Vertical bone regeneration with deproteinised bovine bone mineral or biphasic calcium phosphate in the rabbit calvarium: effect of autologous platelet lysate.

Although bone substitutes associated with platelet concentrates are widely used to vertically reconstruct alveolar ridges, their respective and specific contribution remain controversial. The aim of this study was to evaluate the benefit of using either biphasic calcium phosphate (BCP) or demineralised bovine bone mineral (DBBM) alone or with autologous platelet lysate (APL) in vertical bone regeneration. The study involved fourteen New Zealand rabbits. Autologous APL was prepared by freeze-thawing from a platelet suspension (10(9) platelets/ml). Four CP titanium (cpTi) cylinders were fixed to each calvarium; one cylinder was empty, one was filled with APL alone and the others were filled either with BCP or BCP + APL or DBBM or DBBM + APL. New bone formation and biomaterial resorption were evaluated using non-demineralised histology and histomorphometry. After 6 weeks, new bone formation was observed in all cylinders. The newly formed bone in the cylinders filled with APL alone, DBBM and BCP was significantly increased by (0.6-, 2.5- and 3.3-fold, respectively) (P < 0.0001) compared to results obtained with the empty cylinders. Vertical bone height in the cylinders filled with BCP was greater to that observed with DBBM. The residual material in the cylinders filled with BCP was significantly (P < 0.0001) lower (0.35-fold) than that with DBBM. Both newly formed bone and residual material in the cylinders filled with BCP + APL or DBBM + APL were similar to those filled with either BCP or DBBM, respectively. This study provided evidence that APL alone, as well as DBBM and BCP, have a beneficial effect on vertical bone formation and remodelling. APL associated with either DBBM or BCP did not provide additional benefits.

Long-term results of electrical stimulation of the lower esophageal sphincter for the treatment of gastroesophageal reflux disease.

BACKGROUND AND STUDY AIMS: In patients with gastroesophageal reflux disease (GERD), temporary electrical stimulation of the lower esophageal sphincter (LES) increases LES pressure without interference with LES relaxation. The aim of the current study was to investigate the safety and efficacy of long term LES electrical stimulation therapy (LES-EST), using a permanently implanted stimulator for the treatment of GERD. PATIENTS AND METHODS: Patients with GERD who were at least partially responsive to proton pump inhibitors (PPIs) and who had hiatal hernia of ≤ 3 cm and esophagitis of Los Angeles Grade A, B, or C were included in the study. Stimulation electrodes were placed in the LES and a pulse generator (EndoStim LES Stimulation System; EndoStim BV, The Hague, The Netherlands) was implanted laparoscopically. LES stimulation was delivered at 20 Hz, 215 µs, 3 - 8 mA in multiple 30-minute sessions. Patients were evaluated at follow-up using the GERD Health-Related Quality of Life (HRQL) questionnaire, daily symptom and medication diaries, the SF-12 Health Survey, esophageal pH testing, and high resolution manometry. RESULTS: A total of 24 patients (mean age 53 ± 12 years; 14 men) were implanted and 23 completed the 12-month evaluation. No serious implantation or stimulation-related adverse affects or sensations were reported. Median composite GERD-HRQL score at 12 months was 2.0 (interquartile range [IQR] 0 - 3.0), which was significantly better than baseline scores both on PPI therapy (median 9.0, IQR 6.0 - 10.0; P = 0.002) and off PPIs (median 23.5, IQR 21 - 25.75; P < 0.001). The median percentage of the 24-hour period with esophageal pH < 4.0 at baseline was 10.1 % (IQR 7.7 - 15.5), which was reduced to 3.3 % (1.8 - 6.9) at 12 months (P < 0.001), with 69 % of patients showing either normalization or > 50 % improvement in their distal esophageal pH. At 12 months, 96 % of patients (22/23) were completely off PPI medication. CONCLUSION: During the long term follow-up of 12 months, LES - EST was safe and effective for the treatment of GERD. There was a significant and sustained improvement in GERD symptoms, reduction in esophageal acid exposure with elimination of daily PPI usage, and no stimulation-related adverse effects.

Redefining the role of lymphocytes in gastroesophageal reflux disease and eosinophilic esophagitis.

Eosinophilic esophagitis (EoE) and reflux esophagitis (RE) overlap clinically and histologically. RE is characterized by epithelial infiltration with small numbers of neutrophils and eosinophils, EoE by a prominent eosinophilic infiltrate. Lymphocytic esophagitis (LE), a new entity characterized by peripapillary lymphocytosis, questions the role lymphocytes play in esophageal inflammation. We test the hypothesis that lymphocyte infiltration in RE differs from EoE. One blinded pathologist read esophageal biopsies from 39 RE and 39 EoE patients. Both groups demonstrated significant numbers of lymphocytes (RE 22.7 +/- 2.2/HPF, EoE 19.8 +/- 1.8/HPF). Eosinophils/HPF in RE and EoE were 2.8 +/- 0.7 and 74.9 +/- 8.2, respectively (P < 0.001). Neutrophils were uncommon in RE (0.26 +/- 0.16/HPF) and EoE (0.09 +/- 0.04; P = 0.07). Eight of the 39 RE specimens had >or=50 lymphocytes in >or=1 HPF. Two were consistent with LE. There was an inverse correlation between numbers of eosinophils and lymphocytes in EoE (R = -0.47; P = 0.002), and no correlation between them in RE (R = 0.18; P = 0.36). The patients with EoE who used antireflux medications had fewer lymphocytes (16.3 +/- 1.3 vs 22.2 +/- 2.3/HPF; P = 0.030) and eosinophils (55.6 +/- 5.2 vs 76.0 +/- 8.7/HPF; P = 0.042) than those who did not. The pathological role of lymphocytes in RE and EoE may be underestimated. Our observation that 5% of the RE specimens meet histopathological criteria for LE potentially blurs the line between these entities. The observation that eosinophil counts are lower in EoE when antireflux meds are used supports the notion that reflux plays a role in the clinical expression of EoE.

Effect of bolus enteral tube feeding on body weight in ambulatory adults with obesity and type 2 diabetes: a feasibility pilot randomized trial.

BACKGROUND/OBJECTIVES: To ascertain the effect on body weight of 14 days of bolus enteral feeding with mixed meal (MM) and electrolyte solution (ES) in ambulatory adults with type 2 diabetes and obesity, and also the safety and feasibility of using a modified, intraorally anchored enteral feeding tube for this purpose. SUBJECTS/METHODS: We conducted a randomized, crossover pilot trial with 16 participants. A 140 cm, 8-French feeding tube was placed in the jejunum under electromagnetic guidance and anchored intraorally. Participants were randomized to self-administer 120 mL 523 kJ (125 kcal) MM, or 50 kJ (12 kcal) ES four times/day for 14 days. After ≥14 days without the tube, participants crossed over to the other treatment. The primary outcome compared weight change between treatments. Thereafter, participants could elect to undergo additional MM cycles. Participants were encouraged to continue with all usual activities including eating ad lib throughout the study. RESULTS: Ten participants withdrew prior to completing two randomized 14-day cycles (4 social, 3 intolerant of anchor, and 3 intolerant of tube). Six participants were assessed for the primary outcome and showed no significant difference in weight loss between MM and ES (p = 0.082). For the secondary outcome of within-group weight loss, average weight loss from baseline was significant for MM but not for ES: -2.40 kg (95% CI: -3.78, -1.02; p = 0.008) vs. -0.64 kg (95% CI: -2.01, 0.74; p = 0.27). A total of 23 2-week cycles were completed (12 paired, 2 unpaired, and 9 additional), with no significant adverse events for 334 days of tube use. CONCLUSIONS: Repeated bolus nutrient administration via enteral feeding tube is associated with weight loss in adults with obesity and type 2 diabetes, with no significant difference seen between MM and ES feeds. The prototype device was safe, but requires development for further investigation into the effect of bolus jejunal feeding on weight and to improve acceptability.

Circadian patterns of gastric electrical and mechanical activity in dogs.

Gastric motor function assessment, in humans and animals, is typically performed for short recording periods. The aim of this article was to monitor gastric electrical and motor activity in the antrum and fundus simultaneously, for long periods, using a new implantable system. Ten dogs were implanted with fundic and antral electrodes for assessment of impedance and electrical activity. Dogs were studied while in cages, for periods of 22-26 h. From late evening and until feeding on the next day, slow wave (SW) rhythm demonstrated a distinct pattern of intermittent pauses (mean duration = 22.8 +/-4.1 s) that delineated groups of SW's. Phasic increases in fundic tone were seen mostly in association with SW pauses, and were highly correlated with antral contractions, R(2) = 0.652, P < 0.05. The SW rate (events per minute) in the postprandial period, fasting and night time was 4.2 +/- 0.2, 5 +/- 0.2 and 4.7 +/- 0.3, respectively, P < 0.05 postprandial vs other periods. Antral and fundic mechanical activities were highly correlated during fasting, particularly at night. This novel method of prolonged gastric recording provides valuable data on the mechanical and electrical activity of the stomach, not feasible by current methods of recording. During fasting, fundic and antral motor activities are highly correlated and are associated with periodic pauses in electrical activity.

Oral pantoprazole in the form of granules or tablets are pharmacodynamically equivalent in suppressing acid output in patients with gastro-oesophageal reflux disease and a history of erosive oesophagitis.

AIM: To demonstrate the pharmacodynamic comparability between oral 40 mg pantoprazole delayed-release granules and tablets. METHODS: This was a multicentre, randomized, open-label, 2-period, 2-sequence, 9-week crossover study in patients aged 18-65 years with gastro-oesophageal reflux disease and documented erosive oesophagitis. The primary endpoint was a comparison of the inhibition of pentagastrin-stimulated maximum acid output (MAO) at steady state after once daily dosing for 1 week and 23 h after the last dose of pantoprazole granules and tablets. Basal acid output was measured prior to MAO. Standard safety evaluations were performed. The one-sided t-test was used to test the null hypothesis that granules - 1.2 x tablet >/= 0 against the alternative hypothesis that this difference was <0 for both MAO and basal acid output values. RESULTS: Sixty patients completed the study. The mean MAO values were 7.11 +/- 4.98 and 7.29 +/- 4.77 mmol/h, while the mean basal acid output values were 0.74 +/- 0.91 and 0.58 +/- 0.63 mmol/h for the granules and tablets, respectively. The two formulations were shown statistically to be pharmacodynamically equivalent in suppressing MAO (P = 0.006), safe and well tolerated. CONCLUSION: Patients with gastro-oesophageal reflux disease who are unable to swallow the tablet may safely be prescribed the pantoprazole sodium granules.

Three-year oral pantoprazole administration is effective for patients with Zollinger-Ellison syndrome and other hypersecretory conditions.

BACKGROUND: Zollinger-Ellison syndrome and idiopathic hypersecretion are gastrointestinal hypersecretory conditions requiring long-term maintenance. AIMS: The safety and efficacy data for short-term (6-month) treatment of Zollinger-Ellison syndrome and idiopathic hypersecretion with oral pantoprazole were previously published. This study extends the initial observations to 3 years. METHODS: The primary efficacy end point for this report was the control of gastric acid secretion in the last hour before the next dose of oral pantoprazole (acid output of <10 mmol/h; <5 mmol/h in subjects with prior acid-reducing surgery). Dose titration was permitted to a maximum of 240 mg per 24 h. RESULTS: Twenty-four subjects completed the study. The acid output of 28 of 34 subjects was controlled at initial enrolment. The mean acid output rates were <10 mmol/h throughout the 36 months of treatment for 90-100% of the patients. The majority of the patients were controlled with b.d. doses of 40 or 80 mg pantoprazole at 36 months (acid output was controlled in 24 of 24 subjects). Pantoprazole was generally well tolerated with minimal adverse events reported. CONCLUSIONS: Maintenance oral pantoprazole therapy up to 3 years at dosages of 40-120 mg b.d. was effective and well tolerated in patients with Zollinger-Ellison syndrome and other hypersecretory conditions.

Neural gastrointestinal electrical stimulation enhances colonic motility in a chronic canine model of delayed colonic transit.

Neural gastrointestinal electrical stimulation (NGES) induces sequential contractions and enhances emptying in acute canine gastric and colonic models. This study was set to determine (i) the effect of NGES in a chronic canine model of delayed colonic transit and (ii) possible mechanism of action. Four pairs of electrodes were implanted in the distal colon of nine mongrel dogs. Delayed colonic transit was induced by diphenoxylate/atropine and alosetron. Transit was fluoroscopically determined by the rate of evacuation of radiopaque markers, and was tested twice in each dog, in random order, on and off stimulation. Two stimulation sequences, separated by 1 min, were delivered twice a day via exteriorized electrodes. Colonic manometry during stimulation was performed before and after intravenous (i.v.) injection of 1 mg of atropine. Complete evacuation of all markers was significantly shortened by NGES, from 4 days to 2 days, interquartile range 3-4 days vs 2-3 days, respectively, P = 0.016. NGES induced strong sequential contractions that were significantly diminished by atropine: 190.0 +/- 14.0 mmHg vs 48.7 +/- 19.4 mmHg, respectively (P < 0.001). NGES induces strong sequential colonic contractions and significantly accelerates movement of content in a canine model of delayed colonic transit. The effect is atropine sensitive.

Treatment of gastroparesis: a multidisciplinary clinical review.

This clinical review on the treatment of patients with gastroparesis is a consensus document developed by the American Motility Society Task Force on Gastroparesis. It is a multidisciplinary effort with input from gastroenterologists and other specialists who are involved in the care of patients with gastroparesis. To provide practical guidelines for treatment, this document covers results of published research studies in the literature and areas developed by consensus agreement where clinical research trials remain lacking in the field of gastroparesis.

Effects of autologous platelet lysates on ceramic particle resorption and new bone formation in critical size defects: the role of anatomical sites.

This study investigated the effects of rabbit autologous platelet lysates (APL) on the performance of fillers consisting of calcium carbonate ceramic particles (CP) pertinent to new bone formation and repair. Critical-size defects in rabbit femurs and calvaria were filled with CP alone, CP plus APL, and CP plus APL with or without thrombin (THR). After 6 weeks, resorption of CP occurred under all conditions tested in the present study. Compared with respective CP alone controls, addition of APL resulted in significantly higher ceramic resorption, as evidenced by decreased ceramic particle diameter (p < 0.01) and number (p < 0.01) at both defect sites. The presence of THR prevented reduction of both CP diameter and number in the femoral defect sites. Addition of APL to the CP resulted in a significant (p < 0.03) decrease in new bone area at the calvarial sites, but not at the femoral sites; moreover, when THR was added to the CP plus APL fillers, bone formation in the femoral defects was significantly (p < 0.05) reduced. In addition to differences in the respective anatomical and cellular milieu, the biochemical events induced by mechanical loading at the femurs may explain the reduced ceramic particle resorption as well as the enhanced new bone formation when compared with the results obtained at the calvarial defect sites.

Meal-induced secretion of gastrointestinal regulatory peptides is not affected by sleep.

UNLABELLED: The mechanisms responsible for the disruption of the migrating motor complex (MMC) by feeding are not fully understood. Sleep reduces the duration of the postprandial or fed pattern of motility in the intestine. This study was set out to determine if this effect is associated with sleep-induced changes in the secretion of regulatory peptides in response to food. METHODS: Duodenojejunal motility was studied in 15 healthy ambulant subjects for 2 consecutive days. On one day identical solid meals were consumed in the morning and late in the evening, the latter followed by sleep. On the other day, identical liquid meals were infused into the stomach and the duodenum in the morning and late in the evening, the latter after the onset of sleep. Plasma concentrations of gastrin, neurotensin, peptide YY (PYY), pancreatic polypeptide (PP), motilin and glucose were monitored before and after meals. Sleep significantly shortened the duration of the fed pattern after the solid meal and even more so after the liquid meal. The plasma concentrations of all peptides, except motilin, increased significantly following each meal. Blood glucose levels rose after each meal, the changes being similar with all meals. Food-induced gastrointestinal regulatory peptides secretion and intestinal absorption of glucose are not affected by sleep. The vagal response to a meal, as indicated by PP release, is intact during sleep. The results support the importance of neural mechanisms in the modulation of the postprandial pattern of intestinal motility.

Gastric electrical stimulation at proximal stomach induces gastric relaxation in dogs.

Gastric electrical stimulation (GES) improves symptoms in patients with gastroparesis. However, the underlying mechanisms remain unclear. To determine if GES at proximal and distal stomach could affect the biomechanical properties of the stomach, thus contributing to the beneficial effect of GES. Four pairs of electrodes were implanted along the greater curvature of the stomach in seven dogs. Gastric tone and compliance was assessed with a barostat. Measurements were obtained randomly during control and proximal and distal stimulation (4 mA, 375 ms and 6/18 cpm). Data as mean or median (25-75th percentiles). Gastric compliance was not affected by proximal and distal GES. Gastric tone was significantly reduced during proximal GES: 82.0 (66.8, 89.1) mL vs control 49.7 (39.6,75.9) mL at 6 cpm (P = 0.016), and 90.6 (54.5, 117.9) mL vs control 62.8 (39.6, 75.9) mL at 18 cpm (P = 0.031). Tone was not affected by distal GES at 6 cpm: 95.8 (46.3, 106.7) mL vs control 75.2 (49.7, 86.1) mL (P = 0.47) and at 18 cpm: 80.4 (38.1, 170.3) mL vs control 62.8 (44.6, 156.3) mL (P = 0.44). Proximal GES induces gastric relaxation. This effect, if seen also in humans, may explain, in part, the symptomatic improvement associated with GES therapy in patients with gastroparesis.

Liquid chromatographic assay using electrochemical detection for the quantitation of indoramin in human plasma.

An automated high-performance liquid chromatographic method with electrochemical detection is described for the determination of indoramin, a new antihypertensive drug. The procedure involves a single extraction of the drug from alkaline plasma with chlorobutane. The chlorobutane extract is evaporated to dryness, reconstituted in methanol and injected into the chromatograph. Separation is achieved using a CN-bonded silica column and an isocratic elution with 0.01 M sodium phosphate in 50% acetonitrile. Detection is at 0.95 V applied potential on a glassy carbon electrode versus an Ag/AgCl electrode. Electrochemical methods that depend on a high oxidation potential suffer from rapid electrode passivation by significant amounts of impurities extracted from plasma. Therefore, the instrumentation includes a valve-switching unit to divert most of the impurities away from the electrode compartment; thus, maintaining sensitivity during the automated analysis of a large number of samples. An RSD of 5-15% was obtained in the concentration range of 0.5-100 ng/mL plasma. The limit of detection is 0.5 ng/mL. The method has been successfully used for the determination of indoramin in plasma samples from human subjects given a 50-mg oral dose of the drug.

The challenge of irritable bowel syndrome: creating an alliance between patient and physician.

The most important component of the treatment of irritable bowel syndrome (IBS) is to establish a therapeutic physician-patient relationship, coupled with patient education. We describe a stepwise approach to management, including judicious use of invasive tests, and setting realistic treatment goals that address the dominant symptoms, their severity, and psychosocial factors.

Constipation: an approach to diagnosis, treatment, referral.

When a patient reports constipation, a careful history and physical examination may identify the underlying cause. In many patients, though, no underlying cause is identified. Empiric treatment with exercise, hydration, fiber supplementation, and mild laxatives is often effective. If constipation does not resolve with these measures, then the physician may refer the patient for further testing for slow colonic transit, pelvic floor dysfunction, or anatomical defects, and in difficult and recalcitrant cases for surgical treatment.

Diabetic gastropathy: a practical approach to a vexing problem.

The clinical presentation of diabetic gastropathy varies, and a diagnosis usually must be confirmed with tests that evaluate the structure and function of the upper gut. Although glucose control, dietary changes, and drug therapy are the current mainstays of treatment, they may not be effective. Gastric pacing, a new technique that stimulates gastric motility, may give physicians another management tool.

The role of short-term multilumen duodenojejunal manometry in patients with intestinal motor dysfunction.

Short-term duodenojejunal manometry, using a multilumen perfused tube, was performed in 12 patients with symptoms of motor dysfunction, 6 patients with irritable bowel syndrome and predominant diarrhea and 6 patients with chronic constipation. Ten healthy individuals served as controls. The durations, in minutes, of the various phases of the migratory motility complex in the three groups were: phase I: 24.4 +/- 22.1, 26.9 +/- 17.3, and 27.2 +/- 18.5; phase II: 86.7 +/- 25.2, 132 +/- 93, and 73.1 +/- 40.8, and those of phase III: 6 +/- 2.5, 6.8 +/- 5, and 6.4 +/- 1.7, respectively. The differences between patients and controls were not statistically significant. Variables of contractions of phase III in the different groups were: frequency (per minute): 10.9 +/- 0.8, 10.7 +/- 0.4, and 11.3 +/- 0.4; Summation of amplitudes per minute: 205.2 +/- 55.7, 288 +/- 57.9, and 337.8 +/- 76.5; Mean amplitude (mm Hg): 19.1 +/- 4.2, 28.6 +/- 5, and 33.5 +/- 7.1, respectively. Results in the patient groups were not significantly different from controls. Short-term duodenojejunal manometry was normal in patients with irritable bowel syndrome and in those with chronic constipation.

Hardware-software co-design of portable functional gastrointestinal stimulator system.

In the recent years, functional electrical stimulation has been applied to restore impaired motility in the gastrointestinal tract. Unlike other methods of electrical stimulation of the gut, microprocessor-controlled, sequential electrical stimulation has been shown to induce peristalsis and enhance emptying in acute canine gastric and colonic models. This study aims at completing the development of a portable microprocessor-based functional stimulator system consisting of a microelectronic stimulator, patient-specific computer-based real-time software and a programming interfacing device. The ultimate goals of the design are to ensure that (1) the portable stimulator can be efficiently utilized in chronic animal experiments; and (2) the device can be further miniaturized into an implantable version. The designed portable stimulator generates four channel sequential bipolar rectangular pulse trains with programmable parameters within the stimulation requirements obtained from a previously developed computer model. Real-time simulation of colonic peristalsis and a case-specific stimulation model were implemented using patient-specific computer-based software. A chronic canine case study confirmed the feasibility of this microprocessor-controlled stimulation method for future clinical applications in humans.

A review of diabetic gastropathy.

Diabetes mellitus affects various organs, including the gastrointestinal tract. The stomach is commonly affected, and symptoms related to the upper GI tract are frequently reported. Management of diabetic gastropathy involves dietary modifications, pharmacological agents, and occasionally, alternative feeding methods.

Short-term electrical stimulation of the lower esophageal sphincter increases sphincter pressure in patients with gastroesophageal reflux disease.

BACKGROUND: Electrical stimulation (ES) of the lower esophageal sphincter (LES) increases resting LES pressure (LESP) in animal models. Our aims were to evaluate the safety of such stimulation in humans, and test the hypothesis that ES increases resting LESP in patients with gastroesophageal reflux disease (GERD). METHODS: A total of 10 subjects (nine female patients, mean age 52.6 years), with symptoms of GERD responsive to PPIs, low resting LES pressure, and abnormal 24-h intraesophageal pH test were enrolled. Those with hiatal hernia >2 cm and/or esophagitis >Los Angeles Grade B were excluded. Bipolar stitch electrodes were placed longitudinally in the LES during an elective laparoscopic cholecystectomy, secured by a clip and exteriorized through the abdominal wall. Following recovery, an external pulse generator delivered two types of stimulation for periods of 30 min: (i) low energy stimulation; pulse width of 200 µs, frequency of 20 Hz and current of 5-15 mA (current was increased up to 15 mA if LESP was less than 15 mmHg), and (ii) high energy stimulation; pulse width of 375 ms, frequency of 6 cpm, and current 5 mA. Resting LESP, amplitude of esophageal contractions and residual LESP in response to swallows were assessed before and after stimulation. Symptoms of chest pain, abdominal pain, and dysphagia were recorded before, during, and after stimulation and 7-days after stimulation. Continuous cardiac monitoring was performed during and after stimulation. KEY RESULTS: All patients were successfully implanted nine subjects received high frequency, low energy, and four subjects received low frequency, high energy stimulation. Both types of stimulation significantly increased resting LESP: from 8.6 mmHg (95% CI 4.1-13.1) to 16.6 mmHg (95% CI 10.8-19.2), P < 0.001 with low energy stimulation and from 9.2 mmHg (95% CI 2.0-16.3) to 16.5 mmHg (95% CI 2.7-30.1), P = 0.03 with high energy stimulation. Neither type of stimulation affected the amplitude of esophageal peristalsis or residual LESP. No subject complained of dysphagia. One subject had retrosternal discomfort with stimulation at 15 mA that was not experienced with stimulation at 13 mA. There were no adverse events or any cardiac rhythm abnormalities with either type of stimulation. CONCLUSIONS & INFERENCES: Short-term stimulation of the LES in patients with GERD significantly increases resting LESP without affecting esophageal peristalsis or LES relaxation. Electrical stimulation of the LES may offer a novel therapy for patients with GERD.