Faecal freezing preservation period influences colonization ability for faecal microbiota transplantation.

AIMS: There has been growing interest in faecal microbiota transplantation (FMT) as treatment. Although, frozen donor faeces preserved at -20°C has been widely used for practical advantages, freezing at -20°C can affect bacterial viability. Adequacy evaluation of fresh and frozen faeces as the transplant is necessary for the methodological improvement of FMT. METHODS AND RESULTS: The viable bacterial compositions of faecal specimens under fresh and freezing conditions were compared by a microbiome analysis using propidium monoazide (PMA microbiome). In addition, recovery abilities from bacterial reduction by antibiotics were compared between fresh and frozen FMT using a murine model. PMA microbiome results suggested that freezing and freeze-thawing did not significantly affect in vitro faecal bacterial viability. However, the recovery effect from antimicrobial cleansing in frozen FMT was reduced in a freezing time-dependent manner, especially prominent in Actinobacteria and Bacteroidetes phyla. CONCLUSIONS: Short-term freezing preservation of faeces exhibited maintenance of enteric colonization ability in frozen FMT in comparison to 1 month -20°C-preservation. SIGNIFICANCE AND IMPACT OF THE STUDY: Long-term -20°C-preservation of transplanted faeces can result in instability of the clinical outcome in FMT therapy. The standardization of practical procedures of FMT therapy according to disease types is desirable.

Antimicrobial photodynamic therapy using a diode laser with a potential new photosensitizer, indocyanine green-loaded nanospheres, may be effective for the clearance of Porphyromonas gingivalis.

BACKGROUND: Antimicrobial photodynamic therapy (aPDT) is a new treatment method for the removal of infectious pathogens using a photosensitizer and light of a specific wavelength, e.g., toluidine blue with a wavelength of about 600 nm. We explored a new photosensitizer and focused on indocyanine green (ICG), which has high absorption at a wavelength of 800-805 nm. We investigated the bactericidal effect of PDT on Porphyromonas gingivalis using a new photosensitizer, ICG-loaded nanospheres with an 805 nm wavelength low-level diode laser irradiation. METHODS: We designed ICG-loaded nanospheres coated with chitosan (ICG-Nano/c) as a photosensitizer. A solution containing Porphyromonas gingivalis (10(8)  CFU/mL) with or without ICG-Nano/c (or ICG) was prepared and irradiated with a diode laser or without laser irradiation as a negative control. The irradiation settings were 0.5 W with a duty ratio of 10%, for 3-100 ms in repeated pulse (RPT) or continuous wave mode. CFU were counted after 7 d of anaerobic culture. RESULTS: We observed that ICG-Nano/c could adhere to the surface of P. gingivalis. When ICG-Nano/c was used for aPDT, irradiation with RPT 100 ms mode gave the lowest increase in temperature. Laser irradiation with ICG-Nano/c significantly reduced the number of P. gingivalis (i.e., approximately 2-log10 bacterial killing). The greatest bactericidal effect was found in the RPT 100 ms group. However, laser irradiation (RPT 100 ms) with ICG, as well as without photosensitizer, had no effect on the number of bacteria. CONCLUSIONS: Within the limits of this study, ICG-Nano/c with low-level diode laser (0.5 W; 805 nm) irradiation showed an aPDT-like effect, which might be useful for a potential photodynamic periodontal therapy.

Efficacy of the 5-HT1A agonist tandospirone citrate in improving symptoms of patients with functional dyspepsia: a randomized controlled trial.

OBJECTIVES: Functional dyspepsia (FD) is a common condition in the general population; however, its treatment remains a challenge. The aim of this study was to examine the efficacy of tandospirone citrate, a new partial agonist of the 5-hydroxytryptamine 1A (5-HT1A) receptor, in improving the symptoms of patients with FD. METHODS: In this double-blind, placebo-controlled, multicenter study, FD patients were randomized to treatment with 10 mg t.i.d. tandospirone citrate or to placebo for 4 weeks. The primary end point was change in abdominal symptom scores. The difference in the proportion of responders (a total abdominal symptom score of 0 or 1) was also assessed. The quality-of-life questionnaire, the SF-8, and a psychological test questionnaire, the State-Trait Anxiety Inventory (STAI), were completed at baseline and at weekly intervals. RESULTS: Data were available for 144 patients: 73 for tandospirone and 71 for placebo. Improvements in total abdominal scores were significantly larger with tandospirone than placebo at weeks 1, 2, and 4. Significantly greater improvements in the tandospirone group were observed in upper abdominal pain (P=0.02) and discomfort (P=0.002) at week 4. The proportion of responders was significantly greater in the active treatment arm at weeks 3 (P=0.017) and 4 (P=0.0016). Significant improvements in STAI (P<0.0001) were reported in both arms, as well as in the majority of questions in the SF-8 (P=0.04). No serious adverse events were reported, with similar rates in both study arms. CONCLUSIONS: Despite a considerable placebo effect, the benefits of tandospirone were shown in terms of improvement in abdominal symptom scores.

Rikkunshito simultaneously improves dyspepsia correlated with anxiety in patients with functional dyspepsia: A randomized clinical trial (the DREAM study).

BACKGROUND: Functional dyspepsia (FD), a heterogeneous disorder, involves multiple pathogenetic mechanisms. Developing treatments for FD has been challenging. We performed a randomized, placebo-controlled, double-blind clinical trial to determine the efficacy of rikkunshito, a Japanese herbal medicine, in FD patients. METHODS: FD patients (n = 192) who met the Rome III criteria without Helicobacter pylori infection, predominant heartburn, and depression were enrolled at 56 hospitals in Japan. After 2 weeks of single-blind placebo treatment, 128 patients with continuous symptoms were randomly assigned to 8 weeks of rikkunshito (n = 64) or placebo (n = 61). The primary efficacy endpoint was global assessment of overall treatment efficacy (OTE). The secondary efficacy endpoints were improvements in upper gastrointestinal symptoms evaluated by the Patient Assessment of Upper Gastrointestinal Disorders-Symptom Severity Index (PAGI-SYM), the Global Overall Symptom scale (GOS), and the modified Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease (m-FSSG), and psychological symptoms evaluated by the Hospital Anxiety and Depression Scale (HADS). KEY RESULTS: Rikkunshito increased OTE compared to placebo at 8 weeks (P = .019). Rikkunshito improved upper gastrointestinal symptoms (PAGI-SYM, GOS, and m-FSSG) at 8 weeks, especially postprandial fullness/early satiety (P = .015 and P = .001) and bloating (P = .007 and P = .002) of the PAGI-SYM subscales at 4 weeks and 8 weeks. Improvement of HADS at 8 weeks (P = .027) correlated with those of PAGI-SYM (r = .302, P = .001), GOS (r = .186, P = .044), and m-FSSG (r = .462, P < .001), postprandial fullness/early satiety (r = .226, P = .014), dyspepsia (r = .215, P = .019), and PDS (r = .221, P = .016). CONCLUSION & INFERENCES: Rikkunshito may be beneficial for FD patients to simultaneously treat gastrointestinal and psychological symptoms.

Efficacy of rabeprazole on heartburn symptom resolution in patients with non-erosive and erosive gastro-oesophageal reflux disease: a multicenter study from Japan.

BACKGROUND: Few studies have compared the efficacy of proton pump inhibitors in resolving the symptoms of non-erosive reflux disease (NERD) and of erosive gastro-oesophageal reflux disease (GERD) in Japan. AIM: To investigate and compare the efficacy of 4-week course of rabeprazole 10 mg/day on symptom resolution in NERD and erosive GERD in Japan. METHODS: The modified Los Angeles classification was used to grade endoscopically GERD in patients with heartburn (Grades N and M: NERD, Grades A and B: mild reflux oesophagitis (RO), and Grades C and D: severe RO). Rabeprazole 10 mg/day was administered for 4 weeks to 180 patients who kept symptom diaries. RESULTS: Complete relief of the symptoms was achieved in 35.8% of the NERD group and 55.4% of the erosive GERD group (mild RO: 51.1% and severe RO: 77.8%). Rabeprazole was significantly more effective in erosive GERD than in NERD patients. Among the NERD subgroups (Grades N and M), no difference in symptom improvement was observed. CONCLUSIONS: Four-week, rabeprazole 10 mg/day acid suppression therapy was effective in resolving symptoms in Japanese GERD patients. This therapy was more effective in erosive GERD than in NERD patients, and in those with severe RO than in those with mild RO.

Phase I/II clinical trial to assess safety and efficacy of intratumoral and subcutaneous injection of HVJ-E in castration-resistant prostate cancer patients.

Inactivated Sendai virus particles (hemagglutinating virus of Japan envelope (HVJ-E)) have a novel antitumor effect: HVJ-E fused to prostate cancer cells via cell surface receptor causes apoptosis of prostate cancer cells in vitro and in vivo. HVJ-E also induces antitumor immunity by activating natural killer (NK) cells and cytotoxic T cells and suppressing regulatory T cells in vivo. We conducted an open-label, single-arm, phase I/II clinical trial in patients with castration-resistant prostate cancer (CRPC) to determine the safety and efficacy of intratumoral and subcutaneous injection of HVJ-E. Patients with CRPC who were docetaxel-resistant or could not receive docetaxel treatment were eligible. HVJ-E was injected directly into the prostate on day 1 and subcutaneously on days 5, 8 and 12 in two 28-day treatment cycles using a 3+3 dose-escalation design. The primary end points were to evaluate safety and tolerability of HVJ-E. The secondary end points were to analyze tumor immunity and antitumor effect. The study is registered at UMIN Clinical Trials Registry, number UMIN000006142. Seven patients were enrolled, and six patients received HVJ-E. Grade 2 or 3 adverse events (Common Terminology Criteria for Adverse Events Ver. 4.0) were urinary retention and lymphopenia from which the patients recovered spontaneously. No Grade 4 adverse events were observed. Radiographically, three patients had stable disease in the low-dose group, and one patient had stable disease and two had progressive disease in the high-dose group. The prostate-specific antigen (PSA) declined from 14 to 1.9 ng ml-1 in one patient in the low-dose group after two cycles of HVJ-E treatment, and the PSA response rate was 16.6%. NK cell activity was elevated from day 12 to day 28 after HVJ-E administration, whereas serum interleukin-6, interferon (IFN)-α, IFN-ß and IFN-γ levels were not affected by HVJ-E treatment. Intratumoral and subcutaneous injections of HVJ-E are feasible and PSA response was observed in a subgroup of CRPC patients.

Inhibition of benzo(a)pyrene-induced mouse forestomach neoplasia by dietary soy sauce.

We show that Japanese-style fermented soy sauce (shoyu) contains anticarcinogenic activity. Female ICR mice were fed a semipurified diet containing soy sauce (0-30%). Two weeks later a regimen consisting of 4 doses of benzo(a)pyrene (1 dose/week p.o. for 4 weeks) was begun to initiate forestomach neoplasia. Twenty-three weeks after the first intubation the animals were sacrificed, and forestomach neoplasms were counted and histologically confirmed. Soy sauce produced a significant dose-dependent reduction in forestomach neoplasms, which appeared to be maximal when soy sauce constituted 20% of the diet. Exposure to nitrite (0-500 ppm through drinking water) neither enhanced nor diminished the anticarcinogenic effect of the dietary soy sauce. Soy sauce was found to contain antioxidant activity which may be related to the observed anticarcinogenic effect. Contrary to expectations, mouse forestomach ornithine decarboxylase activity was induced by soy sauce. This appeared to be due at least in part to the relatively high sodium chloride content of soy sauce.

Inhibition of benzo[a]pyrene-induced mouse forestomach neoplasia by a principal flavor component of Japanese-style fermented soy sauce.

A refined diet supplemented with Japanese-style fermented soy sauce (shoyu) inhibits benzo[a]pyrene-induced forestomach neoplasia in mice (Cancer Res., 51:2940-2942, 1991). In the present study, soy sauce was extracted with ethyl acetate. The soluble fraction contained flavor/aroma compounds and antioxidants, whereas amino-carbonyl compounds that impart color were concentrated in the ethyl acetate insoluble fraction. Both fractions inhibited benzo[a]pyrene-induced forestomach neoplasia in a protocol in which the test material was fed following exposure to the carcinogen. A principal flavor/aroma component of soy sauce, 4-hydroxy-2(or 5)-ethyl-5(or 2)-methyl-3(2H)-furanone, was fed to mice following benzo[a]pyrene administration and found to inhibit the subsequent development of forestomach neoplasia. 4-Hydroxy-2(or 5)-ethyl-5(or 2)-methyl-3(2H)-furanone was effective when fed at 4 mg/kg body weight/day, indicating that it is a potent anticarcinogen.

Difference in efficacy of proton pump inhibitor between new-onset and recurrent gastroesophageal reflux disease: Result from a study of on-demand versus continuous maintenance therapy in Japan.

BACKGROUND-OBJECTIVE: No study has focused on the difference in efficacy of maintenance therapy between patients with new-onset and recurrent gastroesophageal reflux disease (GERD). The aim of this study is to reveal this point. METHODS: Endoscopically proven GERD patients who had completed 8-week initial therapy were sequentially randomized to continuous arm (Omeprazole 20mg od) or on-demand arm (Omeprazole 20mg on-demand). Patients filled in daily symptoms and tablet usages for 24 weeks. Patients underwent upper GI endoscopy at 24 weeks. Symptom relief was defined as no symptoms for>6 days during a week. The numbers of patients who achieved symptom relief and mucosal healing were compared between the new-onset and recurrent groups in the continuous arm and in the on-demand arm, respectively. RESULTS: Among new-onset GERD [n=82 (continuous: 42 patients, on-demand: 40)], continuous arm achieved significant symptom-relief than in on-demand arm at 4*,5*,6** and 17*week. Among recurrent GERD [n=36(continuous: 17 patients, on-demand: 19)], continuous arm achieved significant symptom-relief at 1**,2*,3*,4*,5**,7**,8**,17* and 18* week, respectively (*<0.05,**<0.01). The number of healed patients was significantly higher in new-onset group (60/68, 88.2%) than in recurrent group (17/30, 56.7%) (<0.01). CONCLUSION: Since therapeutic response during maintenance therapy was poor in recurrent GERD, continuous therapy is recommended in order to maintain symptom-relief and mucosal healing. Hippokratia 2015, 19 (1): 53-56.

Involvement of the amygdaloid complex in neuromodulatory influences on memory storage.

Neuromodulatory systems activated by training experiences appear to play a role in influencing memory storage processes. The research summarized in this paper examined the effects, on memory, of posttraining administration of treatments affecting adrenergic, opioid peptidergic and GABAergic systems. When administered after training, drugs affecting these systems all produce dose- and time-dependent effects on memory storage. The drug effects on memory are blocked by lesions of the amygdaloid complex as well as lesions of the stria terminalis, a major amygdala pathway. The effects of drugs affecting these neuromodulatory systems are also blocked by injections of beta-adrenergic antagonists administered to the amygdaloid complex. Thus, the findings suggest that the neuromodulatory systems affect memory storage through influences involving the activation of beta-adrenergic receptors within the amygdala. These findings are consistent with the view that the amygdala is involved in regulating the storage of memory in other brain regions.

Age-related changes in c-fos mRNA induction after open-field exposure in the rat brain.

In the present study, functional activation of brain regions was measured by the induction of c-fos and c-jun mRNA following exposure to a novel open field. Fischer 344 rats at 5 months, 14 months, and 21 months were exposed to a square open field for 20 min. Rats were then immediately sacrificed and their brains were examined for c-fos and c-jun mRNA using in situ hybridization. Control rats were sacrificed directly from their home cage. Results showed no significant age-related changes in locomotor activity. Autoradiogram analyses showed that open-field exposure induced c-fos mRNA throughout the brain, while c-jun mRNA was induced in a few brain regions. Aged rats showed a lower elevation of c-fos mRNA in the prelimbic cortex compared to 5-month rats. In addition, grain analyses revealed age-related decreases in c-fos mRNA induction in the medial prefrontal cortex, caudate, and ventral lateral septum. These findings indicate age-related changes in the induction of c-fos mRNA in certain brain regions following exploration of a novel environment.

A dislocated and enlarged proliferative zone in human gastric intestinal metaplasia.

There are many published reports suggesting a close relationship between intestinal metaplasia and gastric carcinogenesis, but there are few studies that examine the cellular kinetics of these tissues in humans. Thus, we sought to characterize the proliferative zone of intestinal metaplasia of the human stomach and correlate this with its known malignant potential. We examined the incorporation of bromodeoxyuridine into 228 human endoscopic biopsy specimens from duodenal mucosa (n=35) and non-intestinalized antral mucosa (n=127) as well as antral mucosa with intestinal metaplasia (n = 66). The proliferative zone in specimens with intestinal metaplasia was deeper when compared to non-intestinalized antral mucosa, but was more superficial than that of duodenal mucosa. Although the labeling index of intestinalized mucosa was similar to that of non-intestinalized antral mucosa, the size of the proliferative zone was significantly increased in intestinal metaplasia. The dislocation of the proliferative zone with an increase in its size in intestinal metaplasia is considered to be a hallmark of gastric intestinal metaplasia.

Suppressive effect of tetraprenylacetone on gastric atrophy induced by short-term administration of N-methyl-N'-nitro-N-nitrosoguanidine in rats.

BACKGROUND: Several studies have been reported on the effects of various therapeutic agents in enhancing or suppressing the carcinogenic activity of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). However, it is still unknown whether a mucosal protective agent could suppress its carcinogenic activity. METHODS: Twenty-five Wistar male rats were divided into four groups: group 1, MNNG alone; group 2, MNNG + tetraprenylacetone; group 3, control; group 4, tetraprenlacetone alone. MNNG 100 mg/mL, was freely given to groups 1 and 2, and tetraprenylacetone (200 mg/kg intraperitoneal) was additionally administered every other day to the rats in groups 2 and 4. The animals were sacrificed at 10 weeks and the gastric mucosa examined. RESULTS: Atrophic changes were observed in the antrum after 8 weeks of oral administration of MNNG. Furthermore, using immunohistological analysis with 5-bromo-2'-deoxyuridine (BrdU), the proliferative zone was found to be enlarged and shifted upward, although the BrdU labelling index of the proliferative zone was unaltered. Intraperitoneal administration of tetraprenylacetone every other day suppressed the MNNG-induced atrophic change and the alterations proliferative markers. Tetraprenylacetone alone did not have an effect either on morphological or proliferative markers. CONCLUSION: These observations suggest that gastric mucosal defensive factors may play critical roles in suppressing atrophic change inducing carcinogenesis by an exogenic carcinogen.

Five-day proton pump inhibitor-based quadruple therapy regimen is more effective than 7-day triple therapy regimen for Helicobacter pylori infection.

BACKGROUND: There have been no reports that describe whether 5-day quadruple therapy (rabeprazole + amoxicillin + clarithromycin + metronidazole; RACM) could substitute for standard 7-day triple therapy as a first-line therapy for Helicobacter pylori. PATIENTS AND METHODS: This study was designed as a randomized prospective single centre study. A total of 160 H. pylori-positive patients who had not received therapy were given either a 5-day RACM regimen (n=80, rabeprazole 20 mg b.d., amoxicillin 750 mg b.d., clarithromycin 200 mg b.d. and metronidazole 250 mg b.d.) or a 7-day RAC regimen (n=80, rabeprazole 20 mg b.d., amoxicillin 750 mg b.d. and clarithromycin 200 mg b.d.). Cure of the infection was assessed by a (13)C urea breath test 1 month after the completion of therapy. RESULTS: The eradication rates of the 5-day RACM regimen and the 7-day RAC regimen were 93% (95% CI: 84--97%) and 81% (95% CI: 71--89%) by intention-to-treat analysis, 94% (95% CI: 86--98%) and 83% (95% CI: 73--91%) by all-patients-treated analysis analysis and 95% (95% CI: 87--98%; P < 0.05) and 82% (95% CI: 72--90%) by per protocol analysis, respectively. No serious adverse effect was observed, and 99% of the patients reported complete compliance. CONCLUSIONS: The cure rate of the 5-day RACM regimen was more effective than the 7-day RAC regimen, suggesting that this regimen could be preferable as a first-line therapy for H. pylori infection.

Is antimicrobial susceptibility testing necessary before second-line treatment for Helicobacter pylori infection?

BACKGROUND: An antimicrobial susceptibility test for Helicobacter pylori before second-line treatment is often performed, although whether the test is truly necessary remains unknown. PATIENTS AND METHODS: Eighty-two patients with H. pylori infection for whom first-line treatment with a 1-week proton pump inhibitor/amoxicillin-clarithromycin (AC) regimen had failed were randomly assigned to two groups: those having or not having the susceptibility test before re-treatment. The cure rates for these two groups were compared. RESULTS: Five of the 82 patients were excluded from the analysis. For 38 patients in the susceptibility-test group, we used what we considered the best regimen based on susceptibility testing: 10 patients [no resistance to clarithromycin (CAM)] received the lansoprazole-amoxicillin-clarithromycin regimen, 22 patients [19 CAM resistant, metronidazole (MNZ) susceptible; three failure of culture] were given the lansoprazole-amoxicillin-metronidazole (LAM) regimen, and six patients (both MNZ and CAM resistant) received dual therapy with omeprazole (OPZ) and amoxicillin (AMOX) in which the OPZ dose was determined by the CYP2C19 gene polymorphism. For 39 patients in the group with no susceptibility testing, LAM regimens were prescribed. The intention-to-treat (ITT)-based cure rates in the groups with and without susceptibility testing were 81.6% (95% confidence interval; 66-92%) and 92.4% (79-98%), respectively, and there was no significant difference between these two groups. CONCLUSION: Susceptibility testing is not necessarily required before second-line therapy if the first-line treatment has been performed using proton pump inhibitor/AC regimens.

Impact of rabeprazole, a new proton pump inhibitor, in triple therapy for Helicobacter pylori infection-comparison with omeprazole and lansoprazole.

BACKGROUND: A recent trend in curative therapy for Helicobacter pylori infection is the so-called triple therapy, which consists of a proton pump inhibitor (PPI) and two different antimicrobials. Various regimens employing this triple therapy have been reported. However, little is known about the effectiveness of rabeprazole, a recently developed proton pump inhibitor, when used in the triple therapy. AIM: To validate its usefulness by comparing rabeprazole with omeprazole and lansoprazole, in combination with amoxycillin and clarithromycin. PATIENTS AND METHODS: 221 H. pylori-positive patients with peptic ulcer disease were randomized to receive one of three different proton pump inhibitor/amoxycillin-clarithromycin (PPI/AC) regimens for 7 days. (i) OAC regimen (n = 75): omeprazole 20 mg b.d., amoxycillin (AMOX) 500 mg t.d.s. and clarithromycin (CAM) 200 mg b.d.; (ii) LAC regimen (n = 74): lansoprazole 30 mg b.d. , AMOX 500 mg t.d.s. and CAM 200 mg b.d.; and (iii) RAC regimen (n = 72): rabeprazole 20 mg b.d., AMOX 500 mg t.d.s. and CAM 200 mg b.d. Cure of the infection was determined by the 13C urea breath test 1 month after completion of the treatment. RESULTS: Intention-to-treat based cure rates for OAC, LAC and RAC regimens were 85% (95% CI, 75-92), 84% (95%, CI 73-91) and 88% (95% CI, 78-94), respectively, and per protocol based cure rates of these regimens were 88% (95% CI, 78-94), 91% (95%, CI 82-99) and 93% (95% CI, 84-98), respectively. Adverse effects in the entire study population, which included diarrhoea, glossitis or skin rash, were reported by 15% of the patients, and complete compliance was achieved in 95% of these patients. CONCLUSION: 1-week proton pump inhibitor/AC regimens for H. pylori infection were effective in the Japanese population. Rabeprazole can be considered as equivalent to omeprazole and lansoprazole in the PPI/AC triple therapy.

Cure of Helicobacter pylori infection does not improve symptoms in non-ulcer dyspepsia patients-a double-blind placebo-controlled study.

BACKGROUND: It remains controversial whether the cure of H. pylori infection improves NUD symptoms. AIM: To conduct a double-blind placebo-controlled single centre study with concealed allocation to investigate this question. PATIENTS AND METHODS: Ninety NUD patients with H. pylori infection were randomly assigned to either the treatment group (50 patients) or placebo group (40 patients). The treatment group received omeprazole, amoxycillin, clarithromycin and the placebo group received omeprazole and placebos for 7 days. Symptoms were assessed every week for up to 12 weeks after completion of medication by a symptom questionnaire. Alteration of histological parameters for gastritis was also evaluated. RESULTS: The infection was cured in 41 out of 48 patients in the treatment group and none in the placebo group. There was no significant difference in the mean symptom scores at any assessment point up to 12 weeks between the treatment and placebo groups. Regarding histological parameters, activity and inflammation, not atrophy or intestinal metaplasia, were significantly improved in the treatment group. CONCLUSION: Although histological parameters were significantly improved in the treatment group, there was no significant improvement in symptoms of NUD in the treatment group compared to placebo.