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ManoScan and Sandhill high-resolution manometry (HRM) systems are used worldwide; however, the diagnosis of achalasia on the Starlet HRM system is not fully characterized. Furthermore, the impact of calcium channel blockers and nitrites in treating achalasia has not been investigated using HRM. Management of recurrent cases is a priority issue, although few studies have examined patient characteristics.We conducted a multicenter, large-scale database analysis. First, the diagnosis of treatment-naive achalasia in each HRM system was investigated. Next, patient characteristics were compared between type I-III achalasia, and the impact of patient characteristics, including calcium channel blocker and nitrite use for integrated relaxation pressure (IRP) values, were analyzed. Finally, patient characteristics with recurrent achalasia were elucidated.The frequency of type I achalasia with Starlet was significantly higher than that with ManoScan and Sandhill HRM systems. In achalasia, multivariate analysis identified male sex, advanced age, long disease duration, obesity, type I achalasia, and sigmoid type as risk factors related to normal IRP values (26 mmHg). Calcium channel blockers and nitrites use had no significant impact on the IRP values, although achalasia symptoms were indicated to be alleviated. In recurrent cases, the IRP value was significantly lower, and advanced age, long disease duration, and sigmoid type were more common than in treatment-naive patients.We should cautiously interpret the type of achalasia and IRP values in the Starlet HRM system. Symptoms of recurrent cases are related to disease progression rather than IRP values, which should be considered in decision making.

The risk of bleeding after gastric endoscopic submucosal dissection (ESD) in antithrombotic agent users has increased, and its management remains a problem. Second-look endoscopy (SLE) following gastric ESD in antithrombotic agent users may be effective in preventing delayed bleeding, but this requires elucidation. Therefore, this study aimed to investigate the efficacy of SLE in reducing bleeding after gastric ESD in patients receiving antithrombotic agents.This retrospective cohort study was conducted at 19 referral hospitals in Japan. A total of 1,245 patients who were receiving antithrombotic agents underwent gastric ESD between January 2013 and July 2018. The incidence of delayed bleeding was compared between SLE and non-SLE groups using propensity score matching analysis.Overall, 858 patients (SLE group, 657 patients; non-SLE group, 201 patients) were analyzed. After matching, 198 pairs were created. Delayed bleeding occurred in 10 patients (5.1%) in the SLE group and 16 patients (8.1%) in the non-SLE group [odds ratio (OR) 0.605, 95% confidence interval (CI) 0.23-1.46, p = 0.310]. In the subgroup analysis, SLE reduced the incidence of delayed bleeding in patients receiving heparin bridging therapy (6.3% and 40.0%, respectively; p = 0.004). In the SLE group, prophylactic coagulation did not significantly reduce delayed bleeding compared to the no treatment group (14.6% and 8.6%, respectively; p = 0.140).SLE was ineffective in reducing bleeding after gastric ESD in antithrombotic agent users, overall. A prospective comparative study is warranted to definitively evaluate the effectiveness of SLE in reducing bleeding in high-risk patients.

Patients with achalasia-related esophageal motility disorders (AEMDs) frequently present with dilated and sigmoid esophagus, and develop esophageal diverticulum (ED), although the prevalence and patients characteristics require further elucidation.We conducted a multicenter cohort study of 3707 patients with AEMDs from 14 facilities in Japan. Esophagography on 3682 patients were analyzed.Straight (n = 2798), sigmoid (n = 684), and advanced sigmoid esophagus (n = 200) were diagnosed. Multivariate analysis revealed that long disease duration, advanced age, obesity, and type I achalasia correlate positively, whereas severe symptoms and integrated relaxation pressure correlate negatively with development of sigmoid esophagus. In contrast, Grade II dilation (3.5-6.0 cm) was the most common (52.9%), while grade III dilation (≥ 6 cm) was rare (5.0%). We found early onset, male, obesity, and type I achalasia correlated positively, while advanced age correlated negatively with esophageal dilation. Dilated and sigmoid esophagus were found mostly in types I and II achalasia, but typically not found in spastic disorders. The prevalence of ED was low (n = 63, 1.7%), and non-dilated esophagus and advanced age correlated with ED development. Patients with right-sided ED (n = 35) had a long disease duration (The etiologies of dilated esophagus, sigmoid esophagus, and ED are considered multifactorial and different. Early diagnosis and optimal treatment of AEMDs are necessary to prevent these conditions.

Background Gastroesophageal reflux disease (GERD) and reflux esophagitis remain problems after peroral endoscopic myotomy (POEM). This study aimed to elucidate the risk factors and long-term course of reflux esophagitis and symptomatic GERD after POEM. Methods This multicenter cohort study involved 14 high volume centers. Overall, 2905 patients with achalasia-related esophageal motility disorders treated with POEM were analyzed for reflux esophagitis, severe reflux esophagitis (Los Angeles classification C or D), and symptomatic GERD. Results Reflux esophagitis was diagnosed in 1886 patients (64.9 %). Age ≥ 65 years (risk ratio [RR] 0.85), male sex (RR 1.11), posterior myotomy (RR 1.12), esophageal myotomy > 10 cm (RR 1.12), and gastric myotomy > 2 cm (RR 1.17) were independently associated with reflux esophagitis. Severe reflux esophagitis was diagnosed in 219 patients (7.5 %). Age ≥ 65 years (RR 1.72), previous treatments (RR 2.21), Eckardt score ≥ 7 (RR 0.68), sigmoid-type achalasia (RR 1.40), and esophageal myotomy > 10 cm (RR 1.59) were factors associated with severe reflux esophagitis. Proton pump inhibitors (PPIs) were more effective for reflux esophagitis at 5-year follow-up (P = 0.03) than after 1 year (P = 0.08). Symptomatic GERD was present in 458 patients (15.9 %). Symptom duration ≥ 10 years (RR 1.28), achalasia diagnosis (RR 0.68), integrated relaxation pressure ≥ 26 (RR 0.60), and posterior myotomy (RR 0.80) were associated with symptomatic GERD. The incidence of symptomatic GERD was lower at 5-year follow-up compared with that after 1 year (P = 0.04), particularly in PPI users (P Conclusions The incidence of severe reflux esophagitis was low after POEM, but excessive myotomy for older patients with previous treatments should be avoided. Early phase symptomatic GERD is non-acid reflux dependent and the natural course is favorable, basically supporting conservative treatment.

No prediction scores for the mortality of both inpatients and outpatients who developed nonvariceal upper gastrointestinal bleeding (UGIB) without endoscopic findings have been established. We aimed to derive and validate a novel prediction score for in-hospital mortality. We conducted a three-stage, multicenter retrospective study. In the derivation stage, patients with nonvariceal UGIB at six institutions were enrolled to derive the prediction score by logistic regression analysis. External validation of the score was performed to analyze discrimination by patients at six other institutions. Then the performance of this score was compared with that of four existing scores. We enrolled 1380 and 825 patients in the derivation and validation cohorts, respectively. A prediction score (CHAMPS-R Score) comprising seven variables (Charlson Comorbidity Index ≥ 2, in-hospital onset, albumin

Peroral endoscopic myotomy (POEM) is conducted for patients with esophageal motility disorders based on high-resolution manometry (HRM) findings. However, the impact of POEM on HRM findings and the associations between post-POEM HRM and outcomes have not been clarified.In a multicenter, observational cohort study, patients with achalasia treated by POEM received follow-up HRM. Associations between patient characteristics, POEM procedures, and post-POEM HRM findings, including integrated relaxation pressure (IRP) and distal contractile integral (DCI), were investigated. Furthermore, the outcomes of the POEM procedure were compared with the post-POEM HRM findings.Of 2,171 patients, 151 (7.0%) showed residual high post-POEM IRP (≥26 mmHg, Starlet). In a multivariate analysis, high pre-POEM IRPs (odds ratio [OR]=24.3) and gastric myotomy2 cm (OR=0.22) were found to be positive and negative predictive factors of high post-POEM IRPs, respectively. Peristalsis recovery (DCI ≥500 mmHg-cm-sec, at least one swallow, Starlet) was visible in 121 (19.6%) of 618 patients, and they were type II-III achalasia. High pre-POEM IRP (OR=2.65) and DCI ≥500 (OR=2.98) predicted peristalsis recovery, while esophageal dilation (OR=0.42) predicted a risk of no recovery. Extended myotomy did not reveal a significant impact on peristalsis recovery. High or low post-POEM IRP and DCI did not increase the incidence of clinical failure, reflux esophagitis, or symptomatic gastroesophageal reflux disease.Extended gastric myotomy decreased IRP values, while peristalsis recovery depended on the characteristics of achalasia. A residual high post-POEM IRP does not necessarily mean clinical failure. Routine HRM follow-up is not recommended after POEM.

Background Peroral endoscopic myotomy (POEM) is effective for the management of achalasia and its variants; however, it can be ineffective in some patients. We aimed to develop and validate a risk scoring system to predict the clinical failure of POEM preoperatively. Methods Consecutive patients who underwent POEM in 14 high volume centers between 2010 and 2020 were enrolled in this study. Clinical failure was defined as an Eckardt score of ≥ 4 or retreatment. A risk scoring system to predict the short-term clinical failure of POEM was developed using multivariable logistic regression and internally validated using bootstrapping and decision curve analysis. Results Of the 2740 study patients, 112 (4.1 %) experienced clinical failure 6 months after POEM. Risk scores were assigned for three preoperative factors as follows: preoperative Eckardt score (1 point), manometric diagnosis (−4 points for type II achalasia), and a history of prior treatments (1 point for pneumatic dilation or 12 points for surgical/endoscopic myotomy). The discriminative capacity (concordance statistics 0.68, 95 %CI 0.62–0.72) and calibration (slope 1.15, 95 %CI 0.87–1.40) were shown. Decision curve analysis demonstrated its clinical usefulness. Patients were categorized into low (0–8 points; estimated risk of clinical failure Conclusions This risk scoring system can predict the clinical failure of POEM preoperatively and provide useful information when making treatment decisions.

Esophageal endoscopic submucosal dissection (ESD) is considered to be more complex than gastric ESD. This study aimed to assess the physical invasiveness of esophageal ESD during perioperative periods by measuring resting energy expenditure (REE). The factors affecting REE that could be used to identify patients requiring perioperative management were also investigated. Overall, 75 patients who had undergone esophageal ESD were prospectively enrolled. REE, body weight, and basal energy expenditure were measured on the day of and the day following ESD. The mean REE/body weight was 20.2 kcal/kg/day on the day of ESD and significantly increased to 23.0 kcal/kg/day one day after ESD. The stress factor on the day after ESD was 1.11. White blood cell, neutrophil, and C-reactive protein levels increased on the day after ESD and correlated with the changes in REE. Among the factors including age, body mass index, total resection area, operation time, and sarcopenia, only the total resection area was associated with changes in REE. In conclusion, energy metabolism increases during the perioperative period for esophageal ESD. The increase in the stress factor for esophageal ESD was higher than that in gastric and colorectal ESD. Furthermore, patients with large resection areas require greater attention in perioperative management.

Little is known about the prognostic factors for survival after endoscopic submucosal dissection (ESD) in elderly patients with early gastric cancer (EGC). The aim of this study is to determine prognostic factors and a prediction model of 3-year survival after ESD for EGC in patients aged ≥ 85 years.We retrospectively evaluated the clinical outcomes of 740 patients with EGC aged ≥ 85 years, who were treated by ESD at 30 institutions in Japan. Overall survival (OS) and disease-specific survival (DSS) were calculated with the Kaplan-Meier method. Prediction models for 3-year OS after ESD were estimated using the Cox proportional hazards model based on Uno's C-statistics.During the follow-up period, 309 patients died of any cause and 10 patients died of gastric cancer. OS and DSS after 3 years were 82.7% and 99.2%, respectively. No significant differences in OS were found among curability categories. The Cox proportional hazards model revealed the geriatric nutritional risk index (GNRI) and the Charlson comorbidity index (CCI) to be predictors of 3-year survival. We established a final model (EGC-2 model) expressed by GNRI - (2.2×CCI) with a cutoff value of 96. The overall survival rate was significantly lower in the model value 96 group than in the model value ≥ 96 group (P 0.001).The prediction model using GNRI and CCI will be useful to support decision-making for the treatment of EGC in elderly patients aged ≥ 85 years.

The etiology of chest pain in achalasia-related esophageal motility disorders and the frequency and risk factors of persistent chest pain after peroral endoscopic myotomy (POEM) remain unclear.A multicenter cohort study including 14 hospitals was conducted to elucidate the characteristics of patients with chest pain and the efficacy of POEM.Consecutive cases of achalasia-related esophageal motility disorders included 2294 (64.2%) and 1280 (35.8%) patients with and without chest pain, respectively. Among the 2107 patients with chest pain who underwent POEM, we observed complete remission in 1464 patients (69.5%) and nonremission in 643 patients (30.5%), including a partial response in 619 patients (29.4%) and resistance in 24 patients (1.1%). Multivariate analysis revealed that advanced age (odds ratio [OR], .28), male sex (OR, .70), prior treatment (OR, 1.39), and sigmoid type (OR, .65) were related to the prevalence of chest pain. Long disease duration (OR, .69) and esophageal dilation (OR, .79) were related to decreased severity. POEM improved patients' quality of life that was hindered by chest pain. Early onset (OR, 1.45), advanced age (OR, .58), male sex (OR, .79), prior treatment (OR, 1.37), and posterior myotomy (OR, 1.42) were associated with nonremission after POEM; high-resolution manometry (HRM) findings and myotomy length showed no statistical significance on pain etiology and persistence after POEM.The prevalence and severity of chest pain were dependent on age, sex, disease duration, prior treatment, and esophageal morphology rather than HRM findings. The efficacy of POEM is satisfactory; however, residual pain was often observed. Excessively long myotomy can be avoided, and anterior myotomy may be recommended.

Article, Immunological medicine. 42(4): 176-184 (2019)

BACKGROUND Although post-bulbar duodenal ulcers (PBDUs) could become a source of upper gastrointestinal bleeding, the whole picture of the disease is unknown. We compared the characteristic features and treatment outcomes after endoscopic hemostasis between PBDUs and bulbar duodenal ulcers (BDUs). METHODS Data on duodenal ulcers with evidence of endoscopically-active bleeding were extracted from the data that were retrospectively collected from 12 institutes in Japan between 2011 and 2018. Rebleeding and in-hospital mortality were compared between patients with PBDUs and those with BDUs by logistic regression analyses. RESULTS Among 468 consecutive patients with bleeding duodenal ulcers, 96 (20.5%) had endoscopically-confirmed PBDUs. PBDUs were more frequently observed in patients with a poor general condition in comparison to BDUs. The rates of rebleeding and in-hospital mortality in patients with PBDUs were approximately three times higher than those in patients with BDUs (PBDU vs. BDU: 29.2% vs. 10.2% [P

Aim To elucidate the impact of the coronavirus disease 2019 (COVID-19) on the practice of high-resolution manometry (HRM) and peroral endoscopic myotomy (POEM) in Japan. Methods We utilized a large-scale database involving 14 high-volume centers in Japan to investigate changes in the numbers of HRM and POEM procedures performed and outcomes of POEM between 2019 and 2020. A questionnaire survey was also conducted to analyze pandemic-associated changes in the HRM and POEM protocols. Results Compared to that in 2019, the number of HRM and POEM procedures decreased by 17.2% (1587-1314) and 20.9% (630-498), respectively. These declines were prominent during the state of emergency from April to May 2020, particularly in pandemic areas. HRM and POEM in nonpandemic areas were relatively unaffected. From 2019 to 2020, there was a 0.4% (254-248) decrease in POEM cases within the prefecture, but the number outside the prefecture decreased by 33.6% (372-247). During the pandemic, the safety and efficacy of POEM were maintained. The implementation of personal protective equipment (PPE) measures varied among facilities, and PPE for POEM was relatively insufficient compared to that for HRM. Conclusion The COVID-19 pandemic influenced HRM and POEM practices in Japan. It is necessary to establish a sufficient system for HRM and POEM in each hospital as well as countrywide to overcome the effects of the pandemic.

A 76-year-old man was referred to our hospital for examination and treatment of dysphagia. He has been taking enteric-coated aspirin for myocardial infarction. Esophagogastroduodenoscopy (EGD) revealed the presence of esophageal ulcers in the distal esophagus and five to six tablets of enteric-coated aspirin. The esophageal ulcers were believed to have been caused by the retention of aspirin within the esophagus due to achalasia. We substituted enteric-coated aspirin with powdered aspirin. A follow-up EGD performed 1 month later showed improvement of esophageal mucosa. The patient was diagnosed with type I achalasia. Per-oral endoscopic myotomy was performed, and his symptoms improved after the procedure. Although a few studies have investigated the direct effect of aspirin, none of them has reported on the direct effect of aspirin on the esophagus. It might be effective to administer powdered aspirin for patients with achalasia to prevent esophageal ulcers caused by the direct effect of aspirin.

Currently, the number of patients treated with immune-checkpoint inhibitor involving nivolumab is increasing. Nevertheless, it causes various immune-related adverse events (irAEs). Here, we report the case of a patient who underwent long-term follow-up after suffering from nivolumab-associated colitis. The patient was a 57-year-old man who underwent resection of a bladder tumor. Following surgery, lymph node metastasis was detected, and he was treated by nivolumab. Two months after treatment with nivolumab, the patient complained of bloody diarrhea. Colonoscopy revealed pancolitis with erosions, loss of vascular pattern and erythema. Pathological findings indicated a disease state of pan-ulcerative colitis. As an irAE by nivolumab, the patient was started with 30 mg of prednisolone. Prednisolone treatment successfully induced clinical remission and mucosal healing. Nevertheless, eight months after stopping the steroid treatment, the colitis relapsed with diarrhea following elevation of fecal immunochemical test (FIT) and fecal calprotectin (CPT). The relapsed colitis was treated by mesalazine, and then diarrhea was improved. Nivolumab-associated colitis relapsed following mucosal healing suggesting that it is necessary to consider maintenance therapy as well as remission induction for long-term survivor. The present case also demonstrates that the FIT and CPT would be effective biomarker to assess the disease activity of nivolumab-associated colitis.

This study aimed to elucidate whether changes in serum opsonic activity measured by lucigenin-dependent chemiluminescence and luminol-dependent chemiluminescence are useful for estimating physical stress during the perioperative period of gastric endoscopic submucosal dissection. Serum opsonic activity in the peripheral blood of 87 patients was examined in the morning of the day of endoscopic submucosal dissection, the next day, and at 4 days after endoscopic submucosal dissection. Peak height and area under the curve for lucigenin-dependent chemiluminescence were 106.1 ± 22.7% and 102.0 ± 24.7% on the day of endoscopic submucosal dissection, which increased significantly to 113.6 ± 29.4% and 111.0 ± 29.1% on the next day (both p

Background/Aims: Behçet’s disease (BD) with intestinal lesions and Crohn’s disease (CD) share clinical features. However, no report has compared the 2 diseases with regard to lesions of the upper gastrointestinal tract (UGT). We aimed to evaluate endoscopic and histologic findings of UGT in CD and BD. Methods: We retrospectively assessed the endoscopic records and biopsy samples of 84 Helicobacter pylori-negative patients (50 CD, 34 BD). In duodenal samples, MUC5AC immunohistochemical analysis was performed to identify gastric foveolar metaplasia. Results: In endoscopic findings, bamboo joint-like appearance (17/50 CD, 0/34 BD) and erosions (14/50 CD, 2/34 BD) were significantly more frequent in CD gastric lesions (p < 0.001, and p = 0.012). In histologic findings of stomach, focal neutrophil infiltration in lamina propria (15/48 CD, 1/34 BD) was significantly more frequent in CD (p < 0.001). In that of duodenum, wide gastric foveolar metaplasia (19/49 CD, 1/34 BD) was significantly more frequent in CD duodenal lesions (p = 0.013). The mean maximum width of the gastric foveolar metaplasia was 114.0 ± 10.6 and 29.5 ± 4.5 μm for CD and BD respectively (p = 0.003). Conclusions: In H. pylori-negative patients, gastric focal neutrophil infiltration and wide duodenal gastric foveolar metaplasia were important for distinguishing CD from BD.

OBJECTS Although anti-thrombotic use is recognized as a risk factor for upper gastrointestinal bleeding (UGIB), there has been no clear evidence that it worsens the outcomes after the bleeding. The aim of this study is to investigate the effects of anti-thrombotic agents on in-hospital mortality following UGIB. METHODS Information on clinical parameters, including usage of anti-thrombotic agents, was retrospectively collected from consecutive patients with UGIB at 12 high-volume centers in Japan between 2011 and 2018. The all-cause in-hospital mortality rate was evaluated according to the usage of anti-thrombotic agents. RESULTS Clinical data were collected from 2205 patients with endoscopically confirmed UGIB. Six hundred and forty-five (29.3%) patients used anti-thrombotic agents. The all-cause in-hospital mortality rate was 5.7% (125 deaths). After excluding 29 cases in which death occurred due to end-stage malignancy, 96 deaths (bleeding-related, n = 22 ; non-bleeding-related, n = 74) were considered "preventable." Overall, the "preventable" mortality rate in anti-thrombotic users was significantly higher than that in non-users (6.0% vs. 3.7%, P

The aim of this study was to assess the perioperative invasiveness of endoscopic submucosal dissection for colorectal cancer quantitatively by using energy metabolism. In fifty-three patients who underwent endoscopic submucosal dissection for colorectal cancer, resting energy expenditure using an indirect calorimeter, body weight and basal energy expenditure using the Harris-Benedict equation before and after endoscopic submucosal dissection. Resting energy expenditure/body weight and resting energy expenditure/basal energy expenditure were 19.7 ± 2.5 kcal/kg/day and 0.96 ± 0.12 on the day of endoscopic submucosal dissection, whereas one day after the endoscopic submucosal dissection they increased to 21.0 ± 2.9 kcal/kg/day and 1.00 ± 0.13 (p

Biliary atresia (BA) is a disease of the newborn that is characterized by progressive, inflammatory and sclerosing cholangiopathy. Innate immune responses to viral components are thought to be involved in the pathogenesis of BA. It is also reported that some chemokines, such as CCL5, are possibly involved in the pathogenesis of experimental animal model of BA. We treated human biliary epithelial HuCCT1 cells with polyinosinic-polycytidylic acid (poly IC), an authentic double-stranded RNA (dsRNA) which mimics viral RNA, and analyzed the CCL5 expression by quantitative reverse transcription-PCR (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA). To examine the regulation mechanisms of CCL5, we subjected the cells to RNA interference (siRNA) against Toll-like receptor 3 (TLR3), interferon (IFN)-β, NF-κB p65 and IFN regulatory factor (IRF) 3. Immunohistochemical staining for CCL5 was also performed in tissues from patients with BA. Poly IC induced CCL5 expression in HuCCT1 cells. CCL5 expression induced by poly IC was inhibited by the knockdown of TLR3, p65 or IRF3, but it was not affected by knockdown of IFN-β. Immunohistochemical staining showed that CCL5 was strongly expressed in biliary epithelial cells of patients with BA. The current study suggests that TLR3 signaling induces CCL5 expression via NF-κB and IRF3 in bile duct cells, and this pathway may be involved in the pathogenesis of BA.

Article, Immunological medicine. 42(3): 135-141 (2019)

Background/Aims: Thiopurines are key drugs for inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD). Recently, NUDT15 polymorphism (R139C, c.415C > T) has been shown to be associated with thiopurineinduced adverse events in Asian populations. In patients with the C/T genotype, low-dose thiopurine treatment is recommended, but its long-term efficacy and tolerability remain unclear. This study aimed to uncover the long-term efficacy and appropriate dosage of thiopurine for IBD patients with the C/T genotype.Methods: A total of 210 patients with IBD (103 UC and 107 CD) determined to have NUDT15 R139C variants were enrolled. Clinical data were retrospectively reviewed from medical records.Results: Of 46 patients (21.9%) with the C/T genotype, 30 patients (65.2%) were treated with thiopurines. Three of whom (10.0%) discontinued thiopurine treatment due to adverse events and 27 of whom continued. The median maintenance dosage of 6-mercaptopurine was 0.25 mg/kg/day (range, 0.19–0.36 mg/kg/day), and 6-thioguanine nucleotides level was 230 (104–298) pmol/8 × 108 red blood cells. Cumulative thiopurine continuation rates for 120 months for patients with the C/C and C/T genotypes were not significantly different (P= 0.895). Cumulative non-relapse rates in the patients with UC treated with thiopurine monotherapy and surgery-free rates in CD patients treated with combination therapy (thiopurines and anti-tumor necrosis factor-α agents) for maintenance remission were not significantly different at 60 months (C/C vs. C/T, P= 0.339 and P= 0.422, respectively).Conclusions: Low-dose thiopurine treatment is an effective and acceptable treatment for patients with C/T genotype.

A 69-year-old woman had received hemodialysis for chronic renal failure and was taking lanthanum carbonate since 63 years of age. She presented with appetite loss and nausea. We performed esophagogastroduodenoscopy, which revealed multiple longitudinal white plaques in the esophagus. Lesion biopsies showed lanthanum deposition, and lanthanum carbonate was found histologically by energy-dispersive X-ray spectroscopy. The plaques of this patient appeared like those of dabigatran-induced esophagitis, and may have occurred due to long-term contact of the esophageal epithelium with lanthanum carbonate because patient spent time in lying state. Although a few studies regarding lanthanum deposition in the stomach have been conducted, there are no reports on lanthanum deposition in the esophagus. This case suggests that the presence of longitudinal white plaques in the esophagus may indicate lanthanum deposition.

Endoscopic sub-mucosal dissection (ESD) is considered as a low-invasive treatment for early-stage colorectal cancer, but the degree of invasiveness has not been well investigated. The aim of this study was to evaluate the physical stress due to colorectal ESD based on changes in serum opsonic activity (SOA). SOA was examined by measuring reactive oxygen species (ROS) produced by neutrophils using lucigenin-dependent chemiluminescence (LgCL) and luminol-dependent chemiluminescence (LmCL). Sixty-nine patients were enrolled into the study and examined SOA in the morning of the day of ESD, the next day, and at four days after ESD. The peak height (PH) and area under the curve (AUC) of LgCL showed no significant difference between the day and the next day, whereas the PH and AUC for LgCL were significantly higher four days after ESD than on the day of ESD (

Biliary atresia (BA) is a disease of the newborn that is characterized by progressive, inflammatory and sclerosing cholangiopathy. Innate immune responses to viral components are thought to be involved in the pathogenesis of BA. It is also reported that some chemokines, such as CCL5, are possibly involved in the pathogenesis of experimental animal model of BA. We treated human biliary epithelial HuCCT1 cells with polyinosinic-polycytidylic acid (poly IC), an authentic double-stranded RNA (dsRNA) which mimics viral RNA, and analyzed the CCL5 expression by quantitative reverse transcription-PCR (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA). To examine the regulation mechanisms of CCL5, we subjected the cells to RNA interference (siRNA) against Toll-like receptor 3 (TLR3), interferon (IFN)-β, NF-κB p65 and IFN regulatory factor (IRF) 3. Immunohistochemical staining for CCL5 was also performed in tissues from patients with BA. Poly IC induced CCL5 expression in HuCCT1 cells. CCL5 expression induced by poly IC was inhibited by the knockdown of TLR3, p65 or IRF3, but it was not affected by knockdown of IFN-β. Immunohistochemical staining showed that CCL5 was strongly expressed in biliary epithelial cells of patients with BA. The current study suggests that TLR3 signaling induces CCL5 expression via NF-κB and IRF3 in bile duct cells, and this pathway may be involved in the pathogenesis of BA.

It has been reported that tumor necrosis factor (TNF)-α plays dual controversial roles, beneficial or detrimental, in the pathogenesis of murine lupus nephritis (LN). However, its precise role in the development of human LN remains to be determined. We examine the effect of pretreatment with TNF-α on the toll-like receptor 3 (TLR3) signaling induced by polyinosinic-polycytidylic acid (poly IC), a synthetic analog of viral dsRNA that makes “pseudoviral” infection in cultured normal human mesangial cells, and analyzed the expression of CC chemokine ligand 5 (CCL5) via TLR3/interferon (IFN)-β/retinoic acid-inducible gene-I (RIG-I) pathway by reverse transcriptase-polymerase chain reaction, Western blotting and enzyme-linked immunosorbent assay. We found synergistic effect of TNF-α, even at low level, on the expression of CCL5 induced by poly IC in a concentration-dependent manner, in comparison with that by poly IC alone. Knockdown of either IFN-β or RIG-I decreased CCL5 expression induced by TNF-α followed by poly IC. Pretreatment with TNF-α leads marked activation of the TLR3/IFN-β/RIG-I/CCL5 axis induced by “pseudoviral” infection. Since chronic local activation of proinflammatory cytokines including TNF-α in resident renal cells may exist in patients with active lupus, synergistic effect of TNF-α and “pseudoviral” infection is possibly involved in the development of LN.

Toll-like receptor (TLR) 4 is a pattern recognition receptor, and recognizes not only bacterial lipopolysaccharide (LPS) but also endogenous danger-associated molecular patterns released from dying or injured cells. It has been reported that TLR4 signaling in astrocytes plays an important role in various neurological diseases. However, details of TLR4 signaling in astrocytes are not fully elucidated. In the present study, we demonstrated that TLR4 signaling, induced by LPS, increases the expression of melanoma differentiation-associated gene 5 (MDA5) and interferon (IFN)-stimulated gene 56 (ISG56) in U373MG human astrocytoma cells. We also found that nuclear factor-κB, p38 mitogen-activated protein kinase and IFN-β are involved in the expression of MDA5 and ISG56 induced by LPS. RNA interference experiments revealed that MDA5 and ISG56 positively regulate the LPS-induced expression of a chemokine CXCL10, but not CCL2. In addition, it was suggested that MDA5 and ISG56 constitute a positive feedback loop. These results suggest that MDA5 and ISG56 may contribute not only to physiological inflammatory reactions but also to the pathogenesis of various neurological diseases elicited by TLR4 in astrocytes, at least in part, by regulating the expression of CXCL10.

A hallmark of Alzheimer's disease (AD) is the aggressive appearance of plaques of amyloid beta (Aβ) peptides, which result from the sequential cleavage of amyloid precursor protein (APP) by the β- and γ-secretases. Aβ production is evaded by alternate cleavage of APP by the α- and γ-secretases. Carnosic acid (CA) has been proven to activate the transcription factor Nrf2, a main regulator of the antioxidant response. We investigated the effects of CA on the production of Aβ 1-42 peptide (Aβ42) and on the expressions of the related genes in SH-SY5Y human neuroblastoma cells. The treatment of cells with CA suppressed Aβ42 secretion (61% suppression at 30μM). CA treatment enhanced the mRNA expressions of an α-secretase TACE (tumor necrosis factor-α-converting enzyme, also called a disintegrin and metalloproteinase-17, ADAM17) significantly and another α-secretase ADAM10 marginally; however, the β-secretase BACE1 (β-site APP-cleaving enzyme-1) was not increased by CA. Knockdown of TACE by siRNA reduced soluble-APPα secretion enhanced by CA and partially recovered the CA-suppressed Aβ42 secretion. These results suggest that CA reduces Aβ42 production by activating TACE without promoting BACE1 in human neuroblastoma cells. The use of CA may have a potential in the prevention of Aβ-mediated diseases, particularly AD.

It is known that recognition of bacterial lipopolysaccharide (LPS) and various endogenous ligands by Toll-like receptor 4 (TLR4) induces inflammatory reactions. However, the role of TLR4 activation in mesangial inflammation remains to be elucidated. Retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) are putative RNA helicases and are involved in immune and inflammatory reactions. The purpose of the present study was to investigate the implication of RIG-I and MDA5 in TLR4 signaling in mesangial cells.Normal human mesangial cells in culture were treated with LPS. Expression of RIG-I, MDA5, interferon-β (IFN-β), CXCL10 and CXCL8 was examined using real-time RT-PCR, Western blotting and ELISA. The cells were also subjected to RNA interference against TLR4, IFN-β, RIG-I or MDA5.LPS induced the expression of IFN-β, RIG-I, MDA5, CXCL8 and CXCL10 in human mesangial cells. RNA interference against either TLR4 or IFN-β inhibited LPS-induced RIG-I and MDA5 expression. Knockdown of TLR4, IFN-β, RIG-I or MDA5 resulted in decreased induction of CXCL10, while only TLR4 knockdown inhibited CXCL8 induction.TLR4 signaling induces the expression of RIG-I and MDA5 in mesangial cells. RIG-I and MDA5 may be involved in inflammatory reactions by regulating CXCL10 expression in the downstream of TLR4 signaling in human mesangial cells.

Background Propolis is a bee product with various biological properties, including an antiviral activity when taken orally. However, its mechanisms at the cellular and molecular level are not well understood. Results We investigated the effect of propolis on antiviral signaling in A549 cells transfected with double-stranded RNA (dsRNA), a model for viral infection. Pretreatment of the cells with propolis inhibited poly I:C (synthetic dsRNA)-induced interferon (IFN)-β expression. Propolis had no effect on the dsRNA-induced expression of RIG-I-like receptors (RLRs), which are known as intracellular viral RNA sensors. As to the effect on antiviral executor genes, propolis enhanced myxovirus resistance 1 (MX1) expression, whereas interferon-inducible gene 6–16 (G1P3) and 2'-5'-oligoadenylate synthetase (OAS) were unaffected. All of these genes belong to the IFN-inducible genes, suggesting that the effect of propolis on antiviral signaling is not necessarily mediated by the autocrine regulation by IFN-β. Propolis pretreatment inhibited dsRNA-induced interleukin-8 (IL8) and CCL5 expression, and consequently lowered polymorphonuclear leukocyte (PMN) chemotactic activity in the cell-conditioned medium. Conclusion Taken together, these results suggest that propolis may suppress excess inflammatory responses without affecting the innate immunity during viral infection.