Significance of kidney biopsy in autosomal dominant tubulointerstitial kidney disease-UMOD: is kidney biopsy truly nonspecific?

BACKGROUND: Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a rare hereditary disease caused by a variety of genetic mutations. Carriers of a mutation in the responsible genes are at risk of reaching end-stage kidney disease typically in middle age. The frequency of this disease is assumed to be underestimated because of a lack of disease-specific signs. Pathological findings obtained from kidney of uromodulin related ADTKD (ADTKD-UMOD) patients are regarded as non-specific and less-informative for its diagnosis. This research was undertaken to evaluate the significance of kidney biopsy in ADTKD-UMOD patients. METHODS: Thirteen patients from 10 families with nine identified uromodulin (UMOD) gene mutations who underwent kidney biopsy in the past were studied. Their kidney tissues were stained with anti-UMOD antibody in addition to conventional methods such as PAS staining. When positive, the numbers of tubules with visible UMOD protein accumulations were calculated based on the total numbers of UMOD expressing tubules. Pathological findings such as tubulointerstitial fibrosis, atrophy, inflammation and glomerulosclerosis were also evaluated and analyzed. RESULTS: Interstitial fibrosis and tubular atrophy were present in all 13 patients. Most atrophic tubules with thickening and lamellation of tubular basement membranes showed negative UMOD staining. In all but two patients with C94F mutations, massive accumulation of UMOD proteins was observed in the renal endoplasmic reticulum. UMOD accumulations were also detectable by PAS staining as polymorphic unstructured materials in the 11 patients at frequencies of 2.6-53.4%. 80.4% of the UMOD accumulations were surrounded by halos. The detection rate of UMOD accumulations positively correlated with eGFR. Glomerulosclerosis was detected in 11/13 patients, with a frequency of 20.0 to 61.1%, while no cystic dilatations of glomeruli were detected. CONCLUSIONS: Massively accumulated UMOD proteins in ADTKD-UMOD kidneys are detectable not only by immunostaining using anti-UMOD antibody but also by conventional methods such as PAS staining, although their detection is not easy. These findings can provide important clues to the diagnosis of ADTKD-UMOD. Kidney biopsy in ADTKD-UMOD may be more informative than assumed previously.

Molecular regulation of skeletal muscle mass and the contribution of nitric oxide: A review.

A variety of internal and external factors such as exercise, nutrition, inflammation, and cancer-associated cachexia affect the regulation of skeletal muscle mass. Because skeletal muscle functions as a crucial regulator of whole body metabolism, rather than just as a motor for locomotion, the enhancement and maintenance of muscle mass and function are required to maintain health and reduce the morbidity and mortality associated with diseases involving muscle wasting. Recent studies in this field have made tremendous progress; therefore, identification of the mechanisms that regulate skeletal muscle mass is necessary for the physical and nutritional management of both athletes and patients with muscle wasting disease. In this review, we present an overall picture of the interactions regulating skeletal muscle mass, particularly focusing on the insulin-like growth factor-I (IGF-I)/insulin-Akt-mammalian target of rapamycin (mTOR) pathway, skeletal muscle inactivity, and endurance and resistance exercise. We also discuss the contribution of nitric oxide (NO) to the regulation of skeletal muscle mass based on the current knowledge of the novel role of NO in these processes.

Terahertz Spectroscopy of Individual Carbon Nanotube Quantum Dots.

We have investigated the electronic structures of metallic carbon nanotube quantum dots (CNT QDs) by terahertz-induced photocurrent spectroscopy. Sharp peaks due to intersublevel transitions in the CNT QDs are observed at the sublevel energy spacings expected from the linear band dispersion. The line width of the photocurrent peak is as narrow as 0.3 meV and is governed by the tunnel coupling with the electrodes, indicating that the scattering time of electrons in the present CNTs is comparable to or longer than 10 ps. The observation of a sharp absorption peak at the bare quantization energy was not consistent with the Tomonaga-Luttinger liquid theory.

Unusual O-alkylation of 2-hydroxy-1,4-naphthoquinone utilizing alkoxymethyl chlorides.

A new type of O-alkylation of 2-hydroxy-1,4-naphthoquinone with alkoxymethyl chlorides is described. The reaction course can be controlled by the choice of base and yields O-alkylated or O-alkoxymethylated products in high yield with high selectivity.

Associated factors of atrophic gastritis diagnosed by double-contrast upper gastrointestinal barium X-ray radiography: a cross-sectional study analyzing 6,901 healthy subjects in Japan.

BACKGROUND: Double-contrast upper gastrointestinal barium X-ray radiography (UGI-XR) is one of the most widely conducted gastric cancer screening methods. It has been executed to find gastric cancer, but has not been usually executed to detect premalignant atrophic mucosa of stomach. To understand the meaning of UGI-XR-based atrophic gastritis, we analyzed its association with several causative factors including Helicobacter pylori (HP) infection. METHODS: We evaluated 6,901 healthy adults in Japan. UGI-XR-based atrophic gastritis was diagnosed based on the irregular shape of areae gastricae and its expansion in the stomach. RESULTS: Of the 6,433 subjects with no history of HP eradication and free from gastric acid suppressants, 1,936 were diagnosed as UGI-XR-based atrophic gastritis (mild: 234, moderate: 822, severe: 880). These were univariately associated with serum HP IgG and serum pepsinogen I/II ratio with statistical significance. The multiple logistic analysis calculating standardized coefficients (ß) and odds ratio (OR) demonstrated that serum HP IgG (ß = 1.499, OR = 4.48), current smoking (ß = 0.526, OR = 1.69), age (ß = 0.401, OR = 1.49), low serum pepsinogen I/II ratio (ß = 0.339, OR = 1.40), and male gender (ß = 0.306, OR = 1.36) showed significant positive association with UGI-XR-based atrophic gastritis whereas drinking and body mass index did not. Among the age/sex/smoking/drinking-matched 227 pairs derived from chronically HP-infected and successfully HP-eradicated subjects, UGI-XR-based atrophic gastritis was detected in 99.1% of the former but in only 59.5% of the latter subjects (p<0.0001). Contrastively, UGI-XR-based atrophic gastritis was detected in 13 of 14 HP-positive proton pump inhibitor users (92.9%) and 33 of 34 HP-positive histamine H2-receptor antagonist users (97.1%), which are not significantly different from gastric acid suppressant-free subjects. CONCLUSIONS: The presence of UGI-XR-based atrophic gastritis is positively associated with Helicobacter pylori infection, current smoking, age, decreased serum pepsinogen I/II ratio, and male gender. Eradication of Helicobacter pylori seems to superficially improve UGI-XR-based atrophic gastritis whereas intake of gastric acid suppressants does not.

Electrophysiological characterization of human Na⁺/taurocholate cotransporting polypeptide (hNTCP) heterologously expressed in Xenopus laevis oocytes.

The Na(+)/taurocholate cotransporting polypeptide (NTCP) plays a major role in Na(+)-dependent bile acid uptake into hepatocytes. The purpose of the present study was to establish the heterologous expression of human NTCP (hNTCP) in Xenopus laevis oocytes and to elucidate whether the transport of bile acid via hNTCP is electrogenic using electrophysiological techniques. First, we evaluated the uptake of taurocholate (TCA) by hNTCP heterologously expressed in Xenopus oocytes utilizing [(3)H]-labeled TCA. The uptake of 1.2 µM TCA by cRNA-injected oocytes increased more than 100-fold compared to H2O-injected oocytes, indicating that hNTCP is robustly expressed in the oocytes. hNTCP-mediated transport of TCA is saturable with a Michaelis constant of 10.5 ± 2.9 µM. The Na(+)-activation kinetics describing the relationship between the concentration of Na(+) and the magnitude of the TCA uptake rate by hNTCP were sigmoidal with a Hill coefficient of 2.3 ± 0.4, indicating the involvement of more than one Na(+) in the transport process. Ntcp in primary cultured hepatocytes from rats exhibited similar Na(+)-activation kinetics of TCA uptake rate with a Hill coefficient of 1.9 ± 0.1, suggesting that hNTCP could be expressed properly in the oocytes and exhibit the electrogenic property of Na(+)-coupled TCA transport. The transport of TCA via hNTCP was subsequently determined in the oocytes by the inward currents induced via TCA uptake under voltage (-50 mV). Two hundred micromolar TCA induced significant inward currents that were entirely abolished by the substitution of Na(+) with N-methyl-d-glucamine (NMDG) in the perfusate, indicating that the TCA-induced currents were obligatorily dependent on the presence of Na(+). The TCA-induced currents were saturable, and the substrate concentration needed for half-maximal induction of the current was consistent with the Michaelis constant. Transportable substrates, such as rosuvastatin and fluvastatin, also induced currents. These results in the hNTCP heterologously expressed in Xenopus oocytes directly demonstrated that hNTCP is an electrogenic Na(+)-dependent transporter.

Gli regulates MUC5AC transcription in human gastrointestinal cells.

MUC5AC is a well-known gastric differentiation marker, which has been frequently used for the classification of stomach cancer. Immunohistochemistry revealed that expression of MUC5AC decreases accompanied with increased malignant property of gastric mucosa, which further suggests the importance of MUC5AC gene regulation. Alignment of the 5'-flanking regions of MUC5AC gene of 13 mammal species denoted high homology within 200 bp upstream of the coding region. Luciferase activities of the deletion constructs containing upstream 451 bp or shorter fragments demonstrated that 15 bp region between -111 and -125 bp plays a critical role on MUC5AC promoter activity in gastrointestinal cells. We found a putative Gli-binding site in this 15 bp sequence, and named this region a highly conserved region containing a Gli-binding site (HCR-Gli). Overexpression of Gli homologs (Gli1, Gli2, and Gli3) clearly enhanced MUC5AC promoter activity. Exogenous modulation of Gli1 and Gli2 also affected the endogenous MUC5AC gene expression in gastrointestinal cells. Chromatin immunoprecipitation assays demonstrated that Gli1 directly binds to HCR-Gli: Gli regulates MUC5AC transcription via direct protein-DNA interaction. Conversely, in the 30 human cancer cell lines and various normal tissues, expression patterns of MUC5AC and Gli did not coincide wholly: MUC5AC showed cell line-specific or tissue-specific expression whereas Gli mostly revealed ubiquitous expression. Luciferase promoter assays suggested that the far distal MUC5AC promoter region containing upstream 4010 bp seems to have several enhancer elements for gene transcription. In addition, treatments with DNA demethylation reagent and/or histone deacetylase inhibitor induced MUC5AC expression in several cell lines that were deficient in MUC5AC expression. These results indicated that Gli is necessary but not sufficient for MUC5AC expression: namely, the multiple regulatory mechanisms should work in the distal promoter region of MUC5AC gene.

Evaluation of a new image-enhanced endoscopic technology using band-limited light for detection of esophageal squamous cell carcinoma.

BACKGROUND: The aim of the present study was to evaluate the clinical utility of a new image-enhanced endoscopy (IEE) technology called optical enhancement imaging (OEI-1, -2, -3) by quantitatively evaluating diagnostic performance in superficial esophageal squamous cell carcinoma (SCC) in order to facilitate detection and characterization of gastrointestinal tumors. PATIENTS AND METHODS: The study involved 10 esophageal SCC resected endoscopically at our hospital. Ex vivo observation of the boundary area between normal and SCC was done using each mode (white light image [WLI], OEI-1, OEI-2, and OEI-3) with and without magnification. The additional effect of OEI on WLI was evaluated by calculating the color difference (expressed as ΔE94 ) between SCC and normal epithelium, and that between the intraepithelial papillary capillary loop (IPCL) and inter-vascular background coloration (IVBC). RESULTS: Mean ΔE94 values between SCC and normal epithelium for WLI, OEI-1, OEI-2, and OEI-3 were 9.37 ± 4.64, 13.82 ± 4.46,13.26 ± 4.73, and 16.44 ± 4.83, respectively; the corresponding values between IPCL and IVBC were 17.57 ± 10.17, 29.32 ± 9.95, 25.41 ± 11.72, and 23.71 ± 11.58, respectively. Compared with WLI, all OEI exhibited significant additional effect on ΔE94 . Furthermore, we found significant additional effect of OEI-3 in observing SCC and normal epithelium, and of OEI-1 in observing IPCL and IVBC, compared with other OEI. CONCLUSION: These results suggest that OEI improves endoscopic detection and characterization of esophageal SCC compared with WLI. Moreover, the data indicate that OEI-3 is useful for detection and OEI-1 is useful for characterization of esophageal SCC.

Background factors of reflux esophagitis and non-erosive reflux disease: a cross-sectional study of 10,837 subjects in Japan.

BACKGROUND: Despite the high prevalence of gastroesophageal reflux disease (GERD), its risk factors are still a subject of controversy. This is probably due to inadequate distinction between reflux esophagitis (RE) and non-erosive reflux disease (NERD), and is also due to inadequate evaluation of adjacent stomach. Our aim is therefore to define background factors of RE and NERD independently, based on the evaluation of Helicobacter pylori infection and gastric atrophy. METHODS: We analyzed 10,837 healthy Japanese subjects (6,332 men and 4,505 women, aged 20-87 years) who underwent upper gastrointestinal endoscopy. RE was diagnosed as the presence of mucosal break, and NERD was diagnosed as the presence of heartburn and/or acid regurgitation in RE-free subjects. Using GERD-free subjects as control, background factors for RE and NERD were separately analyzed using logistic regression to evaluate standardized coefficients (SC), odds ratio (OR), and p-value. RESULTS: Of the 10,837 study subjects, we diagnosed 733 (6.8%) as RE and 1,722 (15.9%) as NERD. For RE, male gender (SC = 0.557, OR = 1.75), HP non-infection (SC = 0.552, OR = 1.74), higher pepsinogen I/II ratio (SC = 0.496, OR = 1.64), higher BMI (SC = 0.464, OR = 1.60), alcohol drinking (SC = 0.161, OR = 1.17), older age (SC = 0.148, OR = 1.16), and smoking (SC = 0.129, OR = 1.14) are positively correlated factors. For NERD, HP infection (SC = 0.106, OR = 1.11), female gender (SC = 0.099, OR = 1.10), younger age (SC = 0.099, OR = 1.10), higher pepsinogen I/II ratio (SC = 0.099, OR = 1.10), smoking (SC = 0.080, OR = 1.08), higher BMI (SC = 0.078, OR = 1.08), and alcohol drinking (SC = 0.076, OR = 1.08) are positively correlated factors. Prevalence of RE in subjects with chronic HP infection and successful HP eradication denotes significant difference (2.3% and 8.8%; p<0.0001), whereas that of NERD shows no difference (18.2% and 20.8%; p = 0.064). CONCLUSIONS: Significantly associated factors of NERD are considerably different from those of RE, indicating that these two disorders are pathophysiologically distinct. Eradication of Helicobacter pylori may have disadvantageous effects on RE but not on NERD.

Narrow band imaging with magnification can pick up esophageal squamous cell carcinoma more efficiently than lugol chromoendoscopy in patients after chemoradiotherapy.

Aim. Little is known about the usefulness of narrow band imaging (NBI) for surveillance of patients after chemoradiotherapy for esophageal neoplasia. Its usefulness in detecting esophageal squamous cell carcinoma (SCC) or high-grade intraepithelial neoplasia (HGIN) in these patients was retrospectively compared to Lugol chromoendoscopy. Patients and Methods. We assessed the diagnostic ability of NBI with magnification based on the biopsy specimens obtained from iodine-unstained lesions. Seventy-two iodine-unstained lesions were biopsied and consecutively enrolled for this study. The lesions were divided into NBI positive and NBI negative. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of NBI with magnification and PPV of Lugol chromoendoscopy was calculated using histological assessment as a gold standard. Results. Forty-six endoscopic examinations using NBI with magnification followed by Lugol chromoendoscopy were performed to 28 patients. The prevalence of SCC and HGIN was 21.4%. Sensitivity, specificity, PPV, NPV, and accuracy of NBI were 100.0%, 98.5%, 85.7%, 100%, and 98.6%, respectively. On the contrary, PPV of Lugol chromoendoscopy were 8.3%. Compared to Lugol chromoendoscopy, NBI with magnification showed equal sensitivity and significantly higher PPV (P < 0.0001). Conclusion. NBI with magnification would be able to pick up esophageal neoplasia more efficiently than Lugol chromoendoscopy in patients after chemoradiotherapy.

Factors predictive of inaccurate determination of horizontal extent of intestinal-type early gastric cancers during endoscopic submucosal dissection: a retrospective analysis.

BACKGROUND: Certain tumor characteristics may pose challenges when endoscopically determining the horizontal extent of early gastric cancers (EGC). In the present study, clinicopathological features related to inaccurate endoscopic evaluation of horizontal extent of intestinal-type EGC were analyzed. PATIENTS AND METHODS: We analyzed 431 lesions with intestinal-type EGC treated by endoscopic submucosal dissection (ESD) at our hospital. We focused on whether pretreatment demarcation was accurate by comparing positional relationships between marking dots and tumor edges in resected specimens, and factors related to inaccurate evaluation were analyzed. Gender, age, tumor size, location, circumference, depth, ulceration, macroscopic type, presence of a flat (0-IIb) component, predominant histological type, mixture of diffuse-type adenocarcinoma, mixed histology, and use of magnification endoscopy with narrow band imaging were analyzed. Reasons for inaccurate evaluation were also investigated by re-examining endoscopic images and prepared histological slides. RESULTS: Rate of inaccurate evaluation of horizontal extent was 7.4% (32/431 lesions). Multivariate analysis revealed the following significant independent variables contributing to inaccurate endoscopic evaluation: presence of a flat component, large size, and predominant histological findings of moderately differentiated adenocarcinoma. Re-examination of prepared histological slides of inaccurately evaluated cases revealed a marginal flat spreading area in 28 of the 32 lesions (87.5%). In 14 of the 32 lesions (43.8%), tumor margins were composed of moderately differentiated adenocarcinoma. CONCLUSIONS: For lesions with a flat component, large lesions, and moderately differentiated adenocarcinoma, determination of the horizontal extent can be challenging in EGC indicated for ESD, even with the best available endoscopic tools.

Cathepsin E is a marker of gastric differentiation and signet-ring cell carcinoma of stomach: a novel suggestion on gastric tumorigenesis.

Gastric cancer (GC) presents various histological features, though the mechanism underlying its diversity is seldom elucidated. It is mainly classified into well differentiated tubular adenocarcinoma (tub1), moderately differentiated tubular adenocarcinoma (tub2), poorly differentiated adenocarcinoma (por), signet-ring cell carcinoma (sig), mucinous adenocarcinoma (muc), and papillary adenocarcinoma (pap). By screening, we found cathepsin E (CTSE) expresses universally in sig-type, occasionally in por-type, and rarely in tub1/tub2-type GC cell lines. In surgically-resected specimens, CTSE was immunostained in 50/51 sig-type (98.0%), 3/10 tub1-type (30.0%), 7/18 tub2-type (38.9%), 15/26 por-type (57.7%), 4/10 pap-type (40.0%), and 0/3 muc-type (0.0%) GC. In endoscopically-resected specimens, 6/7 sig-type (85.7%), 7/52 tub1-type (13.7%), 5/12 tub2-type (41.7%), 2/7 pap-type (28.6%) GC and 0/6 adenoma (0.0%) expressed CTSE. For non-malignant tissues, CTSE is universally expressed in normal fundic, pyloric, and cardiac glands of stomach, but hardly in other digestive organs. In the precancerous intestinal metaplasia of stomach, CTSE is mostly observed in mixed gastric-and-intestinal type and deficient in solely-intestinal type. CTSE expression is positively correlated with gastric marker MUC5AC (p<0.0001) and negatively correlated with intestinal marker MUC2 (p = 0.0019). For sig-type GC, in both tumors and background mucosa, expression of MUC5AC and CTSE is high whereas that of MUC2 is low, indicating that sig-type GC reflects the features of background mucosa. For gastric adenoma and tub1/tub2-type GC, more undifferentiated tumors tend to show higher expression of CTSE with MUC5AC and lower expression of MUC2 in tumors, but they tend to present lower expression of CTSE, MUC5AC and MUC2 in background mucosa. These suggest that more malignant gastric adenocarcinoma with stronger gastric and weaker intestinal properties tend to arise from background mucosa with decreased both gastric and intestinal features. In conclusion, CTSE is a marker of both gastric differentiation and signet-ring cell carcinoma, which should shed light on the mechanism of gastric tumorigenesis.

1,8-cineole, a TRPM8 agonist, is a novel natural antagonist of human TRPA1.

BACKGROUND: Essential oils are often used in alternative medicine as analgesic and anti-inflammatory remedies. However, the specific compounds that confer the effects of essential oils and the molecular mechanisms are largely unknown. TRPM8 is a thermosensitive receptor that detects cool temperatures and menthol whereas TRPA1 is a sensor of noxious cold. Ideally, an effective analgesic compound would activate TRPM8 and inhibit TRPA1. RESULTS: We screened essential oils and fragrance chemicals showing a high ratio of human TRPM8-activating ability versus human TRPA1-activating ability using a Ca2+-imaging method, and identified 1,8-cineole in eucalyptus oil as particularly effective. Patch-clamp experiments confirmed that 1,8-cineole evoked inward currents in HEK293T cells expressing human TRPM8, but not human TRPA1. In addition, 1,8-cineole inhibited human TRPA1 currents activated by allyl isothiocyanate, menthol, fulfenamic acid or octanol in a dose-dependent manner. Furthermore, in vivo sensory irritation tests showed that 1,8-cineole conferred an analgesic effect on sensory irritation produced by TRPA1 agonists octanol and menthol. Surprisingly, 1,4-cineole, which is structurally similar and also present in eucalyptus oil, activated both human TRPM8 and human TRPA1. CONCLUSIONS: 1,8-cineole is a rare natural antagonist of human TRPA1 that has analgesic and anti-inflammatory effects possibly due to its inhibition of TRPA1.

Endoscopic mucosal resection with a ligation device or endoscopic submucosal dissection for rectal carcinoid tumors: an analysis of 24 consecutive cases.

AIMS: Endoscopic submucosal dissection (ESD) has several advantages over conventional endoscopic mucosal resection, including a higher en bloc resection rate and more accurate pathological estimation. However, ESD is a complex procedure that requires advanced endoscopic skills. The aim of our study is to evaluate the efficacy of endoscopic mucosal resection with a ligation device (EMR-L) compared to ESD for rectal carcinoid tumors. METHODS: Between September 2003 and April 2011, 24 rectal carcinoid tumors in 24 patients treated by ESD or EMR-L were retrospectively analyzed. The indications for endoscopic treatment were node-negative rectal carcinoid tumors. We compared the therapeutic outcomes of the ESD group (n = 13) and the EMR-L group (n = 11). RESULTS: Both groups had similar mean tumor sizes (ESD: 5.5 ± 2.1 mm; EMR-L: 4.4 ± 2.2 mm). The rates of en bloc and complete resection were, respectively, 100% and 92.3% for ESD, and 100% and 100% for EMR-L. Perforations did not occur in either group. Postoperative bleeding occurred in one EMR-L case, and it was endoscopically managed. However, there were no differences in therapeutic outcomes between the two groups. The mean procedure time was longer in the ESD group (28.8 ± 16.2 min) than in the EMR-L group (17.4 ± 4.4 min), without a significant difference. The mean hospitalization period was significantly shorter in the EMR-L group (1.8 ± 3.1 day) than in the ESD group (6.2 ± 2.1 day), and eight EMR-L cases were treated in an outpatient setting. CONCLUSIONS: EMR-L is a simple and effective procedure that compares favorably to ESD for small rectal carcinoid tumors.

Rebamipide induces dendritic cell recruitment to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-exposed rat gastric mucosa based on IL-1ß upregulation.

Rebamipide is usually used for mucosal protection, healing of gastric ulcers, treatment of gastritis, etc., but its effects on gastric malignancy have not been elucidated. Using Lewis and Buffalo rat strains treated with peroral administration of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), we evaluated the effect of rebamipide on the induction of tumor-suppressive dendritic cells, which are known to be heterogeneous antigen-presenting cells of bone marrow origin and are critical for the initiation of primary T-cell responses. Using CD68 as a marker for dendritic cells, the stomach pyloric mucosae of Lewis and Buffalo rats were immunohistochemically analyzed in the presence or absence of rebamipide and MNNG. After a 14-day treatment of rebamipide alone, no significant change in number of CD68-expressing cells was detected in either rat strain. However, after concurrent exposure to MNNG for 14 days, treatment with rebamipide slightly increased CD68-positive cells in the Lewis strain, and significantly increased them in the Buffalo strain. Analysis of two chemotactic factors of dendritic cells, IL-1ß and TNF-α, in the gastric cancer cells showed that expression of IL-1ß, but not TNF-α, was induced by rebamipide in a dose-dependent manner. A luciferase promoter assay using gastric SH-10-TC cells demonstrated that an element mediating rebamipide action exists in the IL-1ß gene promoter region. In conclusion, rebamipide has potential tumor-suppressive effects on gastric tumorigenesis via the recruitment of dendritic cells, based on the upregulation of the IL-1ß gene in gastric epithelial cells.

Lifestyle factors affecting gastroesophageal reflux disease symptoms: a cross-sectional study of healthy 19864 adults using FSSG scores.

BACKGROUND: Gastroesophageal reflux disease (GERD) is a very common disorder worldwide, comprised of reflux esophagitis (RE) and non-erosive reflux disease (NERD). As more than half of GERD patients are classified into the NERD group, precise evaluation of bothersome epigastric symptoms is essential. Nevertheless, compared with many reports targeting endoscopic reflux esophagitis, large-scale studies focusing on GERD symptoms have been very scarce. METHODS: To elucidate lifestyle factors affecting GERD symptoms, 19,864 healthy adults in Japan were analyzed. Sub-analyses of 371 proton pump inhibitor (PPI) users and 539 histamine H2-receptor antagonist (H2RA) users were also performed. Using the FSSG (Frequency Scale for the Symptoms of GERD) score as a response variable, 25 lifestyle-related factors were univariately evaluated by Student's t-test or Pearson's correlation coefficient, and were further analyzed with multiple linear regression modelling. RESULTS: Average FSSG scores were 4.8 ± 5.2 for total subjects, 9.0 ± 7.3 for PPI users, and 8.2 ± 6.6 for H2RA users. Among the total population, positively correlated factors and standardized coefficients (ß) for FSSG scores are inadequate sleep (ß = 0.158), digestive drug users (ß = 0.0972 for PPI, ß = 0.0903 for H2RA, and ß = 0.104 for others), increased body weight in adulthood (ß = 0.081), dinner just before bedtime (ß = 0.061), the habit of midnight snack (ß = 0.055), lower body mass index (ß = 0.054), NSAID users (ß = 0.051), female gender (ß = 0.048), lack of breakfast (ß = 0.045), lack of physical exercise (ß = 0.035), younger age (ß = 0.033), antihyperglycemic agents non-users (ß = 0.026), the habit of quick eating (ß = 0.025), alcohol drinking (ß = 0.025), history of gastrectomy (ß = 0.024), history of cardiovascular disease (ß = 0.020), and smoking (ß = 0.018). Positively correlated factors for PPI users are female gender (ß = 0.198), inadequate sleep (ß = 0.150), lack of breakfast (ß = 0.146), antihypertensive agent non-users (ß = 0.134), and dinner just before bedtime (ß = 0.129), whereas those for H2RA users are inadequate sleep (ß = 0.248), habit of midnight snack (ß = 0.160), anticoagulants non-users (ß = 0.106), and antihypertensive agents non-users (ß = 0.095). CONCLUSIONS: Among many lifestyle-related factors correlated with GERD symptoms, poor quality of sleep and irregular dietary habits are strong risk factors for high FSSG scores. At present, usual dose of PPI or H2RA in Japan cannot fully relieve GERD symptoms.

Evaluation of safety of endoscopic biopsy without cessation of antithrombotic agents in Japan.

BACKGROUND: Although guidelines in Japan recommend the cessation of antithrombotic agents before endoscopic biopsy, the safety of biopsy without the cessation of these agents has not been evaluated to date in this country. Therefore, we aimed to assess the feasibility of biopsy without cessation of antithrombotic agents in Japan. METHODS: This was a prospective single-arm study from a single institution. From May 2010 to November 2011, 112 outpatients who were receiving antithrombotic agents because of their high-risk status for a thromboembolic event (after implantation of coronary stent, after valve replacement, or a previous history of thromboembolic event or heart failure due to atrial fibrillation) were enrolled. We evaluated the rate of severe bleeding complications within 2 weeks after endoscopy and the endoscopic bleeding time (EBT) after biopsy in patients who underwent biopsy for endoscopic findings requiring pathology assessment. RESULTS: Among the 112 participants, 101 biopsies were performed for 48 and 12 outpatients who had had esophagogastroduodenoscopy and colonoscopy, respectively. All the biopsies provided enough specimens to evaluate pathologically. Hemostasis after biopsy was confirmed for all biopsies during endoscopic observation. No patients complained of any bleeding symptoms in the 2-week observation period after biopsy (0/101; 95% confidence interval [CI] 0-3.6%). Concerning the EBT (median 2.2 ± 1.8 min, range 0.5-9 min), there were no significant differences between patients receiving single antithrombotic agents and those receiving multiple agents (2.4 ± 1.4 vs. 2.1 ± 2.1 min), nor were there any significant differences between patients not receiving and receiving warfarin (2.3 ± 1.8 vs. 2.2 ± 1.8 min). CONCLUSION: Biopsy without cessation of antithrombotic agents, as recommended in Western guidelines, can also be acceptable for Japanese people if performed carefully.

Pretransplantation combined therapy with plasmapheresis and rituximab in a second living-related kidney transplant pediatric recipient with a very high risk for focal segmental glomerulosclerosis recurrence.

Prophylactic PP can provide some protection against post-transplantation recurrences of FSGS, but it cannot prevent recurrences in all cases. Therefore, new preventive therapies are needed. We report on a 7.9-yr-old girl treated with pretransplantation prophylactic combined therapy consisting of four sessions of PP and one dose of rituximab before a second living-related KTX. The patient had a very high risk of post-transplantation FSGS recurrence because this had occurred after the first KTX. During the 36 months since the second transplantation, she has had no evidence of proteinuria or significant infectious complications. Although our experience is too preliminary to draw any generalizable conclusions, pretransplantation combined therapy with PP and rituximab might be a possible option for the prevention of FSGS recurrence in very high-risk recipients undergoing living-donor KTXs.

Postprandial fullness correlates with rapid inflow of gastric content into duodenum but not with chronic gastritis.

BACKGROUND: The aim of this study is evaluating the correlation of postprandial fullness with chronic gastritis or rapid inflow of gastric content into duodenum, based on double-contrast barium X-ray imaging. METHODS: 253 healthy subjects who underwent upper gastrointestinal barium X-ray examination were analyzed. Chronic gastritis was judged from mucosal atrophy and hypertrophic thickened folds on barium X-ray images. For the gastric excretion, the tips of barium flow on the single-contrast frontal barium X-ray images of the stomach were classified into four categories; V type (all the barium remained in the stomach), V-H type (some barium had flowed into the duodenum but the tip of barium remained in the proximal half of the duodenal bulb), H-V type (some barium had flowed into the duodenum and the tip of barium was in the distal half of duodenal the bulb, but no barium was observed in the descending part of the duodenum), and H type (some barium had flowed into the descending part of the duodenum). The chi-square test and Cochran-Mantel-Haenzel test were used for evaluation. RESULTS: Chronic gastritis was observed in 72 subjects, among which 21 subjects (29.2%) presented with postprandial fullness. For the remaining 181 subjects without chronic gastritis, 53 subjects (29.3%) complained of postprandial fullness. There is no significant correlation between chronic gastritis and postprandial fullness (p = 0.973). For the rapid flow of gastric content into duodenum, all the 253 subjects comprised 136 subjects with V type (in the stomach), 40 subjects with V-H type (in the proximal half of the duodenal bulb), 21 subjects with H-V type (in the distal half of the duodenal bulb), and 56 subjects with H type (in the descending part of the duodenum). Postprandial fullness was present in 30 subjects with V type (22.1%), 9 subjects with V-H type (22.5%), 8 subjects with H-V type (38.1%), and 27 subjects with H type (48.2%). There is a distinct correlation between postprandial fullness and gastric barium excretion on barium X-ray imaging (p = 0.002). CONCLUSIONS: Bothersome postprandial fullness correlates with rapid inflow of gastric content into duodenum, but not with chronic gastritis.