus persistence of insomnia symptoms following treatment of obstructive sleep apnea (OSA) with positive airway pressure (PAP) therapy.Archival data from 68 PAP-treated sleep apnea patients aged 25-83 were analyzed using nonparametric tests and stepwise regression to assess the relationships between insomnia symptoms, multiple OSA variables, and PAP use over time.Pretreatment insomnia symptom severity (ISS; b = -0.72, p0.001), PAP average use (b = -0.01, p = 0.01) and respiratory disturbance index (RDI; b = -0.02, p = 0.03) predict change in insomnia following PAP therapy. Forty-five percent (24/53) of the subjects with moderate to severe insomnia at pretreatment reported no/mild symptoms after PAP therapy and were considered improved. Improved subjects had lower pretreatment ISS (p0.001), higher RDI (p = 0.01), and higher average PAP use (p0.035) than subjects with persistent insomnia. Number of medications and comorbidities were similar between improved and persistent groups. New onset of insomnia symptoms occurred in 13% (2/15) of the patients with no/mild pretreatment insomnia.Although ISS declines following PAP treatment, 55% of OSA patients have persistent moderate to severe symptoms despite treatment. More severe OSA is linked to higher likelihood of insomnia improvement and the effect of PAP therapy on insomnia may be mediated by OSA severity. Persistent insomnia is unrelated to medication use or comorbidities and may represent an independent, self-sustaining disorder requiring targeted intervention.

Background/Aims To evaluate the effectiveness of pantoprazole magnesium (pantoprazole-Mg) 40 mg in the relief of esophageal and extra- esophageal symptoms of gastroesophageal reflux disease (GERD), particularly night-time symptoms. Methods Patients (aged 18-50 years) with 3-month history of heartburn and/or acid regurgitation plus at least one other symptom in the last week were enrolled in a nationwide, prospective and observational study in Mexico. Patients received pantoprazole-Mg 40 mg once daily during 4 weeks. Symptoms were assessed through a physician-administered structured interview and the patient- completed ReQuest in PracticeTM questionnaire. Night-time GERD was defined as arousal from sleep during the night due to GERD-associated symptoms. Results Out of 4,343 patients included at basal visit, 3,665 were considered for the effectiveness per protocol analysis. At baseline, patients had a median of 8 GERD related symptoms. Patients with night-time GERD symptoms (42.7%) were more likely to have extra-esophageal symptoms (P ＜ 0.001) than other GERD patients. Pantoprazole-Mg 40 mg once daily for 4 weeks improved a broad range of GERD-associated symptoms from baseline (80% reduction on physicians assessments; 68-77% reduction on ReQuest in PracticeTM dimensions), including both day- and night-time GERD symptoms; improvements were the greatest for extra-esophageal symptoms in patients with night-time symptoms. Pantoprazole-Mg was well tolerated. Conclusions Pantoprazole-Mg 40 mg significantly improved a broad range of esophageal and extra-esophageal GERD related symptoms including sleep disturbances, as well as well-being, in patients with daytime or night-time GERD, making it a good option for patients with GERD, especially when extra-esophageal and night-time symptoms are present. (J Neurogastroenterol Motil 2014;20:64-73)

OBJECTIVE. Ineffective esophageal motility is frequently found in patients with gastroesophageal reflux diseases. Secondary peristalsis contributes to esophageal acid clearance. Mosapride improves gastrointestinal (GI) motility by acting on 5-hydroxytrypatamine4 receptors. The authors aimed to evaluate the effect of mosapride on secondary peristalsis in patients with ineffective esophageal motility. MATERIAL AND METHODS. After recording primary peristalsis baseline, secondary peristalsis was stimulated by slowly and rapidly injecting mid-esophageal air in 18 patients. Two separate experiments were randomly performed with 40 mg oral mosapride or placebo. RESULTS. Mosapride had no effect on the threshold volume of secondary peristalsis during slow air distension (9.8 ± 0.97 vs. 10.2 ± 1.0 mL; p = 0.84), but decreased the threshold volume during rapid air distension (4.1 ± 0.2 vs. 4.6 ± 0.3 mL; p = 0.001). The efficiency of secondary peristalsis during rapid air distension increased with mosapride (70% [40-95%]) compared with placebo (60% [10-85%]; p = 0.0003). Mosapride had no effect on the amplitudes of distal pressure wave of secondary peristalsis during slow (94.3 ± 9 vs. 101.9 ± 9.1 mmHg; p = 0.63) or rapid air distension (89.3 ± 9 vs. 95.2 ± 8.3 mmHg; p = 0.24). CONCLUSIONS. Mosapride improves esophageal sensitivity of secondary peristalsis by abrupt air distension but has limited effect on the motor properties of secondary peristalsis in ineffective esophageal motility patients. Despite its well-known prokinetic effect, mosapride enhances the efficiency of secondary peristalsis in patients with ineffective esophageal motility through augmenting esophageal sensitivity instead of motility.

PURPOSE Poor sleep quality is associated with adverse health consequences. Sleep disturbances can impact the immune function and process of inflammation. The relationship between sleep quality and the inflammatory bowel disease (IBD) has not been well studied. METHODS A prospective observational cohort study was performed to assess the correlation of the quality of sleep and disease activity in IBD. We used the Pittsburgh Sleep Quality Index (PSQI) to measure sleep quality. IBD disease activity was measured by using the Harvey-Bradshaw Index or Modified Mayo Score. RESULTS Forty-one patients were enrolled with mean age of 37 ± 15.4 years and 27 (66%) women. Abnormal PSQI was present in all 23 (100%) of the clinically active patients and in 13 (72%) of those with inactive disease (odds ratio = 2.8, P = 0.007). All 30 patients with histologic evidence of inflammation on recent ileocolonoscopy also had abnormal PSQI scores, which were independent of their clinical disease activity status. Only 6 of 11 patients with histologically quiescent disease had abnormal PSQI scores (odds ratio = 6.0, P < 0.0001). There was no difference in disease type, use of steroids, the presence of depression or anxiety, and body mass index between the patients with normal and abnormal sleep. An abnormal PSQI had a positive predictive value for histologic inflammatory activity of 83%. CONCLUSIONS Our data show a strong association between clinically active IBD and poor sleep quality and demonstrate that patients in clinical remission with abnormal sleep have a high likelihood of subclinical disease activity.

Background Low basal lower esophageal sphincter (LES) pressure and transient LES relaxations are major causes of gastroesophageal reflux disease (GERD). Pumosetrag, a novel selective partial 5HT3 receptor agonist, showed a promising effect on reducing reflux events in health. We aimed to evaluate the effect of pumosetrag on changes in reflux episodes, lower esophageal sphincter pressure (LESP), and specific symptoms in patients with GERD receiving a refluxogenic meal. Methods Patients with GERD, who developed heartburn and/or regurgitation after ingestion of a refluxogenic meal, were randomized to 1 of 3 dose levels of pumosetrag (0.2, 0.5, or 0.8 mg) or placebo. Before and after 7 days of treatment, patients underwent manometry, intraesophageal multichannel, intraluminal impedance and pH after a standard refluxogenic meal. Key Results A total of 223 patients with GERD [125 (56%) women, mean (SD) age = 36 (12) years] were enrolled. No overall treatment effects were detected for the total number of reflux episodes (acidic and weakly acidic) (p > 0.5); however, significant treatment effects (p

This study investigated whether the complaint of night-time heartburn (NHB) as opposed to daytime heartburn (DHB) is a reliable reflection of actual sleep-related reflux events. Three groups of individuals were studied: individuals with complaints of NHB at least twice per week (n = 24), individuals with complaints of DHB (n = 23), and normal participants without any complaints of regular heartburn during the day or night (n = 25). All three groups were studied on one occasion with combined pH monitoring and polysomnography, and subjective questionnaires about sleep disturbance and sleep quality were given to all participants. The NHB group had significantly more sleep-related reflux events compared with both DHB and control groups (P < 0.01). DHB subjects had significantly (P < 0.05) more sleep-related reflux events than normal controls. Total acid contact time (ACT) was significantly (P < 0.05) elevated in the NHB group compared with both the DHB and control group. Sleep-related ACT was also significantly (P < 0.05) elevated in the NHB group compared with the other two groups, while upright (daytime) ACT was not significantly different. The NHB group was significantly (P < 0.05) worse regarding measures of both objective and subjective sleep quality. Subjects with exclusively DHB do have sleep-related reflux that is greater than normal controls. Subjects with NHB have significantly more sleep-related reflux, and both objective and subjective sleep abnormalities compared with normal controls. Complaints of NHB reflect sleep-related reflux events and may be indicative of a more clinically significant condition.

Sleep disturbance is common in patients with gastroesophageal reflux disease (GERD). Secondary peristalsis is important for clearance of the refluxate from the esophagus. We aimed to test the hypothesis whether secondary peristalsis is impaired in GERD patients with sleep disturbance.Secondary peristalsis was stimulated with slow and rapid air injections into mid-esophagus in 8 age-matched health controls and 41 patients with GERD. Sleep disturbance was assessed by the Pittsburg Sleep Quality Index (PSQI). Objective sleep measures were assessed by ambulatory actigraphy.The threshold volume for inducing secondary peristalsis during slow air injection was significantly higher in GERD patients with sleep disturbance than healthy controls (14.3 ± 1.2 vs. 8.9 ± 0.5 mL, p .05). GERD patients with sleep disturbance had higher threshold volume of secondary peristalsis during rapid air injection than GERD patients without sleep disturbance (5.1 ± 0.4 vs. 3.9 ± 0.2 mL, p .05) and healthy controls (5.1 ± 0.4 vs. 3.6 ± 0.2 mL, p .05). There was a negative correlation between PSQI score and peristaltic frequency during rapid air injection (r = -.39, p = .01). Secondary peristaltic amplitude during rapid air injection was negatively correlated with wake after sleep onset (r = -.34, p = .04).Sleep disturbance is associated with secondary peristaltic response to distension-induced esophageal stimulation in patients with GERD. Our study suggests that sleep disturbance per se may adversely influence the effectiveness of esophageal peristalsis and bolus clearance during sleep in patients with GERD.

Esophageal infusion of capsaicin-containing red pepper sauce induced heartburn symptoms in patients with gastroesophageal reflux disease (GERD). We aimed to test the hypothesis whether sleep disturbance modulates esophageal sensitivity to capsaicin infusion in patients with GERD.We enrolled 40 patients with their sleep quality measured by the Pittsburg Sleep Quality Index with 5 indicating sleep disturbance. Esophageal sensation to capsaicin infusion was documented via measures of lag time to initial heartburn perception, heartburn intensity rating, and sensitivity score by esophageal infusion of capsaicin-containing red pepper sauce. Objective sleep measures were assessed by ambulatory actigraphy.We found 22 patients with sleep disturbance. The patients with sleep disturbance had shorter lag time to initial heartburn perception (P = 0.03) and greater sensory intensity rating (P = 0.02). The sensitivity score for capsaicin infusion was greater in patients with sleep disturbance when compared with those without sleep disturbance (P = 0.04). Actigraphy measures revealed that patients with sleep disturbance also had poor sleep efficiency (P = 0.04), longer average awakening time (P = 0.03), and greater total activity account (P = 0.04). The lag time for perceiving capsaicin infusion was positively correlated with total sleep time (r = 0.43, P = 0.03).We have shown that GERD patients with sleep disturbance have significantly enhanced heartburn perception to capsaicin infusion as compared with those with normal sleep. Our findings suggest that sleep disturbance is associated with esophageal hypersensitivity to capsaicin infusion in patients with GERD.

Peroxiredoxin 4 (Prx4) has been implicated in a wide variety of biological processes, including development, progression of cancer, inflammation, and antioxidant function. The purpose of this study was to provide further insight into its multiple roles at the whole-animal level, using Drosophila. Reduced expression of dPrx4 (up to 90%) resulted in greater sensitivity to oxidative stress, an elevated H2O2 flux, and increases in lipid peroxidation, but no effect on longevity. Overexpression at low levels (5-fold) had a dramatically reduced life span (by 20–80%) and increased apoptosis. Analysis of these overexpressors revealed an aberrant redistribution of the dPrx4 protein from the endoplasmic reticulum (ER) to cytosol and hemolymph. In addition to the known proapoptotic effects of the cytosolic form of dPrx4, dPrx4 overexpression triggered an NF-κB-mediated proinflammatory response, similar to that observed in cells under ER stress or when microbially challenged. Finally, we provide the first evidence that dPrx4, on secretion into the hemolymph, elicits a JAK/STAT-mediated response. The effects on fly survival and homeostasis appear to represent a combination of differential effects dictated in large part by dPrx4 subcellular and tissue-specific localization.—Radyuk, S. N., Klichko, V. I., Michalak, K., Orr, W. C. The effect of peroxiredoxin 4 on fly physiology is a complex interplay of antioxidant and signaling functions.

This review addresses current advances in gastroesophageal reflux disease (GERD) and its influence on sleep and health-related quality of life (QOL). Sleep difficulties are highly prevalent among adults with GERD, especially those who experience nighttime symptoms. These sleep difficulties result in substantial costs to the health care system by increasing provider visits. Because continued sleep disruption leads to increased daytime sleepiness and fatigue, nocturnal heartburn can reduce work productivity, as well as reduce function when performing normal daily activities. The continued presence of nocturnal symptoms in routine medical treatment is strongly associated with decreases in health-related quality of life. There is a greater loss of productivity to the employer and poorer health-related QOL (HRQOL) for the patient. Obstructive sleep apnea syndrome and obesity seem to predispose some patients to nocturnal GERD, and the presence of either of these conditions may help to identify patients with symptoms consistent with GERD. Appropriate management of GERD must include treatment of nighttime reflux symptoms that affect difficulty in both initiating and maintaining sleep.

Obstructive sleep apnea (OSA) is a disorder with high prevalence in primary care. However, little research exists on screening for OSA in primary care samples.One hundred family medicine patients completed standardized symptom and demographic questionnaires and a structured clinical interview for sleep disorders. Two-step logistic regression was performed to determine the independent predictive value of insomnia for clinical identification of OSA. Additional t tests were computed to examine age and sex patterns of insomnia.A model including body mass index and daytime sleepiness predicted OSA status (χ(2) = 18.63; P.001) and explained 27% of the variance in OSA clinical diagnosis. Addition of insomnia scores to the model significantly improved predictive utility (χ(2) = 25.79; P.001) and explained 36% of the variance in OSA. Insomnia scores were higher for women compared with men (P = .033) and women with OSA compared with women without OSA (P = .007).Inquiry regarding insomnia may improve clinical identification of OSA when screening for OSA in primary care. This finding possibly is unique to the evaluation of OSA in a primary care versus sleep laboratory sample. The predictive utility of insomnia may be specific to women.

Background/Aims Sleep dysfunction is associated with altered gastrointestinal function and subsequently exacerbations of gastrointestinal problems. We aimed to investigate whether sleep dysfunction would influence anorectal motility as determined by anorectal manometry. The effect of anxiety on anorectal motility was also determined. Methods A total of 24 healthy volunteers underwent anorectal manometry. The anorectal parameters included resting and squeeze sphincter pressure, sensory thresholds in response to balloon distension, sphincter length, rectal compliance, and rectoanal inhibitory reflex. Sleep dysfunction was subjectively assessed by using Pittsburgh Sleep Quality Index (PSQI). Anxiety was assessed by the application of the State-Trait Anxiety Inventory questionnaire. Results There were sixteen subjects without sleep dysfunction (7 women; mean age, 22 years) and eight subjects with sleep dysfunction (2 women; mean age, 22 years). There was no group difference in the volume threshold for rectoanal inhibitory reflux, rectal compliance or sphincter length (P = NS). Anal sphincter pressure did not differ between the groups (P = NS). The rectal sensitivity for different levels of stimulation did not differ between the groups (P = NS). Sleep quality as determined by PSQI correlated with rectal compliance (r = 0.66, P = 0.007). Although there was no differences in any manometric parameters between subjects with and without anxiety, the anxiety score correlated with rectal compliance (r = 0.57, P = 0.003). Conclusions Despite a positive association between rectal compliance and the level of subjective sleep or anxiety, sleep dysfunction did not apparently affect most of anorectal function in healthy subjects, nor did anxiety.

Background/Aims: Sleep dysfunction is associated with altered gastrointestinal functioning and the presence of irritable bowel syndrome (IBS). We aimed to investigate whether sleep dysfunction would influence anorectal motility in IBS patients. Methods: A total of 16 healthy volunteers and 15 IBS patients underwent anorectal manometry. The anorectal parameters included resting and squeeze sphincter pressure, sensory thresholds in response to balloon distension, and rectoanal inhibitory reflex. Sleep dysfunction was assessed by using the Pittsburgh Sleep Quality Index (PSQI). Results: IBS patients had a lower threshold volume for urge (p = 0.04) and pain (p = 0.002) as compared with the controls. IBS patients with sleep dysfunction had a significantly lower threshold volume for urge (p = 0.04) and anal sphincter pressure for maximal squeeze (p = 0.048) as compared with those without sleep dysfunction. In IBS patients, the PSQI score significantly correlated with threshold volume for first sensation (r = –0.55; p = 0.03), urge (r = –0.56; p = 0.03) and pain (r = –0.58; p = 0.03). Conclusions: IBS patients with sleep dysfunction are characterized by lower thresholds for rectal perception. Sleep disturbance might be associated with anorectal dysfunction and appears to create some degree of rectal hyperalgesia in patients with IBS.

Drosophila mitochondria contain two peroxidases, peroxiredoxin 3 (dPrx3) and peroxiredoxin 5 (dPrx5), which together constitute the sole known intramitochondrial mechanism for the catalytic removal of hydrogen and organic peroxides. dPrx3 exists exclusively within mitochondria, whereas dPrx5 is also present in some other intracellular compartments. Levels of these two peroxiredoxins were genetically manipulated, singly and together, in D. melanogaster, for the purpose of understanding their respective functions. Underexpression of dPrx3 by 90-95% had no discernable effect on life span under normal or oxidative stress conditions; the dPrx5 null flies were previously reported to exhibit a 10% shortening of mean life span and an increase in sensitivity to oxidative stress. Flies underexpressing both dPrx3 and dPrx5 showed an 80% decrease in life span, a severe disruption in thiol homeostasis, and a massive induction of apoptosis in the muscle and digestive system tissues. The early mortality in flies underexpressing both peroxiredoxins was partially offset by overexpression of thioredoxin reductase but not mitochondrion-targeted catalase. These results suggest that mitochondrial peroxiredoxins confer specific protection for thioredoxin/glutathione systems, play a critical role in the maintenance of global thiol homeostasis, and prevent the age-associated apoptosis and premature death.

The hypothesis, that structural deterioration of cytochrome c oxidase (CcO) is a causal factor in the age-related decline in mitochondrial respiratory activity and an increase in H₂O₂ generation, was tested in Drosophila melanogaster. CcO activity and the levels of seven different nuclear DNA-encoded CcO subunits were determined at three different stages of adult life, namely, young-, middle-, and old-age. CcO activity declined progressively with age by 33%. Western blot analysis, using antibodies specific to Drosophila CcO subunits IV, Va, Vb, VIb, VIc, VIIc, and VIII, indicated that the abundance these polypeptides decreased, ranging from 11% to 40%, during aging. These and previous results suggest that CcO is a specific intra-mitochondrial site of age-related deterioration, which may have a broad impact on mitochondrial physiology.

This study aimed to compare the effect of intraluminal acidification on esophageal sensory perception and motor activity between older and younger patients with gastroesophageal reflux disease (GERD).All 40 subjects had saline and hydrochloric acid infused into the mid-esophagus. The esophageal perception to acid infusion was documented including lag time, intensity rating, and sensitivity score. Esophageal body motility was recorded.The younger group had a shorter lag time to initial heartburn perception (p = 0.01) and a greater sensory intensity rating (p = 0.001). The acid infusion sensitivity score was lower in the older patients (p = 0.001). Age positively correlated to lag time to initial symptom perception (r = 0.44, p = 0.005), but negatively correlated to sensory intensity (r = -0.40, p = 0.01) and acid infusion sensitivity score (r = -0.39, p = 0.01). When compared with saline infusion, acid infusion induced a significant increase in the deglutition frequency in younger patients (0.51 vs. 0.67, p = 0.005), but not in older patients (0.59 vs. 0.65, p = 0.67).Age-related decrease in sensorimotor response to esophageal acidification may be an important element in the pathogenesis and clinical presentation of GERD in older adults.

FAS and FAS ligand is critical in the control of the extension of extrinsic pathway of apoptosis. In previous studies we have performed transcriptomics peripheral blood cells from centenarians, octogenarians and young persons and we found over expression in centenarians of the FAS receptor. To confirm the role of FAS ligand in longevity across animal species, we have generated Drosophila melanogaster that over expresses this gene using the GAL4-UAS technique. The results show that flies overexpressing FAS increase maximal longevity in twelve percent and average longevity in six percent. Therefore, we confirm that FAS is related to longevity flight.

Gastroesophageal reflux disease (GERD) and obstructive sleep apnea syndrome (OSAS) are often comorbid disorders.1–3 OSAS is a condition marked by pharyngeal narrowing, resulting in upper airway obstruction during sleep, which, in turn, produces repeated episodes of decreased oxygen saturation and brief arousals from sleep. It is well recognized clinically that patients with OSAS often complain of heartburn, and they clearly share a major overlapping risk factor, which is obesity. In one investigation, of the patients referred for overnight sleep studies, 74% reported GERD-related symptoms, including heartburn, acid regurgitation, or both.2 Other studies have also shown a significant increase in reflux symptoms in patients with demonstrated OSAS.1,4 The incidence of significant reflux symptoms in these studies ranges from 62% to 74%. In another study, patients whose OSAS was successfully treated with continuous positive airway pressure (CPAP) had a marked improvement in nighttime reflux, compared with those patients who were noncompliant or did not use CPAP.1 In a study that utilized polysomnography concurrent with distal esophageal pH monitoring, Ing and colleagues5 found that patients with OSAS exhibited more frequent nocturnal reflux than did similar patients with very mild OSAS. In this same study,5 esophageal acid clearance was also prolonged in patients with OSAS with a significantly greater proportion of time at an esophageal pH < 4.0. Similar results were found in a study by Berg et al.,6 who concluded that reflux events and obstructive apnea are not causally linked but may be the consequence of a coexisting pathology. It is also of interest that CPAP treatment itself will significantly lower the percentage of nighttime acid contact.7 Another study has shown that powerful acid inhibition with a proton pump inhibitor (pantoprazole) will markedly improve symptoms of sleepiness and reflux symptoms in patients with documented OSAS.8 Senior et al.3 have shown that a similar treatment in patients with documented OSAS and GERD via 24- hour pH monitoring will significantly reduce the apnea-hypopnea index (AHI). However, it should be noted that this study consisted of only 10 patients, and only 3 actually responded to treatment. The authors did conclude that further investigation is necessary to establish whether reducing gastroesophageal reflux (GER) may alter the upper airway, resulting in a reduction of upper airway obstruction. Thus, it appears that GERD is a common comorbid condition with OSAS and that symptoms are substantially improved by treating obstructive events. It remains to be determined definitely whether suppressing GER improves upper airway anatomy, physiology, or both anatomy and physiology in a way that could result in a reduction in upper airway obstructive events. In the present study, we have undertaken an evaluation of patients with OSAS selected via both polysomnography and 24-hour pH recording to have both mild OSAS and documented GERD. We hypothesized that the treatment of GERD in patients with mild OSAS and objective evidence of significant reflux would reduce the number of obstructive events and that this would be accompanied by improvements in upper airway anatomy and sleep quality. Patients were subjected to powerful acid suppression (ie, rabeprazole 20 mg, twice a day) for 2 months. Patients were assessed with laryngoscopy, as well as full polysomnography and 24-hour esophageal pH monitoring, before and after treatment with powerful acid suppression.

Peroxiredoxin 5 is a distinct isoform of the peroxiredoxin gene family. The antioxidative and anti-apoptotic functions of peroxiredoxin 5 have been extensively demonstrated in cell culture experiments. In the present paper, we provide the first functional analysis of peroxiredoxin 5 in a multicellular organism, Drosophila melanogaster. Similar to its mammalian, yeast or human counterparts, dPrx5 (Drosophila peroxiredoxin 5) is expressed in several cellular compartments, including the cytosol, nucleus and the mitochondrion. Global overexpression of dPrx5 in flies increased resistance to oxidative stress and extended their life span by up to 30% under normal conditions. The dprx5−/− null flies were comparatively more susceptible to oxidative stress, had higher incidence of apoptosis, and a shortened life span. TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling) analysis revealed that the dprx5−/− null mutant had discernible tissue-specific apoptotic patterns, similar to those observed in control flies exposed to paraquat. In addition, apoptosis was particularly notable in oenocytes. During development the dPrx5 levels co-varied with ecdysone pulses, suggesting inter-relationship between ecdystreroids and dPrx5 expression. The importance of dPrx5 for development was further underscored by the embryonic lethal phenotype of progeny derived from the dprx5−/− null mutant. Results from the present study suggest that the antioxidant and anti-apoptotic activities of dPrx5 play a critical role in development and aging of the fly.