Summary
Background
The features of proton pump inhibitor‐responsive oesophageal eosinophilia (PPI‐REE) are similar to those of eosinophilic oesophagitis (EoE), but PPI‐REE demonstrates symptomatic ...and histological responses to PPI therapy. Several studies have shown that basophils play a crucial role in the pathogenesis of allergic diseases.
Aim
To identify and compare basophil infiltration in the oesophageal epithelium in patients with EoE, PPI‐REE, gastroesophageal reflux disease (GERD) and normal oesophagus (controls).
Methods
Biopsy specimens from 43 patients, including 12 with EoE, 11 with PPI‐REE, 10 with GERD and 10 normal oesophagus, were analysed. Immunohistochemistry was performed to quantify the number of basophils and mast cells in the oesophageal epithelium. Double immunofluorescence staining for thymic stromal lymphopoietin (TSLP) and basophils was performed. Patients with EoE were treated with swallowed fluticasone.
Results
There were no differences in clinical, endoscopic or histological features between patients with EoE and PPI‐REE. There were more basophils and mast cells in patients with EoE and PPI‐REE than in patients with GERD and control subjects. Basophil infiltration of the oesophageal epithelium in patients with EoE was higher than that in patients with PPI‐REE (3.6 ± 2.8 per high power field vs. 1.2 ± 0.9 per high power field respectively; P = 0.02); however, there was no significant difference in mast cell infiltration between the two groups. TSLP was highly expressed in the oesophageal epithelium in areas infiltrated by basophils. Steroid therapy significantly decreased intraepithelial basophils in patients with EoE.
Conclusion
Basophils may play an important role in the pathogenesis of eosinophilic oesophagitis.
Enterobacteria and cytokines both play roles in the pathophysiology of NSAID-induced enteropathy. Toll-like receptor (TLR) 4 recognises lipopolysaccharide (LPS), resulting in activation of an ...inflammatory cascade via the accessory protein MyD88.
To investigate role of TLR4 in inflammatory responses in indomethacin-induced enteropathy.
Indomethacin was administered p.o. to non-fasting rats and mice to induce small intestinal damage. The extent of such damage was evaluated by measuring the injured area stained dark blue with Evans blue. Rats were given antibiotics (ampicillin, aztreonam or vancomycin) p.o., or intraperitoneal LPS (a TLR4 ligand) or neutralising antibodies against neutrophils, tumour necrosis factor (TNF)-alpha, or monocyte chemotactic protein (MCP)-1. Furthermore, the intestinal ulcerogenicity of indomethacin was examined in TLR4-mutant, TLR4(-/-), and MyD88(-/-) mice.
Indomethacin induced small intestinal damage with an increase in expression of TNF-alpha and MCP-1 in both rats and mice. Antibodies against neutrophils, TNF-alpha and MCP-1 inhibited the damage by 83%, 67% and 63%, respectively, in rats. Ampicillin and aztreonam also inhibited this damage, and decreased the number of Gram-negative bacteria in the small intestinal contents of the rat. However, vancomycin, which exhibited no activity against Gram-negative bacteria, had no preventive effect against this damage. Administration of LPS 1 h after indomethacin aggravated the damage, whereas LPS pretreatment inhibited it with reduction of expression of TLR4 and cytokines. In TLR4-mutant mice, the damage and cytokine expression were markedly inhibited. TLR4(-/-) and MyD88(-/-) mice were also resistant to the damage.
Indomethacin may injure the small intestine through a TLR4/MyD88-dependent pathway.
This study investigated whether weekly teriparatide (TPTD) injections are as effective as daily teriparatide injections for the treatment of stage 3 bisphosphonate-related osteonecrosis of the jaws ...(BRONJ) and compared serum markers of bone turnover between the two treatment regimens. Daily TPTD treatment has recently been reported to be effective for BRONJ, but there are no reports describing the effectiveness of weekly TPTD injections. We report two patients with stage 3 BRONJ. One patient was successfully treated with weekly TPTD injections and the other with daily TPTD injections. Changes in the levels of serum N-telopeptide of type I collagen (s-NTX) and serum N-terminal propeptide of type I collagen (P1NP) were studied. Two patients with stage 3 BRONJ that was refractory to conservative treatment were treated with TPTD. Their medical records were reviewed and the patients were interviewed. There was complete mucosal coverage of the intraoral defects after 3 months of TPTD treatment in both patients. Progressive bone regeneration in an area of mandibular fracture was identified after 4 months of treatment. The s-NTX level increased slightly in both patients. This is the first report of successful treatment of stage 3 BRONJ with weekly TPTD injections. Either daily or weekly TPTD injections may effectively treat stage 3 BRONJ and should be considered before or perhaps even in lieu of undertaking major resection and reconstruction.
This prospective study aimed to evaluate the feasibility and safety of locoregional mitomycin C (MMC) injection to treat refractory esophageal strictures after endoscopic submucosal dissection (ESD) ...for superficial esophageal carcinoma. Patients with dysphagia and strictures that were refractory to repeated endoscopic balloon dilation (EBD) were eligible. After EBD, MMC was injected into the dilated site. Between June 2009 and August 2010, five patients were recruited. The treatment was performed once in two patients and twice in three patients with recurrent dysphagia or restenosis. In all patients, passing a standard endoscope through the site was easy and the dysphagia grade improved (grade 3→1 in 3 patients, grade 4→2 in 2 patients). No serious complications were noted. During the observation period of 4.8 months, neither recurrent dysphagia nor re-stricture appeared in any of the patients. The combination of locoregional MMC injections and EBD is feasible and safe for the treatment of esophageal strictures after ESD.Recently, endoscopic submucosal dissection (ESD) has been developed and accepted as a new endoscopic treatment for gastrointestinal tumors. ESD is a promising treatment for superficial esophageal carcinoma (SEC), and it has a reliable en bloc resection rate. However, the application of ESD for widespread lesions is challenging because of the high risk of the development of severe strictures, which lead to a low quality of life after ESD. Although endoscopic balloon dilation (EBD) is effective for benign strictures, it needs to be performed frequently until the dysphagia disappears 1. Mitomycin C (MMC), which is a chemotherapeutic agent derived from some Streptomyces species 2, reduces scar formation when topically applied to a surgical lesion. MMC has been applied to treat strictures in a variety of anatomical locations, including a variety of organs 3. The aim of this study was to prospectively evaluate both the feasibility and the safety of locoregional MMC injection therapy in patients with refractory esophageal strictures after ESD for SEC.
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.
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.
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.
Despite a considerable placebo effect, the benefits of tandospirone were shown in terms of improvement in abdominal symptom scores.
Background
Enteric glial cells (EGCs) play important roles in enteric integrity and regulation of gastrointestinal function. However, whether EGCs undergo pathophysiological changes in ...stress‐associated gastrointestinal disorders is unknown. We investigated structural and functional alterations in colonic EGCs and their roles in colonic contraction in an irritable bowel syndrome (IBS) model.
Methods
As a chronic stress, male Wistar rats underwent 3‐h maternal separation during postnatal days 2–14. As an acute stress, we used water‐immersion stress (4 h) in adulthood (at 8 weeks). We quantitatively and morphologically evaluated enteric neurons and EGCs using whole‐mount longitudinal muscle‐myenteric plexus preparations. Colonic contraction was analyzed with electrical field stimulation (EFS).
Key Results
Glial fibrillary acidic protein (GFAP) expression and the number of total, cholinergic, and nitrergic neurons were unchanged in maternally separated rats with acute stress (combined stress: an IBS model) compared with controls. However, the density of GFAP‐positive EGC processes that apparently overlapped with the neurons and the extent of bulbous swelling of terminals increased according to the stress intensity: control, acute stress, maternal separation, and combined stress. EFS‐induced colonic contractions were significantly greater in the combined stress rats than in controls. Higher dose of fluorocitrate, a selective inhibitor of EGC metabolism, was required to inhibit both EFS‐induced contraction and EGCs activation in the combined stress rats than in controls.
Conclusions & Inferences
Colonic EGCs exhibited structural alterations according to the stress intensity. EGCs were associated with stress‐induced colonic hyper‐contraction in the combined stress rats, which may underlie the pathogenesis of IBS.
Enteric glial cells (EGCs) play important roles in the regulation of gastrointestinal function, but manifestations of colonic EGCs in irritable bowel syndrome (IBS) patients remain unknown. EGCs exhibited hyperplasia of their processes that apparently overlapped with the neurons and changes in bulbous swelling of terminals, and were also associated with stress‐induced hyper colonic contraction in the maternally separated rats. Such changes in EGCs may underlie the pathogenesis of IBS.
Bruxism is a repetitive jaw-muscle activity characterized by clenching or grinding of the teeth and/or bracing or thrusting of the mandible. Recent advances have clarified the relationship between ...gastroesophageal reflux and sleep bruxism (SB). However, the influence of pharmacological elimination of gastric acid secretion on SB has not been confirmed. The authors aimed to assess the efficacy of a proton pump inhibitor (PPI) on SB and to examine the gastrointestinal (GI) symptoms and endoscopic findings of the upper GI tract in SB patients. The authors performed a randomized double-blind placebo-controlled crossover study at Kagoshima University Hospital. Twelve patients with polysomnography (PSG)–diagnosed SB underwent an assessment of GI symptoms using the frequency scale for the symptoms of gastroesophageal reflux disease (FSSG) and esophagogastroduodenoscopy. At baseline (i.e., before interventions), the mean frequencies of electromyography (EMG) bursts and rhythmic masticatory muscle activity (RMMA) episodes were 65.4 ± 49.0 bursts/h and 7.0 ± 4.8 episodes/h, respectively, and at least 1 RMMA episode with grinding noise was confirmed in all participants. The mean FSSG score was 8.4 ± 5.6, and 41.7% of patients were diagnosed with gastroesophageal reflux disease. Mild reflux esophagitis was confirmed in 6 patients. PSG, including EMG of the left masseter muscle and audio-video recording, was performed on days 4 and 5 of administration of 10 mg of the PPI (rabeprazole) or placebo. PPI administration yielded a significant reduction in the frequency of EMG bursts, RMMA episodes, and grinding noise. No significant differences were observed regarding the swallowing events and sleep variables. Since the clinical application of PPI for SB treatment should remain on hold at present, the results of this trial highlight the potential application of pharmacological gastroesophageal reflux disease treatment for SB patients. Larger scale studies are warranted to corroborate these findings. (UMIN Clinical Trials Registry: UMIN000004577).
Objective
To develop a model of osteonecrosis using oral bisphosphonate in ovariectomy‐induced osteoporotic rats.
Materials and Methods
Thirty‐six rats were subjected to ovariectomy or sham surgery. ...After 8 weeks, rats received oral alendronate (1.0 mg kg−1) or saline once weekly for 4 weeks; then, serum C‐telopeptide cross‐linked collagen type I levels were measured to evaluate bone metabolism. Twelve rats from each group were injected with either lipopolysaccharide or saline into the bone marrow of the mandibles and femurs, and the areas of osteonecrosis were evaluated by histomorphometry.
Results
Serum C‐telopeptide cross‐linked collagen type I levels were significantly increased in the ovariectomy group (105.1 ± 2.1 ng ml−1) compared with the sham group (78.9 ± 12.5 ng ml−1); they were significantly reduced following oral alendronate administration in the ovariectomy group (91.0 ± 4.4 ng ml−1). Following alendronate and lipopolysaccharide administration, extensive osteonecrosis was observed in the mandibles and femurs of ovariectomy (0.45 ± 0.08 mm2, 1.69 ± 0.72 mm2, respectively) and sham (1.12 ± 0.45 mm2, 1.84 ± 0.66 mm2, respectively) groups. Significantly wider osteonecrosis occurred in the mandibles of sham‐operated rats than ovariectomy rats following alendronate or lipopolysaccharide treatment.
Conclusions
We successfully developed a model of osteonecrosis in ovariectomised rats following oral bisphosphonate administration.
Summary
Background
The efficacy of proton pump inhibitors (PPIs) for treating functional dyspepsia (FD) is not well established.
Aim
This study, named the SAMURAI study, aimed to assess the efficacy ...and dose–response relationship of rabeprazole in Japanese patients with FD in a multicentre, double‐blinded, randomised, placebo‐controlled trial.
Methods
Investigated FD was diagnosed using the Rome III criteria. Subjects who did not respond to 1 week of single‐blind placebo treatment in a run‐in period were randomly assigned to 8 weeks of double‐blind treatment with rabeprazole 10 mg, 20 mg, 40 mg or placebo, once daily. Dyspeptic symptoms were assessed by a dyspepsia symptom questionnaire (7‐point Likert scale) and symptom diary.
Results
Of 392 subjects entered into the run‐in period, 338 were randomly assigned. Although there was no significant difference between placebo and rabeprazole groups in complete symptom relief for four major dyspeptic symptoms, the satisfactory symptom relief of rabeprazole 20 mg was significantly higher than placebo according to the dyspepsia symptom questionnaire (45.3% vs. 28.2%, P = 0.027) and the symptom diary assessment (48.7% vs. 30.0%, P = 0.016). The efficacy was not influenced by syndrome type or Helicobacter pylori status. No statistically significant differences in the incidence of adverse events were seen among treatment groups.
Conclusions
Rabeprazole 20 mg once daily but not 10 or 40 mg significantly provides satisfactory symptom relief for functional dyspepsia (ClinicalTrials.gov, Number NCT01089543).
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