Effects of Pt dispersion on electronic and oxide ionic conductivity in Pr1.90Ni0.71Cu0.24Ga0.05O4.

The effects of dispersing Pt particles in bulk Pr1.90Ni0.71Cu0.21Ga0.05O(4+δ) (PNCG) on the electrical conductivity and oxygen permeability of the material were studied. The different thermal expansion coefficients of PNCG and Pt generated a mechanical compressive strain in the PNCG. This may cause the electrical conductivity to decrease in samples containing Pt. In contrast, the oxide ion conductivity estimated from the oxygen permeability increased upon dispersion of Pt. These variations appear to be related to the electron hole and interstitial oxygen concentrations. Moreover, the present study suggests that the mechanical strain induces a chemical strain via the introduction of oxygen defects as well as changes in cation valences.

Characteristics of nighttime reflux assessed using multichannel intraluminal impedance pH monitoring and a portable electroencephalograph.

Gastroesophageal reflux disease (GERD) is strongly associated with sleep disturbances. Although the mechanisms of this association have not been fully elucidated, nighttime reflux plays a central role. However, the detailed characteristics of nighttime reflux occurring during sleep are unknown. The aim of the present study was to examine the characteristics and prevalence of nighttime reflux in the natural sleep environment of GERD patients. Seventeen patients experiencing daily moderate-to-severe heartburn and/or regurgitation were studied using multichannel intraluminal impedance pH monitoring and electroencephalography off-proton pump inhibitor treatment. Nighttime reflux was divided based on reflux type (liquid or gas), acidity (acidic, weakly acidic, or alkaline) and extent (distal only or proximal migration) according to the standard criteria. Nighttime phases were divided as follows: recumbent-awake before falling asleep, nonrapid eye movement, rapid eye movement, awakening from sleep, and post-awakening in the morning. Among 184 nighttime refluxes, 43 (23%) occurred during recumbent-awake before falling asleep, 28 (15%) during nonrapid eye movement, 14 (8%) during rapid eye movement, 86 (46%) during awakening from sleep, and 13 (7%) during post-awakening in the morning. Liquid reflux was more common in awakening during sleep (92%), nonrapid eye movement (100%), and rapid eye movement (100%) compared with awakening before falling asleep (68%). The prevalence of proximal migration was significantly lower in nonrapid eye movement and rapid eye movement than in the other phases. There were no differences in acidity and bolus clearance time among the phases. Thirteen (65%) of 20 events with GERD symptoms had nighttime reflux, suggesting that only 7.1% (13 of 184) of nighttime refluxes were symptomatic. Nighttime reflux was observed in 48 (11%) of 425 awakening episodes during sleep. Different reflux patterns at each phase during nighttime might explain the pathogenesis of GERD and its related sleep disturbances.

Alterations in 18F-FDG accumulation into neck-related muscles after neck dissection for patients with oral cancers.

BACKGROUND: 18F-fluoro-2-deoxy-D-glucose (18F-FDG) accumulations are commonly seen in the neck-related muscles of the surgical and non-surgical sides after surgery with neck dissection (ND) for oral cancers, which leads to radiologists having difficulty in diagnosing the lesions. To examine the alterations in 18F-FDG accumulation in neck-related muscles of patients after ND for oral cancer. MATERIAL AND METHODS: 18F-FDG accumulations on positron emission tomography (PET)-computed tomography (CT) in neck-related muscles were retrospectively analyzed after surgical dissection of cervical lymph nodes in oral cancers. RESULTS: According to the extent of ND of cervical lymph nodes, the rate of patients with 18F-FDG-PET-positive areas increased in the trapezius, sternocleidomastoid, and posterior neck muscles of the surgical and/or non-surgical sides. In addition, SUVmax of 18F-FDG-PET-positive areas in the trapezius and sternocleidomastoid muscles were increased according to the extent of the ND. CONCLUSIONS: In evaluating 18F-FDG accumulations after ND for oral cancers, we should pay attention to the 18F-FDG distributions in neck-related muscles including the non-surgical side as false-positive findings.

Intraoperative detection of viable bone with fluorescence imaging using Visually Enhanced Lesion Scope in patients with bisphosphonate-related osteonecrosis of the jaw: clinical and pathological evaluation.

UNLABELLED: There is no standard surgical protocol of bisphosphonate-related osteonecrosis of the jaws (BRONJ), because of the impossibility to visualize this feature intraoperatively. The aim of this study was to introduce how to provide preoperative labeling of the viable bone with minocycline bone fluorescence technique (MBFT) by using VELscope® and investigate histopathologically. INTRODUCTION: The American Association of Oral and Maxillofacial Surgeons (AAOMS) and the Japanese Society of Oral and Maxillofacial Surgeons (JSOMS) now recommend a more conservative treatment strategy. There is no standard surgical protocol of bisphosphonate-related osteonecrosis of the jaws (BRONJ) because of the impossibility to visualize this feature intraoperatively. The aim of this study was to introduce a mechanism providing preoperative labeling of a viable bone using minocycline bone fluorescence technique (MBFT) with VELscope® and to histopathologically investigate. METHODS: This report describes a surgical technique used in six patients with BRONJ who underwent jawbone resection under minocycline bone fluorescence imaging using VELscope®. Subsequently, we investigated and compared the clinical findings using VELscope® and histopathological findings. RESULTS: Histopathological examinations showed that the non-fluorescent moiety was consistent with the BRONJ lesions. CONCLUSIONS: The surgical treatments that were exactly performed using MBFT with VELscope® offered successful management of BRONJ. This bone fluorescence helped to define the margins of resection, thus improving surgical therapy for extended osteonecrosis.

Increased prevalence of group A streptococcus isolates in streptococcal toxic shock syndrome cases in Japan from 2010 to 2012.

Streptococcal toxic shock syndrome (STSS) is a severe invasive infection characterized by the sudden onset of shock, multi-organ failure, and high mortality. In Japan, appropriate notification measures based on the Infectious Disease Control law are mandatory for cases of STSS caused by ß-haemolytic streptococcus. STSS is mainly caused by group A streptococcus (GAS). Although an average of 60-70 cases of GAS-induced STSS are reported annually, 143 cases were recorded in 2011. To determine the reason behind this marked increase, we characterized the emm genotype of 249 GAS isolates from STSS patients in Japan from 2010 to 2012 and performed antimicrobial susceptibility testing. The predominant genotype was found to be emm1, followed by emm89, emm12, emm28, emm3, and emm90. These six genotypes constituted more than 90% of the STSS isolates. The number of emm1, emm89, emm12, and emm28 isolates increased concomitantly with the increase in the total number of STSS cases. In particular, the number of mefA-positive emm1 isolates has escalated since 2011. Thus, the increase in the incidence of STSS can be attributed to an increase in the number of cases associated with specific genotypes.

An osteonecrosis model induced by oral bisphosphonate in ovariectomised rats.

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 mm(2) , 1.69 ± 0.72 mm(2) , respectively) and sham (1.12 ± 0.45 mm(2) , 1.84 ± 0.66 mm(2) , 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.

Weekly teriparatide injections successfully treated advanced bisphosphonate-related osteonecrosis of the jaws.

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.

A prospective randomized study on the benefits of a new small-caliber colonoscope.

BACKGROUND AND STUDY AIMS: We compared the performance efficiency of a newly developed small-caliber colonoscope (PCF-PQ260 L) with passive bending, high force transmission, and an outer diameter of 9.2 mm with that of a standard colonoscope, in female and male patients, particularly with regard to passage through acute angulations or into the proximal colon. PATIENTS AND METHODS: A total of 330 patients were randomly allocated to undergo small-caliber (n = 164) or standard (n = 166) colonoscopy. The patients were assessed for pain using a visual analogue scale (0 = none, 100 = extremely painful), and for cecal intubation, withdrawal time, difficulty of colonoscopy, dosage and level of sedation used, and any complications. RESULTS: Median maximum pain and overall pain during colonoscopy were significantly lower in the small-caliber group than in the standard group in women (25 vs. 45, P < 0.001 and 15 vs. 26, P = 0.001, respectively), whereas no significant differences were seen in men (8 vs. 10, P = 0.103 and 16 vs. 20, P = 0.166, respectively). Furthermore, no significant differences were seen between groups in cecal intubation rate or time to cecum in all patients or by sex. CONCLUSIONS: Use of the small-caliber colonoscope reduced pain in female patients, but offered no advantage over standard colonoscopy in male patients. The performance of the small-caliber colonoscope was equivalent to that of the standard colonoscope in terms of cecal intubation rate and time to cecum, regardless of the sex of the patient.

Locoregional mitomycin C injection for esophageal stricture after endoscopic submucosal dissection.

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.

Tongue Muscle for the Analysis of Head Muscle Regeneration Dynamics.

Tongue muscle damage impairs speaking and eating, thereby degrading overall health and quality of life. Skeletal muscles of the body are diverse in embryonic origin, anatomic location, and gene expression profiles. Responses to disease, atrophy, aging, or drugs vary among different muscles. Currently, most muscle studies are focused on limb muscles and the tongue is neglected. The regenerative ability of tongue muscle remains unknown, and thus there is need for tongue muscle research models. Here, we present a comprehensive characterization of the spatiotemporal dynamics in a mouse model of tongue muscle regeneration and establish a method for the isolation of primary tongue-derived satellite cells. We compare and contrast our observations with the tibialis anterior (TA) limb muscle. Acute injury was induced by intramuscular injection of cardiotoxin, a cytolytic agent, and examined at multiple timepoints. Initially, necrotic myofibers with fragmented sarcoplasm became infiltrated with inflammatory cells. Concomitantly, satellite cells expanded rapidly. Seven days postinjury, regenerated myofibers with centralized nuclei appeared. Full regeneration, as well as an absence of fibrosis, was evident 21 d postinjury. Primary tongue-derived satellite cells were isolated by enzymatic separation of tongue epithelium from mesenchyme followed by magnetic-activated cell sorting. We observed that tongue displays an efficient regenerative response similar to TA but with slightly faster kinetics. In vitro, tongue-derived satellite cells differentiated robustly into mature myotubes with spontaneous contractile behavior and myogenic marker expression. Comparison of gene expression signatures between tongue and TA-derived satellite cells revealed differences in the expression of positional-identity genes, including the HOX family. In conclusion, we have established a model for tongue regeneration useful for investigations of orofacial muscle biology. Furthermore, we showed that tongue is a viable source of satellite cells with unique properties and inherited positional memory.

Increased numbers of immature plasma cells in peripheral blood specifically overexpress chemokine receptor CXCR3 and CXCR4 in patients with ulcerative colitis.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease featuring infiltration by plasma cells producing immunoglobulins. We have reported previously the specific and significant proliferation of immature plasma cells in the inflamed colonic and pouch mucosa of UC patients. The aim of this study was to characterize peripheral blood immature plasma cells and the migration mechanisms of such immature plasma cells to inflamed sites in UC. The characteristics of peripheral blood immature plasma cells and chemokine receptor expression were examined by flow cytometry. Expression of mucosal chemokine was quantified using real-time reverse transcription-polymerase chain reaction and immunohistochemistry. The number of peripheral blood immature plasma cells was significantly higher in patients with active UC and active Crohn's disease (CD) than in healthy controls. The proportion of immature plasma cells was correlated positively with clinical activities of UC and CD. Many peripheral blood immature plasma cells were positive for CXCR3, CXCR4, CCR9 and CCR10. Expression of CXCR3 and CXCR4 in UC patients was significantly higher than in controls. CXCL9, CXCL10 and CXCL11 mRNA levels in colonic mucosa of inflamed IBD were higher than in controls. Immunofluorescence study also showed abundant CXCR3-positive immature plasma cells in the inflamed colonic mucosa of UC. Increased numbers of immature plasma cells may migrate towards inflammatory sites of UC via the CXCR3 axis, and may participate in UC pathogenesis.

The cellular and molecular mechanisms of bone invasion by oral squamous cell carcinoma.

Oral squamous cell carcinomas (SCCs) are malignant tumours that frequently invade the mandibular bone and bone invasion is a common clinical problem. Recent studies have revealed that bone resorption by osteoclasts is an important step in the process of bone invasion by oral SCCs. However, the cellular and molecular mechanisms of bone invasion by oral SCCs remain unclear. Oral SCCs invade the mandibular bone through an erosive, mixed or infiltrative pattern that correlates with clinical behaviours. The expressions of interleukin (IL)-6, IL-11, tumour necrosis factor (TNF) α and parathyroid hormone-related protein (PTHrP) were higher in the infiltrative pattern than in the erosive pattern. These cytokines lead to receptor activator of NF-κB ligand (RANKL) expression or osteoprotegerin (OPG) suppression not only in oral SCC cells but also in cancer stromal cells to induce osteoclastogenesis. Taken together, oral SCCs provide a suitable microenvironment for osteoclastogenesis to regulate the balance of RANKL and OPG. In this review, we introduce recent advances in the knowledge of the cellular and molecular mechanisms, by which oral SCC invades mandibular bone based on the recent findings of our lab and others.

The Traditional Japanese Medicine Rikkunshito Promotes Gastric Emptying via the Antagonistic Action of the 5-HT(3) Receptor Pathway in Rats.

The traditional Japanese medicine rikkunshito ameliorates the nitric oxide-associated delay in gastric emptying. Whether rikkunshito affects gastric motility associated with 5-hydroxytryptamine (serotonin: 5-HT) receptors or dopamine receptors is unknown. We examined the effects of rikkunshito on the delay in gastric emptying induced by 5-HT or dopamine using the phenol red method in male Wistar rats. 5-HT (0.01-1.0 mg kg(-1), i.p.) dose dependently delayed gastric emptying, similar to the effect of the 5-HT(3) receptor agonist 1-(3-chlorophenyl) biguanide (0.01-1.0 mg kg(-1), i.p.). Dopamine also dose dependently delayed gastric emptying. The 5-HT(3) receptor antagonist ondansetron (0.04-4.0 mg kg(-1)) and rikkunshito (125-500 mg kg(-1)) significantly suppressed the delay in gastric emptying caused by 5-HT or 1-(3-chlorophenyl) biguanide. Hesperidin (the most active ingredient in rikkunshito) suppressed the 5-HT-induced delayed gastric emptying in a dose-dependent manner, the maximum effect of which was similar to that of ondansetron (0.4 mg kg(-1)). The improvement obtained by rikkunshito or ondansetron in delaying gastric emptying was completely blocked by pretreatment with atropine. Rikkunshito appears to improve delay in gastric emptying via the antagonistic action of the 5-HT(3) receptor pathway.

Heavy chain subclasses of human gamma G-globulin. Serum distribution and cellular localization.

Two antigenic types of naturally occurring proteins related to the papain produced F(c) fragment of gammaG-globulin have been studied. Most normal and myeloma gammaG-globulins are related to one or the other of these proteins, based on antigenic and structural characteristics of their heavy chain. Molecules bearing the determinant "Cr" are approximately 10 times as abundant as those bearing the determinant termed "Zu" in pools of normal gammaG-globulin and among a large group of gammaG-myeloma globulins. Both populations have properties of typical gammaG-globulin antibodies. Splenic cells, stained for these two populations with specific fluorescent antibody preparations, are found to contain one or the other of the two populations of gammaG-globulin, but not both. Approximately 10 times as many cells contain the Cr determinant as contain the Zu determinant.

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.

Long-term efficacy of Helicobacter pylori eradication in patients with idiopathic thrombocytopenic purpura: 7-year follow-up prospective study.

Helicobacter pylori eradication is useful for improvement of a half of patients with idiopathic thrombocytopenic purpura (ITP), but its long-term therapeutic efficacy has not been elucidated. We investigated the long-term efficacy of H. pylori eradication in 30 cases with ITP that were included in our previous study regarding the association between H. pylori infection and ITP. Twenty-one cases were positive and nine cases were negative for H. pylori infection. H. pylori eradication therapy including secondary regimen was successful in 20 cases, half (responder) of whom showed ITP remission 1 month later. Nine responders could be followed up for a long time and did not show re-infection of H. pylori. Eight of nine needed no medication except for eradication therapy. Another case remained in remission for 1 year but thereafter needed a steroid therapy due to the recurrence. Eight nonresponders could be followed up for a long time. All these cases showed a bad clinical course even though they received the other post-treatments including steroid therapy. Three of nine H. pylori-negative cases underwent eradication therapy after obtaining the written informed consent, but none of them showed improvement. Of these three cases, two cases could be followed up. Only one case remained a remission although receiving corticosteroid as a post-treatment. Conditions of H. pylori-negative ITP cases were usually unstable for a long time. H. pylori eradication has a short-term efficacy for about half of H. pylori-positive ITP patients, and the responders to the eradication therapy may receive a long-term clinical benefit without other therapies.

A novel rat model to determine interaction between reflux oesophagitis and bronchial asthma.

BACKGROUND: Several studies have shown a strong association between reflux oesophagitis (RO) and bronchial asthma (BA). The precise mechanisms of interaction between RO and BA are uncertain, possibly due to lack of animal models. AIMS: We established a novel rat model and examined pathogenic interaction of RO and BA. METHODS: RO and BA were induced in Brown-Norway rats by ligating the transitional region between the forestomach and the glandular portion and wrapping the duodenum near the pylorus, and by ovalbumin (OVA) sensitisation and challenge with OVA aerosol. Rats were divided into four groups: control, RO, BA, and RO+BA. OVA-induced airway inflammation was assessed by the number of infiltrating cells and cytokine levels in bronchoalveolar lavage fluid (BALF). Oesophageal lesion index, histology and expression of cytokine mRNA, as determined by real-time RT-PCR, were also examined. RESULTS: Significant increases in the number of cells, especially eosinophils, and IL13 but not IFN-gamma concentration in BALF were observed in the RO+BA group compared with the BA group. These enhancements of OVA-induced airway inflammation were prevented by treatment with rabeprazole. Although the oesophagitis lesion index in the RO+BA group did not differ from that in the RO group, eosinophilic infiltration in the oesophageal submucosa and levels of mRNA expression of cytokines such as IL5, IL10, IL13, and RANTES were significantly increased. CONCLUSION: We established a novel rat model of RO and BA, and found significant interactions of the two diseases. This model thus appears to be useful for examining the association between gastro-oesophageal reflux disease and bronchial asthma.

Non-steroidal anti-inflammatory drug-induced small intestinal damage is Toll-like receptor 4 dependent.

BACKGROUND: 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. AIMS: To investigate role of TLR4 in inflammatory responses in indomethacin-induced enteropathy. METHODS: 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. RESULTS: 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. CONCLUSIONS: Indomethacin may injure the small intestine through a TLR4/MyD88-dependent pathway.