Esophageal acid burden in reflux patients with normal endoscopy: Does esophageal peristalsis matter?

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.

Effects of codeine on esophageal peristalsis in humans using high resolution manometry.

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-s integrated relaxation pressure (IRP-4s) (P = 0.003) and shortened 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.

Effect of prucalopride on sildenafil-induced inhibition of esophageal peristalsis in healthy adults.

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.

Impact of concomitant dyspepsia and irritable bowel syndrome on symptom burden in patients with gastroesophageal reflux disease.

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 < 0.001). Subjects with overlapping dyspepsia or/and IBS showed a significant increase in the severity of depression and poorer sleep quality than subjects with GERD alone. Notably, anxiety scores did not differ significantly between subjects with overlapping diseases and GERD alone. CONCLUSION: Our study demonstrates that disease overlap in GERD population is associated with greater symptom burden, higher depression and poorer sleep quality, but not with anxiety. This study highlights the importance of identifying overlapping conditions as a therapeutic strategy for better management of GERD.

Overexpression of antimicrobial peptides contributes to aging through cytotoxic effects in Drosophila tissues.

The innate immune response tends to become hyperactive and proinflammatory 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-ĸB-like transcription factors, Dif/Dorsal and Relish. It was previously shown that overexpression of the upstream component of the immune pathways shortens lifespan 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 lifespan. Underexpression of Relish in the fat body beginning in the second half of lifespan prevented overactivation 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.

The role of peroxiredoxin 4 in inflammatory response and aging.

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.

Mitochondrial peroxiredoxins are essential in regulating the relationship between Drosophila immunity and aging.

Previously, we have shown that flies under-expressing the two mitochondrial peroxiredoxins (Prxs), dPrx3 and dPrx5, display increases in tissue-specific apoptosis and dramatically shortened life span, associated with a redox crisis, manifested as changes in GSH:GSSG and accumulation of protein mixed disulfides. To identify specific pathways responsible for the observed biological effects, we performed a transcriptome analysis. Functional clustering revealed a prominent group enriched for immunity-related genes, including a considerable number of NF-kB-dependent antimicrobial peptides (AMP) that are up-regulated in the Prx double mutant. Using qRT-PCR analysis we determined that the age-dependent changes in AMP levels in mutant flies were similar to those observed in controls when scaled to percentage of life span. To further clarify the role of Prx-dependent mitochondrial signaling, we expressed different forms of dPrx5, which unlike the uniquely mitochondrial dPrx3 is found in multiple subcellular compartments, including mitochondrion, nucleus and cytosol. Ectopic expression of dPrx5 in mitochondria but not nucleus or cytosol partially extended longevity under normal or oxidative stress conditions while complete restoration of life span occurred when all three forms of dPrx5 were expressed from the wild type dPrx5 transgene. When dPrx5 was expressed in mitochondria or in all three compartments, it substantially delayed the development of hyperactive immunity while expression of cytosolic or nuclear forms had no effect on the immune phenotype. The data suggest a critical role of mitochondria in development of chronic activation of the immune response triggered by impaired redox control.

Relevance of sleep disturbance to the integrity and characteristics of secondary peristalsis in patients with gastroesophageal reflux disease.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Sleep disturbance and enhanced esophageal capsaicin sensitivity in patients with gastroesophageal reflux disease.

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.

Effects of esophageal capsaicin instillation on acid induced excitation of secondary peristalsis in humans.

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 < 0.0001). The frequency of secondary peristalsis subsequent to acid infusion was significantly decreased after capsaicin infusion as compared to saline infusion (70% [60-82.5%] vs 80% [70-90%]; P = 0.03). Capsaicin infusion significantly decreased the pressure wave amplitude of secondary peristalsis subsequent to acid infusion during rapid air injections (90.6 ± 8.7 mmHg vs 111.1 ± 11.1 mmHg; P = 0.03). CONCLUSIONS: Capsaicin appears to desensitize the esophagus to acid induced excitation of secondary peristalsis in humans, which is probably mediated by rapidly adapting mucosal mechanoreceptors. High capsaicin-containing diet might attenuate normal physiological response to abrupt acid reflux by inhibiting secondary peristalsis.

Decrease in cytochrome c oxidase reserve capacity diminishes robustness of Drosophila melanogaster and shortens lifespan.

The phenotypic effects of under- and over-expression of CcO (cytochrome c oxidase) regulatory subunits IV and Vb were examined in Drosophila melanogaster in order to test further the hypothesis that suppression of the activities of mitochondrial ETC (electron-transport chain) oxidoreductases retards the aging process and extends lifespan. Underexpression of both CcO subunits, induced by RNAi, resulted in decreases in the respective mRNA and protein levels, CcO holoenzyme activity, rate of mitochondrial respiration, walking speed and the lifespan of fruitflies. Overexpression of CcO IV or Vb in young fruitflies increased the amount of mRNA, but had no effect on the protein level or CcO catalytic activity. On the other hand, in older fruitflies, overexpression of CcO Vb, but not CcO IV, elevated the mRNA and protein amounts as well as the CcO holoenzyme activity, thereby preventing the typical age-related decline in CcO activity. Nevertheless, lifespans of the fruitflies overexpressing CcO IV or Vb were neither extended nor shortened. Our results demonstrate that: (i) the suppression of CcO function exerts deleterious rather than benign effects on fitness and survival, and (ii) the structure/function of CcO, an ETC oxidoreductase, can be 're-engineered' in vivo.

The effect of peroxiredoxin 4 on fly physiology is a complex interplay of antioxidant and signaling functions.

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 (<2-fold) gave reduced levels of oxidative damage and tended to show an increase in longevity. Flies expressing dPrx4 globally at high 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.

Effects of mosapride on secondary peristalsis in patients with ineffective esophageal motility.

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.

Peroxiredoxins Play an Important Role in the Regulation of Immunity and Aging in Drosophila.

Aberrant immune responses and chronic inflammation can impose significant health risks and promote premature aging. Pro-inflammatory responses are largely mediated via reactive oxygen species (ROS) and reduction-oxidation reactions. A pivotal role in maintaining cellular redox homeostasis and the proper control of redox-sensitive signaling belongs to a family of antioxidant and redox-regulating thiol-related peroxidases designated as peroxiredoxins (Prx). Our recent studies in Drosophila have shown that Prxs play a critical role in aging and immunity. We identified two important 'hubs', the endoplasmic reticulum (ER) and mitochondria, where extracellular and intracellular stress signals are transformed into pro-inflammatory responses that are modulated by the activity of the Prxs residing in these cellular organelles. Here, we found that mitochondrial Prx activity in the intestinal epithelium is required to prevent the development of intestinal barrier dysfunction, which can drive systemic inflammation and premature aging. Using a redox-negative mutant, we demonstrated that Prx acts in a redox-dependent manner in regulating the age-related immune response. The hyperactive immune response observed in flies under-expressing mitochondrial Prxs is due to a response to abiotic signals but not to changes in the bacterial content. This hyperactive response, but not reduced lifespan phenotype, can be rescued by the ER-localized Prx.

Effects of menthol on esophageal motility in humans: Studies using high-resolution manometry.

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.

Peroxiredoxin 5 modulates immune response in Drosophila.

BACKGROUND: Peroxiredoxins are redox-sensing enzymes with multiple cellular functions. Previously, we reported on the potent antioxidant function of Drosophila peroxiredoxin 5 (dPrx5). Studies with mammalian and human cells suggest that peroxiredoxins can modulate immune-related signaling. METHODS: Survivorship studies and bacteriological analysis were used to determine resistance of flies to fungal and bacterial infections. RT-PCR and immunoblot analyses determined expression of dPrx5 and immunity factors in response to bacterial challenge. Double mutants for dprx5 gene and genes comprising the Imd/Relish and dTak1/Basket branches of the immune signaling pathways were used in epistatic analysis. RESULTS: The dprx5 mutant flies were more resistant to bacterial infection than controls, while flies overexpressing dPrx5 were more susceptible. The enhanced resistance to bacteria was accompanied by rapid induction of the Imd-dependent antimicrobial peptides, phosphorylation of the JNK kinase Basket and altered transcriptional profiling of the transient response genes, puckered, ets21C and relish, while the opposite effects were observed in flies over-expressing dPrx5. Epistatic analysis of double mutants, using attacin D and Puckered as read outs of activation of the Imd and JNK pathways, implicated dPrx5 function in the control of the dTak1-JNK arm of immune signaling. CONCLUSIONS: Differential effects on fly survivorship suggested a trade-off between the antioxidant and immune functions of dPrx5. Molecular and epistatic analyses identified dPrx5 as a negative regulator in the dTak1-JNK arm of immune signaling. GENERAL SIGNIFICANCE: Our findings suggest that peroxiredoxins play an important modulatory role in the Drosophila immune response.

The effect of dexlansoprazole MR on nocturnal heartburn and GERD-related sleep disturbances in patients with symptomatic GERD.

OBJECTIVES: Nocturnal heartburn and related sleep disturbances are common among patients with gastroesophageal reflux disease (GERD). This study evaluated the efficacy of dexlansoprazole MR 30 mg in relieving nocturnal heartburn and GERD-related sleep disturbances, improving work productivity, and decreasing nocturnal symptom severity in patients with symptomatic GERD. METHODS: Patients (N=305) with frequent, moderate-to-very severe nocturnal heartburn and associated sleep disturbances were randomized 1:1 in a double-blind fashion to receive dexlansoprazole MR or placebo once daily for 4 weeks. The primary end point was the percentage of nights without heartburn. Secondary end points were the percentage of patients with relief of nocturnal heartburn and of GERD-related sleep disturbances over the last 7 days of treatment. At baseline and week 4/final visit, patients completed questionnaires that assessed sleep quality, work productivity, and the severity and impact of nocturnal GERD symptoms. RESULTS: Dexlansoprazole MR 30 mg (n=152) was superior to placebo (n=153) in median percentage of nights without heartburn (73.1 vs. 35.7%, respectively; P<0.001). Dexlansoprazole MR was significantly better than placebo in percentage of patients with relief of nocturnal heartburn and GERD-related sleep disturbances (47.5 vs. 19.6%, 69.7 vs. 47.9%, respectively; P<0.001), and led to significantly greater improvements in sleep quality and work productivity and decreased nocturnal symptom severity. Adverse events were similar across treatment groups. CONCLUSIONS: In patients with symptomatic GERD, dexlansoprazole MR 30 mg is significantly more efficacious than placebo in providing relief from nocturnal heartburn, in reducing GERD-related sleep disturbances and the consequent impairments in work productivity, and in improving sleep quality/quality of life.

Evidence for altered anorectal function in irritable bowel syndrome patients with sleep disturbance.

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.

Hydrogen peroxide scavenging rescues frataxin deficiency in a Drosophila model of Friedreich's ataxia.

Friedreich's ataxia (FRDA) is a neurodegenerative disorder arising from a deficit of the mitochondrial iron chaperone, frataxin. Evidence primarily from yeast and mammalian cells is consistent with the hypothesis that a toxic hydroxyl radical generated from hydrogen peroxide (H2O2) via iron-catalyzed Fenton chemistry at least partially underlies the pathology associated with this disease. However, no whole-organism studies have been presented that directly test this hypothesis. We recently developed a Drosophila model that recapitulates the principal hallmarks of FRDA [Anderson PR, Kirby K, Hilliker A, Phillips JP (2005) Hum Mol Genet 14:3397-3405]. Using the Drosophila FRDA model, we now report that ectopic expression of enzymes that scavenge H2O2 suppresses the deleterious phenotypes associated with frataxin deficiency. In contrast, genetic augmentation with enzymes that scavenge superoxide is without effect. Augmentation of endogenous catalase restores the activity of the reactive oxygen species (ROS)-sensitive mitochondrial enzyme, aconitase and enhances resistance to H2O2 exposure, both of which are diminished by frataxin deficiency. Collectively, these data argue that H2O2 is an important pathogenic substrate underlying the phenotypes arising from frataxin deficiency in Drosophila and that interventions that reduce this specific ROS can effectively ameliorate these phenotypes. The therapeutic implications of these findings are clear and we believe warrant immediate clinical investigation.