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Background/aims: The aim of our study was to investigate the inhibitory effects on gastric acid secretion of a single oral dose of a proton pump inhibitor, esomeprazole 20 mg and omeprazole 20 mg., Methodology: A total of 14 Helicobacter pylori-negative male subjects participated in this study. Intragastric pH was monitored continuously for 6 hours after a single oral dose of omeprazole 20 mg and a single oral dose of esomeprazole 20 mg. Each administration was separated by a 7-day washout period., Results: During the 6-hour study period, the average pH after administration of esomeprazole was higher than that after the administration of omeprazole. Also during the 6-hour study period, each of pH > 2, 3, 3.5, 4, and 5 was maintained for a longer duration after administration of esomeprazole 20 mg than after administration of omeprazole 20 mg (median: 75.4% vs. 53.8%, p = 0.0138; 52.1% vs. 33.4%, p = 0.0188; 45.8% vs. 28.2%, p = 0.0262; 42.5% vs. 20.7%, p = 0.0414; 35.8% vs. 11.6%, p = 0.0262; respectively)., Conclusions: In Helicobacter pylori-negative healthy male subjects, single oral administration of esomeprazole 20 mg increased the intragastric pH more rapidly than single oral administration of omeprazole 20 mg.

Amorphous copper oxide (Cu(II)) nanoclusters function as efficient electrocatalysts for the reduction of carbon dioxide (CO2) to carbon monoxide (CO). In addition to promoting electrocatalytic activity, Cu(II) nanoclusters act as efficient cocatalyts for CO2 photoreduction when grafted onto the surface of a semiconductor (light harvester), such as niobate (Nb3O8(-)) nanosheets. Here, the photocatalytic activity and reaction pathway of Cu(II)-grafted Nb3O8(-) nanosheets was investigated using electron spin resonance (ESR) analysis and isotope-labeled molecules (H2(18)O and (13)CO2). The results of the labeling experiments demonstrated that under UV irradiation, electrons are extracted from water to produce oxygen ((18)O2) and then reduce CO2 to produce (13)CO. ESR analysis confirmed that excited holes in the valence band of Nb3O8(-) nanosheets react with water, and that excited electrons in the conduction band of Nb3O8(-) nanosheets are injected into the Cu(II) nanoclusters through the interface and are involved in the reduction of CO2 into CO. The Cu(II) nanocluster-grafted Nb3O8(-) nanosheets are composed of nontoxic and abundant elements and can be facilely synthesized by a wet chemical method. The nanocluster grafting technique described here can be applied for the surface activation of various semiconductor light harvesters, such as metal oxide and/or metal chalcogenides, and is expected to aid in the development of efficient CO2 photoreduction systems.

Objectives: Primary or metastatic lung cancer or mediastinal tumours may at times involve the phrenic nerve and pericardium. To remove the pathology en bloc, the phrenic nerve must be resected. This results in phrenic nerve paralysis, which in turn reduces pulmonary function and quality of life. As a curative measure of this paralysis and thus a preventive measure against decreased pulmonary function and quality of life, we have performed immediate phrenic nerve reconstruction under complete video-assisted thoracic surgery, and with minimal additional stress to the patient. This study sought to ascertain the utility of this procedure from an evaluation of the cases experienced to date., Methods: We performed 6 cases of complete video-assisted thoracic surgery phrenic nerve reconstruction from October 2009 to December 2013 in patients who had undergone phrenic nerve resection or separation to remove tumours en bloc. In all cases, it was difficult to separate the phrenic nerve from the tumour. Reconstruction involved direct anastomosis in 3 cases and intercostal nerve interposition anastomosis in the remaining 3 cases., Results: In the 6 patients (3 men, 3 women; mean age 50.8 years), we performed two right-sided and four left-sided procedures. The mean anastomosis time was 5.3 min for direct anastomosis and 35.3 min for intercostal nerve interposition anastomosis. Postoperative phrenic nerve function was measured on chest X-ray during inspiration and expiration. Direct anastomosis was effective in 2 of the 3 patients, and intercostal nerve interposition anastomosis was effective in all 3 patients. Diaphragm function was confirmed on X-ray to be improved in these 5 patients., Conclusions: Complete video-assisted thoracic surgery phrenic nerve reconstruction was effective for direct anastomosis as well as for intercostal nerve interposition anastomosis in a small sample of selected patients. The procedure shows promise for phrenic nerve reconstruction and further data should be accumulated over time., (© The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: Small bowel angioectasia is reported as the most common cause of bleeding in patients with obscure gastrointestinal bleeding. Although the safety and efficacy of endoscopic treatment have been demonstrated, rebleeding rates are relatively high. To establish therapeutic and follow-up guidelines, we investigated the long-term outcomes and clinical predictors of rebleeding in patients with small bowel angioectasia., Methods: A total of 68 patients were retrospectively included in this study. All the patients had undergone CE examination, and subsequent control of bleeding, where needed, was accomplished by endoscopic argon plasma coagulation. Based on the follow-up data, the rebleeding rate was compared between patients who had/had not undergone endoscopic treatment. Multivariate analysis was performed using Cox proportional hazard regression model to identify the predictors of rebleeding. We defined the OGIB as controlled if there was no further overt bleeding within 6 months and the hemoglobin level had not fallen below 10 g/dl by the time of the final examination., Results: The overall rebleeding rate over a median follow-up duration of 30.5 months (interquartile range 16.5-47.0) was 33.8% (23/68 cases). The cumulative risk of rebleeding tended to be lower in the patients who had undergone endoscopic treatment than in those who had not undergone endoscopic treatment, however, the difference did not reach statistical significance (P = 0.14). In the majority of patients with rebleeding (18/23, 78.3%), the bleeding was controlled by the end of the follow-up period. Multiple regression analysis identified presence of multiple lesions (≥3) (OR 3.82; 95% CI 1.30-11.3, P = 0.02) as the only significant independent predictor of rebleeding., Conclusion: In most cases, bleeding can be controlled by repeated endoscopic treatment. Careful follow-up is needed for patients with multiple lesions, presence of which is considered as a significant risk factor for rebleeding.

Background: To develop appropriate management strategies for patients who take low-dose aspirin, it is important to identify the risk factors for GI injury. However, few studies have described the risk factors for small-bowel injury in these patients., Objective: To investigate factors influencing the risk of small-bowel mucosal breaks in individuals taking continuous low-dose aspirin., Design: Capsule endoscopy data were collected prospectively from 5 institutions., Setting: Yokohama City University Hospital and 4 other hospitals., Patients: A total of 205 patients receiving treatment with low-dose aspirin for over 3 months., Interventions: Colonoscopic and upper GI endoscopy had been performed in all of the patients before the capsule endoscope evaluation., Main Outcome Measurements: Risk factors for small-bowel mucosal breaks., Results: Of the 198 patients (141 male; mean age 71.9 years) included in the final analysis, 114 (57.6%) had at least 1 mucosal break. Multivariate analysis identified protein pump inhibitor (PPI) use (OR 2.04; 95% confidence interval [CI], 1.05-3.97) and use of enteric-coated aspirin (OR 4.05; 95% CI, 1.49-11.0) as independent risk factors for the presence of mucosal breaks., Limitations: Cross-sectional study., Conclusion: PPI use appears to increase the risk of small-bowel injury in patients who take continuous low-dose aspirin. Clinicians should be aware of this effect of PPIs; new strategies are needed to treat aspirin-induced gastroenteropathy., (Copyright © 2014 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Aberrant DNA methylation plays an important role in genesis of colorectal cancer (CRC). Previously, we identified Group 1 and Group 2 methylation markers through genome-wide DNA methylation analysis, and classified CRC and protruded adenoma into three distinct clusters: high-, intermediate- and low-methylation epigenotypes. High-methylation epigenotype strongly correlated with BRAF mutations and these aberrations were involved in the serrated pathway, whereas intermediate-methylation epigenotype strongly correlated with KRAS mutations. Here, we investigated laterally spreading tumors (LSTs), which are flat, early CRC lesions, through quantitative methylation analysis of six Group 1 and 14 Group 2 methylation markers using pyrosequencing. Gene mutations in BRAF, KRAS and PIK3CA, and immunostaining of TP53 and CTNNB1 as well as other clinicopathological factors were also evaluated. By hierarchical clustering using methylation information, LSTs were classified into two subtypes; intermediate-methylation epigenotype correlating with KRAS mutations (p = 9 × 10(-4)) and a granular morphology (LST-G) (p = 1 × 10(-7)), and low-methylation epigenotype correlating with CTNNB1 activation (p = 0.002) and a nongranular morphology (LST-NG) (p = 1 × 10(-7)). Group 1 marker methylation and BRAF mutations were barely detected, suggesting that high-methylation epigenotype was unlikely to be involved in LST development. TP53 mutations correlated significantly with malignant transformation, regardless of epigenotype or morphology type. Together, this may suggest that two molecular pathways, intermediate methylation associated with KRAS mutations and LST-G morphology, and low methylation associated with CTNNB1 activation and LST-NG morphology, might be involved in LST development, and that involvement of TP53 mutations could be important in both subtypes in the development from adenoma to cancer., (© 2014 UICC.)

Background/aims: The aim of this study was to determine the possible existence of a correlation between the gastric transit time (GTT) measured by video capsule endoscopy (VCE) and the parameters of gastric emptying determined using 13C breath test (BreathID system)., Methods: Eight healthy male volunteers participated in this randomized, two-way crossover study. The subjects were randomly assigned to undergo VCE using the PillCam SB capsule endoscopy system or the 13C breath test for 4 hours after a test meal (400 kcal per 400 mL) containing 100 mg of 13C acetic acid administered after overnight fasting. The VCE images were analyzed and the GTT was determined using the proprietary RAPID software. The parameters, namely T lag, T 1/2 and GEC were calculated using the Oridion Research Software (β version). The GTT measured by VCE and the parameters of gastric emptying were compared statistically., Results: No significant correlation was observed between the GTT and T lag (p = 0.5263), T 1/2 (p = 0.4100) or GEC (p = 0.2410), as determined by calculation of the Spearman’s rank correlation coefficient., Conclusions: GTT measured by VCE cannot serve as asubstitute for the gastric emptying time measured bythe 13C breath test.

Leptin, secreted by the adipose tissue and known to be related to obesity, is considered to be involved in the onset and progression of colorectal cancer. However, the exact role of leptin in colorectal carcinogenesis is still unclear, as several controversial reports have been published on the various systemic effects of leptin. The aim of this study was to clarify the local and precise roles of leptin receptor (LEPR)-mediated signaling in colonic carcinogenesis using intestinal epithelium-specific LEPRb conditional knockout (cKO) mice. We produced and used colonic epithelium-specific LEPRb cKO mice to investigate the carcinogen-induced formation of aberrant crypt foci (ACF) and tumors in the colon, using their littermates as control. There were no differences in the body weight or systemic condition between the control and cKO mice. The tumor sizes and number of large-sized tumors were significantly lower in the cKO mice as compared with those in the control mice. On the other hand, there was no significant difference in the proliferative activity of the normal colonic epithelial cells or ACF formation between the control and cKO mice. In the control mice, marked increase of the LEPRb expression level was observed in the colonic tumors as compared with that in the normal epithelium; furthermore, signal transducer and activator of transcription (STAT3) was activated in the tumor cells. These findings suggest that STAT3 is one of the important molecules downstream of LEPRb, and LEPRb/STAT3 signaling controls tumor cell proliferation. We demonstrated the importance of local/regional LEPR-mediated signaling in colorectal carcinogenesis., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Aberant DNA methylation is a common epigenomic alteration in carcinogenesis. Comprehensive analyses of DNA methylation have stratified gastrointestinal cancer into several subgroups according to specific DNA methylation accumulation. In gastric cancer, Helicobacter pylori infection is a cause of methylation accumulation in apparently normal mucosa. Epstein-Barr virus infection is another methylation inducer that causes more genome-wide methylation, resulting in the formation of unique epigenotype with extensive methylation. In colorectal carcinogenesis, accumulation of high levels of methylation in combination with BRAF mutation is characteristic of the serrated pathway, but not of the adenoma-carcinoma sequence through conventional adenoma. In a de novo pathway, laterally spreading tumours generate intermediate- and low-methylation epigenotypes, accompanied by different genetic features and different macroscopic morphologies. These methylation epigenotypes, with specific genomic aberrations, are mostly completed by the adenoma stage, and additional molecular aberration, such as TP53 mutation, is suggested to lead to cancer development with the corresponding epigenotype. Accumulation of DNA methylation and formation of the epigenotype is suggested to occur during the early stages of carcinogenesis and predetermines the future cancer type., (© The Authors 2014. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.)

Titanium dioxide (TiO2), as an excellent photocatalyst, has been intensively investigated and widely used in environmental purification. However, the wide band gap of TiO2 and rapid recombination of photogenerated charge carriers significantly limit its overall photocatalytic efficiency. Here, efficient visible-light-active photocatalysts were developed on the basis of TiO2 modified with two ubiquitous nanoclusters. In this photocatalytic system, amorphous Ti(IV) oxide nanoclusters were demonstrated to act as hole-trapping centers on the surface of TiO2 to efficiently oxidize organic contaminants, while amorphous Fe(III) or Cu(II) oxide nanoclusters mediate the reduction of oxygen molecules. Ti(IV) and Fe(III) nanoclusters-modified TiO2 exhibited the highest quantum efficiency (QE = 92.2%) and reaction rate (0.69 μmol/h) for 2-propanol decomposition among previously reported photocatalysts, even under visible-light irradiation (420-530 nm). The desirable properties of efficient photocatalytic performance with high stability under visible light with safe and ubiquitous elements composition enable these catalysts feasible for large-scale practical applications.

Despite the recent advances in the therapeutic modalities, colorectal cancer (CRC) remains to be one of the most common causes of cancer-related death. CRC arises through accumulation of multiple genetic and epigenetic alterations that transform normal colonic epithelium into adenocarcinomas. Among crucial roles of epigenetic alterations, gene silencing by aberrant DNA methylation of promoter regions is one of the most important epigenetic mechanisms. Recent comprehensive methylation analyses on genome-wide scale revealed that sporadic CRC can be classified into distinct epigenotypes. Each epigenotype cooperates with specific genetic alterations, suggesting that they represent different molecular carcinogenic pathways. Precursor lesions of CRC, such as conventional and serrated adenomas, already show similar methylation accumulation to CRC, and can therefore be classified into those epigenotypes of CRC. In addition, specific DNA methylation already occurs in the normal colonic mucosa, which might be utilized for prediction of the personal CRC risk. DNA methylation is suggested to occur at an earlier stage than carcinoma formation, and may predict the molecular basis for future development of CRC. Here, we review DNA methylation and CRC classification, and discuss the possible clinical usefulness of DNA methylation as biomarkers for the diagnosis, prediction of the prognosis and the response to therapy of CRC.

The aim of this study was to investigate the usefulness of lubiprostone for bowel preparation and as a propulsive agent in small bowel endoscopy. Six healthy male volunteers participated in this randomized, 3-way crossover study. The subjects received a 24 μg tablet of lubiprostone 60 minutes prior to the capsule ingestion for capsule endoscopy (CE) and a placebo tablet 30 minutes before the capsule ingestion (L-P regimen), a placebo tablet 60 minutes prior to CE and a 24 μg tablet of lubiprostone 30 minutes prior to CE (P-L regimen), or a placebo tablet 60 minutes prior to r CE and a placebo tablet again 30 minutes prior to CE (P-P regimen). The quality of the capsule endoscopic images and the amount of water in the small bowel were assessed on 5-point scale. The median SBTT was 178.5 (117-407) minutes in the P-P regimen, 122.5 (27-282) minutes in the L-P regimen, and 110.5 (11-331) minutes in the P-L regimen (P = 0.042). This study showed that the use of lubiprostone significantly decreased the SBTT. We also confirmed that lubiprostone was effective for inducing water secretion into the small bowel during CE.

Osteoclasts (OCLs) are multinucleated bone-resorbing cells that are differentiated by receptor activator of nuclear factor kappa-B ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). Our recent studies have shown that heme-oxygenase-1 (HO-1), a stress-induced cytoprotective enzyme, plays an important role in OCL differentiation, although the pharmacological significance of this effect remains unknown. In this study, we investigated the effects of tert-butylhydroquinone (tBHQ), a pharmacological HO-1 inducer, on in vitro differentiation of bone marrow-derived macrophages (BMMs) or murine monocytic cell line RAW-D into OCLs. tBHQ inhibited the formation and the bone-resorbing activity of OCLs. Moreover, tBHQ treatment decreased the expression of nuclear factor of activated T cells cytoplasmic-1 (NFATc1), a master regulator of OCL differentiation, and of OCL markers transcriptionally regulated by NFATc1, such as Src and cathepsin K. In addition, tBHQ impaired phosphorylation of extracellular signal-regulated kinase, p38 mitogen-activated protein kinase (MAPK), Jun N-terminal kinase, Akt, and inhibitor of nuclear factor kappa B alpha (IκBα). Finally, we show that tBHQ inhibited the release of high mobility group box 1 (HMGB1), a recently identified activator of OCL differentiation. Thus, tBHQ inhibits OCL differentiation through the HO-1/HMGB1 pathways., (Copyright © 2012 John Wiley & Sons, Ltd.)

Two new β-carboline alkaloids, variabines A (1) and B (2), were isolated from the Indonesian marine sponge Luffariella variabilis. Their structures were elucidated from spectral data, and 1 was found to be a sulfonated derivative of 2. Although numerous β-carboline alkaloids have been isolated from natural sources to date, 1 is the first β-carboline derivative containing a sulfate group. Compound 2 inhibited chymotrypsin-like activity of the proteasome and Ubc13 (E2)-Uev1A interaction with IC50 values of 4 and 5 μg/mL, respectively, whereas 1 had little effect on the activity or interaction.

Cathepsin E is an endosomal aspartic proteinase that is predominantly expressed in immune-related cells. Recently, we showed that macrophages derived from cathepsin E-deficient (CatE(-/-)) mice display accumulation of lysosomal membrane proteins and abnormal membrane trafficking. In this study, we demonstrated that CatE(-/-) macrophages exhibit abnormalities in autophagy, a bulk degradation system for aggregated proteins and damaged organelles. CatE(-/-) macrophages showed increased accumulation of autophagy marker proteins such as LC3 and p62, and polyubiquitinated proteins. Cathepsin E deficiency also altered autophagy-related signaling pathways such as those mediated by the mammalian target of rapamycin (mTOR), Akt, and extracellular signal-related kinase (ERK). Furthermore, immunofluorescence microscopy analyses showed that LC3-positive vesicles were merged with acidic compartments in wild-type macrophages, but not in CatE(-/-) macrophages, indicating inhibition of fusion of autophagosome with lysosomes in CatE(-/-) cells. Delayed degradation of LC3 protein was also observed under starvation-induced conditions. Since the autophagy system is involved in the degradation of damaged mitochondria, we examined the accumulation of damaged mitochondria in CatE(-/-) macrophages. Several mitochondrial abnormalities such as decreased intracellular ATP levels, depolarized mitochondrial membrane potential, and decreased mitochondrial oxygen consumption were observed. Such mitochondrial dysfunction likely led to the accompanying oxidative stress. In fact, CatE(-/-) macrophages showed increased reactive oxygen species (ROS) production and up-regulation of oxidized peroxiredoxin-6, but decreased antioxidant glutathione. These results indicate that cathepsin E deficiency causes autophagy impairment concomitantly with increased aberrant mitochondria as well as increased oxidative stress.

A 77-year-old man was diagnosed as having cholangiocellular carcinoma. The patient underwent partial right hepatectomy in June 2008, and multiple bone metastases occurred approximately 9 months after surgery. He refused salvage chemotherapy and radiation therapy. Although he had been treated with opiate analgesics, he was unable to sit up owing to severe pain in the left ilium. He was hospitalized because of buttock pain and left leg numbness. Even a combination of fentanyl patch, gabapentin, and subarachnoid block was ineffective in controlling pain. Strontium-89 (89Sr) therapy was successful in eliminating the intractable pain, and there were no serious side effects during therapy. The patient was discharged from the hospital, and he received palliative care at home for a short period.

Nanoparticles of an n-type WO3 semiconductor were segregated on the surface of p-type CaFe2O4 particles by a heterogeneous nucleation process under controlled hydrothermal conditions. By use of this approach, WO3 nanoparticles were selectively deposited on the surface of CaFe2O4, resulting in a significant increase in the photocatalytic reaction rate of the WO3/CaFe2O4 composite for the decomposition of gaseous acetaldehyde under visible-light irradiation. The high visible-light activity of the WO3/CaFe2O4 composite was due to efficient charge recombination through the junctions that formed between the two semiconductors.

Background/aims: Left-sided diverticulitis is increasing in Japan, and many studies report that left-sided diverticulitis is more likely to be severe. Therefore, it is important to identify the features and risk factors for left-sided diverticulitis. We hypothesized that left-sided diverticulitis in Japan is related to obesity and conducted a study of the features and risk factors for this disorder in Japan., Methods: Right-sided diverticulitis and left-sided diverticulitis patients (total of 215) were compared with respect to background, particularly obesity-related factors to identify risk factors for diverticulitis., Results: There were 166 (77.2%) right-sided diverticulitis patients and 49 (22.8%) left-sided diverticulitis patients. The proportions of obese patients (body mass index ≥25 kg/m(2), p=0.0349), viscerally obese patients (visceral fat area ≥100 cm(2), p=0.0019), patients of mean age (p=0.0003), and elderly patients (age ≥65 years, p=0.0177) were significantly higher in the left-sided-diverticulitis group than in the right-sided-diverticulitis group. The proportion of viscerally obese patients was significantly higher in the left-sided-diverticulitis group than in the left-sided-diverticulosis group (p=0.0390)., Conclusions: This study showed that obesity, particularly visceral obesity, was a risk factor for left-sided diverticulitis in Japan.

Acute encephalopathy with febrile convulsive status epilepticus (AEFCSE) is the most common type of acute encephalopathy in childhood in Japan, which develops with prolonged febrile convulsion, followed by mild unconsciousness. It is generally sporadic and nonrecurrent. In this report, a 1-year-old girl showed signs of AEFCSE triggered by respiratory syncytial virus infection. Two years later, she presented with AEFCSE triggered by influenza virus infection, resulting in severe neurologic sequelae. The patient had a thermolabile genotype of carnitine palmitoyltransferase II (CPT II) variations consisting of three single nucleotide polymorphisms in exons 4 [1055T > G/F352C and 1102G > A/V368I] and 5 [1939A > G/M647V]. The polymorphism has been identified as a genetic predisposition for acute encephalopathy. This report presents the first case of recurrent encephalopathy with CPT II variations that may partially associate with pathogenesis of recurrent AEFCSE., (Georg Thieme Verlag KG Stuttgart · New York.)

Aim: To identify the predictive factors for the presence of small bowel lesions in patients with obscure gastrointestinal bleeding (OGIB)., Methods: A total of 242 patients with OGIB (overt 149: occult 93) were retrospectively included in the present study. Capsule endoscopy (CE) was carried out to investigate the small bowel, and detected lesions were classified according to the P0-P2 system. Only P2 lesions were defined as significant lesions. Univariate and multivariate logistic regression analyses were carried out to define the predictive factors for the presence of small bowel lesions., Results: In patients with overt OGIB, chronic kidney disease (CKD) ≥stage 4 (odds ratio [OR] 4.03; 95% confidence interval [CI] 1.45-11.1, P = 0.007) was identified as an independent predictor of the presence of vascular lesions, and a history of non-steroidalanti-inflammatory drug (NSAID) use as that of erosive/ulcerated lesions (OR 4.73; 95% CI 1.47-15.2, P = 0.009). However, in patients with occult OGIB, no significant predictors of the presence of vascular lesions were identified, whereas a history of low-dose aspirin (LDA) (OR 3.57; 95% CI 1.21-10.5, P = 0.02) and proton pump inhibitor (PPI) use (OR 3.18; 95% CI 1.02-9.92, P = 0.05) were identified as independent predictors of the presence of erosive/ulcerated lesions., Conclusions: Our results indicated that bleeding pattern and clinical characteristics could contribute to predicting the origin of OGIB., (© 2012 The Authors. Digestive Endoscopy © 2012 Japan Gastroenterological Endoscopy Society.)

Schizosaccharomyces pombe and Saccharomyces cerevisiae are excellent model organisms to study lifespan. We conducted screening to identify novel genes that, when overexpressed, extended the chronological lifespan of fission yeast. We identified seven genes, among which we focused on SPBC16A3.08c. The gene product showed similarity to Ylr150w of S. cerevisiae, which has affinity for guanine-quadruplex nucleic acids (G4). The SPBC16A3.08c product associated with G4 in vitro and complemented the phenotype of an S. cerevisiae Ylr150w deletion mutant. From these results, we proposed that SPBC16A3.08c encoded for a functional homolog of Ylr150w, which we designated ortholog of G4-associated protein (oga1 (+)). oga1 (+) overexpression extended the chronological lifespan and also decreased mating efficiency and caused both high and low temperature-sensitive growth. Deleting oga1 (+) resulted in caffeine-sensitive and canavanine-resistant phenotypes. Based on these results, we discuss the function of Oga1 on the chronological lifespan of fission yeast.

Natural medicinal exudates such as gum arabic are high-molecular-weight natural polysaccharides and are highly soluble in water. The dissolved solutions of these exudates show viscous behavior and exhibit favorable emulsion stability. These exudates have been widely used not only as a medicinal additive, such as a coating agent for tablets and as an emulsifier and stabilizer in beverage and food products, but also for other industrial applications, such as paints and ink. Gum ghatti was originally used as an alternative to gum arabic due to its similar properties to those found in gum arabic. Gum ghatti has been used as a food additive due to its excellent emulsification properties. In this study, we obtained gum ghatti nodules and branches as botanical specimens, which were collected from the same harvesting area. Refined gum ghatti processed from the collected gum ghatti nodules was found to comply with the specifications set by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) and also to be identical to commercially available gum ghatti products as a food additive. Component analysis of the refined gum ghatti samples revealed that they contain arabinose (34.0-38.0 %), galactose (21.0-24.6 %), mannose (5.3-7.9 %), xylose (0.8-1.2 %), rhamnose (0.8-1.2 %), and glucuronic acid (15.4-18.6 %) as constituent sugars, protein (2.7-3.6 %), moisture (4.9-8.3 %), and tannin (0.041-0.092 %). As a result of the investigation of collected branches as botanical specimens, they were identified as Anogeissus latifolia Wallich. Detailed observation of their morphological characteristics revealed that many crystal cells were aligned in the lengthwise section of branch specimens.

Aspartic proteinases form a widely distributed protein superfamily, including cathepsin D, cathepsin E, pepsins, renin, BACE and napsin. Human napsin genes are located on human chromosome 19q13, which comprises napsin A and napsin B. Napsin B has been annotated as a pseudogene because it lacks an in-frame stop codon; its nascent chains are cotranslationally degraded. Until recently, there have been no studies concerning the molecular evolution of the napsin protein family in the human genome. In the present study, we investigated the evolution and gene organization of the napsin protein family. Napsin B orthologs are primarily distributed in primates, while napsin A orthologs are the only napsin genes in other species. The corresponding regions of napsin B in the available sequences from primate species contain an in-frame stop codon at a position equivalent to that of human napsin A. In addition, a rare single-nucleotide polymorphism (SNP) that creates a proper stop codon in human napsin B was identified using HapMap populations. Recombinant protein expression and three-dimensional comparative modeling revealed that napsin B exhibits residual activity toward synthetic aspartic protease substrates compared with napsin A, presumably through a napsin B-specific Arg287 residue. Thus, napsin B was duplicated from napsin A during the early stages of primate evolution, and the subsequent loss of napsin B function during primate evolution reflected ongoing human-specific napsin B pseudogenization., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background/aims: The gastrointestinal motility effects of endogenous incretin hormones enhanced by dipeptidyl peptidase-IV (DPP-IV) inhibitors have not yet been sufficiently investigated. The aim of this study was to determine whether single pre-prandial sitagliptin, the DPP-IV inhibitor, administration might have an effect on the rate of liquid gastric emptying using the (13)C-acetic acid breath test., Methods: Ten healthy male volunteers participated in this randomized, two-way crossover study. The subjects fasted for overnight and were randomly assigned to receive 50 mg sitagliptin 2 hours before ingestion of the liquid test meal (200 kcal per 200 mL, containing 100 mg (13)C-acetate) or the test meal alone. Under both conditions, breath samples were collected for 150 minutes following the meal. Liquid gastric emptying was estimated by the values of the following parameters: the time required for 50% emptying of the labeled meal (T1/2), the analog to the scintigraphy lag time for 10% emptying of the labeled meal (Tlag), the gastric emptying coefficient and the regression-estimated constants (β and κ), calculated by using the (13)CO2 breath excretion curve using the conventional formulae. The parameters between the 2 test conditions were compared statistically., Results: No significant differences in the calculated parameters, including T1/2, Tlag, gastric emptying coefficient or β and κ, were observed between the 2 test conditions., Conclusions: The present study revealed that single-dose sitagliptin intake had no significant influence on the rate of liquid gastric emptying in asymptomatic volunteers.

Osteoclasts (OCLs) are multinucleated bone-resorbing cells that are differentiated by stimulation with receptor activator of nuclear factor kappa-B ligand (RANKL) and macrophage colony-stimulating factor. We recently demonstrated that regulation of heme-oxygenase 1 (HO-1), a stress-induced cytoprotective enzyme, also functions in OCL differentiation. In this study, we investigated effects of fisetin, a natural bioactive flavonoid that has been reported to induce HO-1 expression, on the differentiation of macrophages into OCLs. Fisetin inhibited the formation of OCLs in a dose-dependent manner and suppressed the bone-resorbing activity of OCLs. Moreover, fisetin-treated OCLs showed markedly decreased phosphorylation of extracellular signal-regulated kinase, Akt, and Jun N-terminal kinase, but fisetin did not inhibit p38 phosphorylation. Fisetin up-regulated mRNA expression of phase II antioxidant enzymes including HO-1 and interfered with RANKL-mediated reactive oxygen species (ROS) production. Studies with RNA interference showed that suppression of NF-E2-related factor 2 (Nrf2), a key transcription factor for phase II antioxidant enzymes, rescued fisetin-mediated inhibition of OCL differentiation. Furthermore, fisetin significantly decreased RANKL-induced nuclear translocation of cFos and nuclear factor of activated T cells cytoplasmic-1 (NFATc1), which is a transcription factor critical for osteoclastogenic gene regulation. Therefore, fisetin inhibits OCL differentiation through blocking RANKL-mediated ROS production by Nrf2-mediated up-regulation of phase II antioxidant enzymes.

Obscure gastrointestinal bleeding (OGIB) is one of the common complications in patients with chronic kidney disease (CKD), especially those who are on maintenance hemodialysis (HD). However, little is known about the characteristics of the small-bowel lesions in these patients, or of the factors that could predict the presence of such lesions. Therefore we enrolled a total of 42 CKD patients (including 19 HD patients and 23 non-HD patients), and compared the incidence of the small-bowel lesions among two groups. Furthermore, to identify predictive factors for the presence of small-bowel lesions, we performed multivariate logistic-regression-analyses. The incidence of small-bowel vascular lesions was significantly higher in CKD patients than in age-and-sex matched non-CKD patients (P < 0.001). On the other hand, there was any significant difference of the incidence of small-bowel lesions between HD and non-HD patients. In CKD patients, past history of blood transfusion (OR 5.66; 95% CI 1.10-29.1, P = 0.04) was identified as an independent predictor of the presence of vascular lesions, and history of low-dose aspirin use (OR 6.00; 95% CI 1.13-31.9, P = 0.04) was identified as that of erosive/ulcerated lesions. This indicated that proactive CE examination would be clinically meaningful for these patients.

Aim: To clarify the relationship of human rectal aberrant crypt foci and formation of colorectal polyp., Methods: Eighty-nine subjects were recruited from the population of Japanese individuals who underwent polypectomy at Yokohama City University Hospital. All patients had baseline adenomas removed at year 0 colonoscopy. Aberrant crypt foci (ACF) were defined as lesions in which the crypts were more darkly stained with methylene blue than normal crypts and had larger diameters, often with oval or slit-like lumens and a thicker epithelial lining., Results: A total of 366 ACFs were identified in 89 patients; all had baseline adenomas removed at the first examination (year 0) colonoscopy and returned for the second (year 1). ACF in the lower rectum were assessed at year 0 and study group were divided into two groups depend on ACF numbers, 0-3 or over 3. All participants were examined in the number and maximum size of adenoma. There was no statistical difference in number and maximum size of ACF at year 0, however, maximum size of adenoma was larger in over 3 group than 0-3 group at year 1., Conclusion: The number of ACF may be a predictive factor of relatively large adenoma incidence in the pilot phase study.

Background: Oral sumatriptan administration has been reported to delay gastric emptying after liquid meals. The aim of this study was to determine whether delayed gastric emptying is caused by enhanced gastric accommodation, impaired antral contractions, or both using ultrasonography., Methods: Ten healthy volunteers were enrolled in this randomized two-way crossover study. After overnight fasting, the subjects received the liquid meal 60 min after ingesting a 50 mg sumatriptan tablet with 50 mL of water or 50 mL of water alone (control). The cross-sectional area of the proximal stomach was measured in a supine position after every 100 mL. The frequency and amplitude of the antral contractions were measured in a slightly backward sitting position. The intragastric distribution of the liquid meal was assessed by calculating the proximal stomach/distal stomach ratio (prox/distal ratio)., Key Results: The cross-sectional area after drinking 100, 200, and 300 mL of the liquid meal (oral sumatriptan vs control) was 34.49 vs 15.11 cm(2) (P = 0.0051), 48.00 vs 30.61 cm(2) (P = 0.0166), and 58.67 vs 47.19 cm(2) (P = 0.0125), respectively. There was no significant difference in the amplitude of contractions, contraction cycle, motility index, and prox/distal ratio (97.15 vs 97.93%, P = 0.0745; 19.42 vs 19.5 s, P= 0.8590; and 887.58 vs 889.22, P = 0.5751; 9.75 vs 8.41, P = 0.8785; respectively)., Conclusions & Inferences: Oral sumatriptan administration enhanced gastric accommodation after the ingestion of liquid nutrients, but had no significant effect on antral contractions or intragastric distribution in healthy subjects., (© 2012 Blackwell Publishing Ltd.)

Background: The severity of the 2009 pandemic H1N1 influenza (H1N1 pdm 09) in immune deficient children is unknown. The aim of the present study was to investigate this in a case of complete IgG3 deficiency complicated by pneumonia and asthma attack., Methods: The clinical parameters of the IgG3 deficiency patient were compared with those of four control patients using 95% confidence intervals. These control patients were selected from 71 patients admitted due to pneumonia or bronchitis caused by H1N1 pdm 09, and were chosen according to age, absence of pretreatment with oseltamivir before admission, presence of a past history of asthma, use of antibiotics, and combination of inhalation of a beta2 agonist and treatment with i.v. methylprednisolone for asthma attack., Results: The IgG3 deficiency patient had significantly longer duration of admission and period of oseltamivir, with a significantly decreased pulse oxygen saturation and increased maximum serum C-reactive protein, creatine kinase and urinary excretion of β2-microglobulin/creatinine, compared with the controls (P < 0.05)., Conclusions: Complete IgG3 deficiency is possibly associated with severity of the clinical course of pneumonia and asthma attack in children suffering from H1N1 pdm 09., (© 2012 The Authors. Pediatrics International © 2012 Japan Pediatric Society.)

Aim: A case-controlled study was performed to investigate the association of colonic angiectasia with other conditions and to identify risk factors for bleeding., Method: Information was collected from all patients who underwent colonoscopy at our hospital between January 2008 and December 2010. Data on 90 individuals with angiectasia [58 men; median age 69 (26-92) years] were compared with those of 180 individuals without angiectasia, matched for gender and age., Results: Multivariate analysis showed that occult gastrointestinal bleeding [odds ratio (OR) 2.523; 95% confidence interval (CI) 1.238-5.142], liver cirrhosis (OR 13.195; 95% CI 3.502-49.711), chronic renal failure (OR 6.796; 95% CI 1.598-28.904) and valvular heart disease (OR 6.425; 95% CI 1.028-40.165) were identified as significant predictors of the presence of colonic angiectasia. Eight patients were diagnosed with bleeding from angiectasia. Cardiovascular disease (OR 22.047; 95% CI 1.063-457.345) and multiple angiectasias (P-value 0.0019) were identified as significant risk factors for active bleeding. Medication and a large size were not associated with an increased risk of bleeding., Conclusion: The presence of colonic angiectasia was associated with valvular heart disease, liver cirrhosis and chronic renal failure. Valvular heart disease and multiple lesions increased the risk of bleeding., (© 2012 The Authors. Colorectal Disease © 2012 The Association of Coloproctology of Great Britain and Ireland.)

Background: The differences in the small intestinal toxicity of low-dose aspirin based on the type of aspirin used remains unclear. The purpose of this study was to evaluate the differences in the small bowel mucosal injury between buffered and enteric-coated aspirin users by capsule endoscopy., Methods: We retrospectively reviewed the findings in chronic low-dose aspirin users (>3 months) who underwent capsule endoscopy for the investigation of obscure gastrointestinal bleeding. The patients were classified into two groups based on the type of low-dose aspirin that they had been prescribed (enteric-coated aspirin group or buffered aspirin group), and evaluated the numbers of small bowel lesions and the Lewis score., Results: Capsule-endoscopic findings of a total of 70 patients taking low-dose aspirin were reviewed. Significant differences in the number of erosions and ulcers were observed between the buffered and enteric-coated aspirin groups (P=0.017 and P=0.037, respectively). The median Lewis score for the small bowel mucosal inflammatory change was significantly higher in the enteric-coated aspirin group than in the buffered aspirin group (P=0.035)., Conclusions: The results of this study suggested that enteric-coated aspirin might be more injurious to the small bowel mucosa than buffered aspirin., (Copyright © 2012 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: Colorectal cancer (CRC) is one of the most commonly occurring neoplasms and a leading cause of cancer death worldwide, and new preventive strategies are needed to lower the burden of this disease. Eicosapentaenoic acid (EPA), the omega-3 polyunsaturated fatty acid that is widely used in the treatment of hyperlipidemia and prevention of cardiovascular disease, has recently been suggested to have a suppressive effect on tumorigenesis and cancer cell growth. In CRC chemoprevention trials, in general, the incidence of polyps or of the cancer itself is set as the study endpoint. Although the incidence rate of CRC would be the most reliable endpoint, use of this endpoint would be unsuitable for chemoprevention trials, because of the relatively low occurrence rate of CRC in the general population and the long-term observation period that it would necessitate. Moreover, there is an ethical problem in conducting long-term trials to determine whether a test drug might be effective or harmful. Aberrant crypt foci (ACF), defined as lesions containing crypts that are larger in diameter and stain more darkly with methylene blue than normal crypts, are considered as a reliable surrogate biomarker of CRC. Thus, we devised a prospective randomized controlled trial as a preliminary study prior to a CRC chemoprevention trial to evaluate the chemopreventive effect of EPA against colorectal ACF formation and the safety of this drug, in patients scheduled for polypectomy., Methods: This study is a multicenter, double-blind, placebo-controlled, randomized controlled trial to be conducted in patients with both colorectal ACF and colorectal polyps scheduled for polypectomy. Eligible patients shall be recruited for the study and the number of ACF in the rectum counted at the baseline colonoscopy. Then, the participants shall be allocated randomly to either one of two groups, the EPA group and the placebo group. Patients in the EPA group shall receive oral 900-mg EPA capsules thrice daily (total daily dose, 2.7 g per day), and those in the placebo group shall receive oral placebo capsules thrice daily. After one month's treatment with EPA/placebo, colonoscopic examination and polypectomy will be performed to evaluate the formation of ACF, and the cell-proliferative activity and cell-apoptotic activity in normal colorectal mucosa and colorectal polyps., Discussion: This is the first study proposed to explore the effect of EPA against colorectal ACF formation in humans.This trial has been registered in the University hospital Medical Information Network (UMIN) Clinical Trials Registry as UMIN000008172.

Aim: To reveal the frequency, characteristics and prognosis of chronic intestinal pseudo-obstruction (CIP) in mitochondrial disease patients., Methods: Between January 2000 and December 2010, 31 patients (13 males and 18 females) were diagnosed with mitochondrial diseases at our hospital. We conducted a retrospective review of the patients' sex, subclass of mitochondrial disease, age at onset of mitochondrial disease, frequency of CIP and the age at its onset, and the duration of survival. The age at onset or at the first diagnosis of the disorder that led to the clinical suspicion of mitochondrial disease was also examined., Results: Twenty patients were sub-classified with mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS), 8 with chronic progressive external ophthalmoplegia (CPEO), and 3 with myoclonus epilepsy associated with ragged-red fibers (MERRF). Nine patients were diagnosed with CIP, 8 of the 20 (40.0%) patients with MELAS, 0 of the 8 (0.0%) patients with CPEO, and 1 of the 3 (33.3%) patients with MERRF. The median age (range) at the diagnosis and the median age at onset of mitochondrial disease were 40 (17-69) and 25 (12-63) years in patients with CIP, and 49 (17-81) and 40 (11-71) years in patients without CIP. During the survey period, 5 patients (4 patients with MELAS and 1 with CPEO) died. The cause of death was cardiomyopathy in 2 patients with MELAS, cerebral infarction in 1 patient with MELAS, epilepsy and aspiration pneumonia in 1 patient with MELAS, and multiple metastases from gastric cancer and aspiration pneumonia in 1 patient with CPEO., Conclusion: Patients with CIP tend to have disorders that are suspected to be related to mitochondrial diseases at younger ages than are patients without CIP.

Aim: Endoscopic screening and removal of colorectal adenomas can reduce the incidence of colorectal cancer. However, given the possibility of adenoma recurrence, surveillance colonoscopy is currently recommended after the initial screening and removal of colorectal adenomas. Aberrant crypt foci (ACF) have been shown to serve as a reliable surrogate marker of colorectal carcinogenesis. In this study, the relationship between the number of ACF at the initial endoscopic polypectomy and the likelihood of colorectal adenoma recurrence after polypectomy were investigated., Methods: High-magnification chromoscopic colonoscopy was performed in 82 subjects who underwent endoscopic polypectomy to identify ACF in the lower rectum. Surveillance colonoscopy was then performed 3 years after the baseline polypectomy at Yokohama City University Hospital., Results: The number of ACF was greater in patients who showed adenoma recurrence (7.88 ± 6.35) than in those who did not (2.19 ± 2.95) (P < 0.001). Receiver-operating curve analysis showed that the number of ACF was a highly specific predictor of the risk of adenoma recurrence., Conclusions: This is the first study conducted to investigate the relationship between the number of ACF after endoscopic polypectomy and the likelihood of recurrence of colorectal adenomas. These results suggest that the number of ACF is a useful predictor of the likelihood of colorectal adenoma recurrence., (© 2012 The Authors. Digestive Endoscopy © 2012 Japan Gastroenterological Endoscopy Society.)

Deltamethrin is a widely used pyrethroid pesticide. Although the cytotoxicity of deltamethrin has been reported, especially in neuronal cells, there is no information concerning the effects of deltamethrin on osteoclasts (OCLs). In this study, we showed that deltamethrin inhibited OCL differentiation in vitro. The effects of deltamethrin on OCL differentiation by receptor activator of nuclear factor kappa-B ligand (RANKL) were investigated in bone marrow-derived macrophages (BMMs) or the murine monocytic cell line RAW-D. Treatment with deltamethrin inhibited OCL formation and bone resorption and up-regulated expression of heme oxygenase-1 (HO-1), an anti-oxidative stress enzyme. Deltamethrin also decreased the protein levels of nuclear factor of activated T cells cytoplasmic-1 (NFATc1), which is a master regulator for OCL differentiation, and concomitantly reduced the expression levels of Src and cathepsin K, which are transcriptionally regulated by NFATc1. The effects of deltamethrin on intracellular signaling during the OCL differentiation of BMMs indicated that deltamethrin-treated OCLs displayed impaired phosphorylation of extracellular signal-regulated kinase, p38 mitogen-activated protein kinase, Jun N-terminal kinase, and Akt, and slightly delayed phosphorylation of inhibitor of nuclear factor kappa B alpha (IκBα) compared with untreated OCLs. Thus, deltamethrin possibly affects bone metabolism by inhibiting OCL differentiation., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Purpose: To assess a newly developed eyelid pressure measurement system called a blepharo-tensiometer that uses a tactile pressure sensor., Methods: The tactile sensor was 10 mm in diameter and approximately 0.4 mm thick. The sensor was covered with silicon rubber and was placed between a soft contact lens on the cornea and the inner surface of the eyelid. Under these conditions, the sensor measured the pressure of the eyelid on the ocular surface. The pressure of the upper and lower eyelids were measured separately while the eyelids were closed for at least 5 seconds in 34 eyes of 34 normal volunteers. To determine the reliability of the blepharo-tensiometer, the pressures of the upper and lower eyelids were measured on 3 separate days in both eyes of 12 normal volunteers. The correlation between the age and the eyelid pressure was calculated., Results: The intraclass correlation coefficients for the 3 measurements ranged from 0.675 to 0.911 for the upper eyelid and 0.663 to 0.925 for the lower eyelid. The mean eyelid pressure was 16.95±6.08 mm Hg for the upper lid and 16.11±7.27 mm Hg for the lower lid. The eyelid pressure decreased with increasing age, and both the upper and lower eyelid pressures were significantly and negatively correlated with age (upper eyelid pressures, P<0.0001; lower eyelid pressures, P=0.000432). No complication was detected after the measurements in all of the subjects., Conclusions: Our blepahro-tensiometer can obtain repeatable measurements of the eyelid pressure and can be used to evaluate the pressure of the eyelids on the ocular surface in normal and diseased eyes.

Aim: To determine the effect of oral sumatriptan on gastric emptying using a continuous ¹³C breath test (BreathID system)., Methods: Ten healthy male volunteers participated in this randomized, 2-way crossover study. The subjects fasted overnight and were randomly assigned to receive a test meal (200 kcal/200 mL) 30 min after pre-medication with sumatriptan 50 mg (sumatriptan condition), or the test meal alone (control condition). Gastric emptying was monitored for 4 h after administration of the test meal by the ¹³C-acetic acid breath test performed continually using the BreathID system. Then, using Oridion Research Software (β version), the time taken for emptying of 50% of the labeled meal (T(1/2)) similar to the scintigraphy lag time for 10% emptying of the labeled meal (T(lag)), the gastric emptying coefficient (GEC), and the regression-estimated constants (β and κ) were calculated. The statistical significance of any differences in the parameters were analyzed using Wilcoxon's signed-rank test., Results: In the sumatriptan condition, significant differences compared with the control condition were found in T(1/2) [median 131.84 min (range, 103.13-168.70) vs 120.27 min (89.61-138.25); P = 0.0016], T(lag) [median 80.085 min (59.23-125.89) vs 61.11 min (39.86-87.05); P = 0.0125], and β [median 2.3374 (1.6407-3.8209) vs 2.0847 (1.4755-2.9269); P = 0.0284]. There were no significant differences in the GEC or κ between the 2 conditions., Conclusion: This study showed that oral sumatriptan significantly delayed gastric emptying of a liquid meal.

Background: Capsule endoscopy with flexible spectral imaging color enhancement (CE-FICE) has been reported to improve the visualization and detection of small-bowel lesions, however, its clinical usefulness is still not established. Therefore, we conducted a study to evaluate whether CE-FICE contributes to improve the detectability of small-bowel lesions by CE trainees., Methods: Four gastroenterology trainees without prior CE experience were asked to read and interpret 12 CE videos. Each of the videos was read by conventional visualization method and under three different FICE settings. To evaluate whether the lesion recognition ability of the CE trainees could be improved by the FICE technology, the lesion detection rate under each of the three FICE settings was compared with that by conventional CE. CE trainees tend to miss small-bowel lesions in bile-pigment-positive condition, therefore we evaluated whether CE-FICE contributes to reducing the bile-pigment effect. The bile-pigment condition was determined by the color values around the small-bowel lesions according to the results of the receiver-operating-characteristic analysis. Moreover, we also evaluated whether poor bowel preparion might affect the accuracy of lesion recognition by CE-FICE., Results: Of a total of 60 angioectasias, CE trainees identified 26 by conventional CE, 40 under FICE setting 1, 38 under FICE setting 2, and 31 under FICE setting 3. Of a total of 82 erosions/ulcerations, CE trainees identified 38 by conventional CE, 62 under FICE setting 1, 60 under FICE setting 2, and 20 under FICE setting 3. Compared with conventional CE, FICE settings 1 and 2 significantly improved the detectability of angioectasia (P = 0.0017 and P = 0.014, respectively) and erosions/ulcerations (P = 0.0012 and P = 0.0094, respectively). Although the detectability of small-bowel lesions by conventional CE (P = 0.020) and under FICE setting 2 (P = 0.0023) was reduced by the presence of bile-pigments, that under FICE setting 1 was not affected (P = 0.59). Our results also revealed that in poor bowel visibility conditions, CE-FICE yielded a high rate of false-positive findings., Conclusions: CE-FICE may reduce the bile-pigment effect and improve the detectability of small-bowel lesions by CE trainees; the reliability of CE-FICE may be improved by good bowel preparation.

Genetic improvement of resistance to infectious diseases is a challenging goal in animal breeding. Infection resistance involves multiple immunological characteristics, including natural and acquired immunity. In the present study, we developed an experimental model based on genetic selection, to improve immunological phenotypes. We selectively established three mouse lines based on phagocytic activity, antibody production and the combination of these two phenotypes. We analyzed the immunological characteristics of these lines using a lipopolysaccharide (LPS), which is one of the main components of Gram-negative bacteria. An intense immunological reaction was induced in each of the three mouse lines. Severe loss of body weight and liver damage were observed, and a high level of cytokine messenger RNA was detected in the liver tissue. The mouse line established using a combination of the two selection standards showed unique characteristics relative to the mouse lines selected on the basis of a single phenotype. Our results indicate that genetic selection and breeding is effective, even for immunological phenotypes with a relatively low heritability. Thus, it may be possible to improve resistance to infectious diseases by means of genetic selection., (© 2011 The Authors. Animal Science Journal © 2011 Japanese Society of Animal Science.)

We report a case of systemic sclerosis with interstitial pneumonia and severe pulmonary hypertension treated with bosentan, an endothelin receptor antagonist. Within a short period of administration of the bosentan the skin sclerosis improved., (© 2010 The Authors. Australasian Journal of Dermatology © 2010 The Australasian College of Dermatologists.)

Although aberrant crypt foci (ACF) are estimated to have potential usefulness as a biomarker for colorectal carcinoma (CRC), this remains uncertain because the natural history of ACF has not been well-clarified. To determine the usefulness of ACF as a surrogate marker for CRC, it is necessary to understand the natural history of ACF. A total of 82 subjects who underwent total colonoscopy and whose ACF number was examined at least 2 times at Yokohama City University Hospital were enrolled. We retrospectively evaluated the changes in the ACF number at four different surveillance periods (6 months, 1 year, 2 years, 3 years) and in groups with and without colorectal neoplasms. Furthermore, we classified the subjects into an increased ACF group and a no change/decreased ACF group, and investigated the relationship between the changes in the ACF number and known risk factors for CRC. No significant differences were observed in the ACF number between the first and second observations in any surveillance period groups, and in the groups classified according to the presence or absence of colorectal neoplasms. There were no significant differences between the increased and no change/decreased ACF group in terms of gender, smoking habit, current alcohol consumption, age, BMI, HbA1c or serum triglyceride level (TG), whereas a significant difference between the groups was observed in the serum total cholesterol level (TC) (p=0.012). ACF are a reliable surrogate marker that are not affected by any risk factors for adenomas or CRC, except TC, and may therefore be considered as a useful marker in chemopreventive trials.

Osteoclasts (OCLs) are multinucleated giant cells and are formed by the fusion of mononuclear progenitors of monocyte/macrophage lineage. It is known that macrophages derived from different genetic backgrounds exhibit quite distinct characteristics of immune responses. However, it is unknown whether OCLs from different genetic backgrounds show distinct characteristics. In this study, we showed that bone-marrow macrophages (BMMs) derived from C57BL/6, BALB/c and ddY mice exhibited considerably distinct morphological characteristics and cell differentiation into OCLs. The differentiation of BMMs into OCLs was comparatively quicker in the C57BL/6 and ddY mice, while that of BALB/c mice was rather slow. Morphologically, ddY OCLs showed a giant cell with a round shape, C57BL/6 OCLs were of a moderate size with many protrusions and BALB/c OCLs had the smallest size with fewer nuclei. The intracellular signaling of differentiation and expression levels of marker proteins of OCLs were different in the respective strains. Treatment of BMMs from the three different strains with the reducing agent N-acetylcysteine (NAC) or with the oxidation agent hydrogen peroxide (H(2)O(2)) induced changes in the shape and sizes of the cells and caused distinct patterns of cell differentiation and survival. Thus, genetic backgrounds and redox conditions regulate the morphological characteristics and cell differentiation of OCLs.

Background: Colorectal cancer is one of the major neoplasms and a leading cause of cancer death worldwide, and new preventive strategies are needed to lower the burden of this disease. Metformin, a biguanide, which is widely used for treating diabetes mellitus, has recently been suggestive to have a suppressive effect on tumorigenesis and cancer cell growth. In a previous study conducted in non-diabetic subjects, we showed that oral short-term low-dose metformin suppressed the development of colorectal aberrant crypt foci (ACF). ACF have been considered as a useful surrogate biomarker of CRC, although the biological significance of these lesions remains controversial. We devised a prospective randomized controlled trial to evaluate the chemopreventive effect of metformin against metachronous colorectal polyps and the safety of this drug in non-diabetic post-polypectomy patients., Methods/design: This study is a multi-center, double-blind, placebo-controlled, randomized controlled trial to be conducted in non-diabetic patients with a recent history of undergoing colorectal polypectomy. All adult patients visiting the Yokohama City University hospital or affiliated hospitals for polypectomy shall be recruited for the study. Eligible patients will then be allocated randomly into either one of two groups: the metformin group and the placebo group. Patients in the metformin group shall receive oral metformin at 250 mg per day, and those in the placebo group shall receive an oral placebo tablet. At the end of 1 year of administration of metformin/placebo, colonoscopy will be performed to evaluate the polyp formation., Discussion: This is the first study proposed to explore the effect of metformin against colorectal polyp formation. Metformin activates AMPK, which inhibits the mammalian target of rapamycin (mTOR) pathway. The mTOR pathway plays an important role in the cellular protein translational machinery and cell proliferation. Patients with type 2 diabetes taking under treatment with metformin have been reported to be at a lower risk of cancer development than those not taking under treatment with metformin. We showed in a previous study that metformin suppressed the formation of human colorectal ACF. We therefore decided to conduct a study to determine whether metformin might suppress the formation of human colorectal polyps., Trial Registration: This trial has been registered in the University hospital Medical Information Network (UMIN) Clinical Trials Registry as UMIN000006254.

Background/aims: Before the introduction of capsule endoscopy and double-balloon endoscopy, there were no effective modalities for reliable evaluation of the small bowel. Recently, the SmartPill, a wireless pH/ pressure recording capsule, has been utilized to measure the whole gut transit time. However, there are few studies on the small bowel pH. The aim of this study was to investigate the relationship between small bowel disease and the small bowel pH, we designed a new modality, the 'pH capsule', to non-invasively record sequential images and the pH., Methodology: Ten healthy male volunteers swallowed the 'pH capsule' with 50mL of water. The 'pH capsule' transmitted the acquired images and the pH to the recorder unit located outside the body for about ten hours while the subject was fasting., Results: All subjects completed this study. The intragastric pH was low and the pH in the whole small intestine was 7.61, 7.55: 7.2-8.1 (mean, median: range). The pH value increased from the duodenum to the terminal ileum (p<0.0001)., Conclusions: We could non-invasively monitor sequential images and the pH of the small intestine with this new modality. The 'pH capsule' is expected to become a valuable tool for clinical assessment of the small bowel.

The differentiation of osteoclasts is regulated by several essential cytokines, such as receptor activator of nuclear factor κB ligand (RANKL) and macrophage colony-stimulating factor. Recently, high mobility group box 1 (HMGB1), a chromatin protein, also has been identified as one of these osteoclast differentiation cytokines. However, the molecular mechanisms that control HMGB1 release from osteoclast precursor cells are not known. Here, we report that RANKL-induced suppression of heme oxygenase-1 (HO-1), a heme-degrading enzyme, promotes HMGB1 release during osteoclastogenesis. In contrast, induction of HO-1 with hemin or curcumin in bone marrow-derived macrophages or RAW-D murine osteoclast precursor cells inhibited osteoclastogenesis and suppressed HMGB1 release. Since an inhibitor for p38 mitogen-activated protein kinase (MAPK) prevented the RANKL-mediated HO-1 suppression and extracellular release of HMGB1, these effects were p38 MAPK-dependent. Moreover, suppression of HO-1 in RAW-D cells by RNA interference promoted the activation of caspase-3 and HMGB1 release, whereas overexpression of HO-1 inhibited caspase-3 activation as well as HMGB1 release. Furthermore, these effects were regulated by redox conditions since antioxidant N-acetylcysteine abolished the HO-1/HMGB1/caspase-3 axis. These results suggest that RANKL-dependent HO-1 suppression leads to caspase-3 activation and HMGB1 release during osteoclastogenesis., (Copyright © 2011 Wiley Periodicals, Inc.)

In experimental models, mucin-depleted foci (MDF), formed by dysplastic crypts devoid of mucin production have been recognized to be correlated with colorectal carcinogenesis and to serve as preneoplastic lesions of colorectal cancer (CRC). In humans, there is only one report of identification of MDF in patients with familial adenomatous polyposis and CRC; however, the histological characteristics of human MDF are not discussed extensively in the report. In the present study, colonic samples from 53 patients with sporadic CRC were stained with Alcian blue and examined for the presence of MDF. Subsequently, the samples were examined for the presence of aberrant crypt foci (ACF) by methylene blue staining. We classified MDF into two categories: flat-MDF and protruded-MDF (having the characteristics of both ACF and MDF). We found a total of 354, 41 and 19 colonic mucosal lesions with a mean multiplicity of 44, 38.9 and 66.9 crypts (ACF, flat-MDF and protruded-MDF, respectively). The density of MDF was 0.0082 lesions/cm(2) . The ACF identified in sporadic CRC patients corresponded to hyperplastic or non-dysplasic lesions. However, MDF identified in these patients corresponded to low-grade dysplasia. In addition, we found that Paneth cell metaplasia and inflammatory cell infiltration were specific histological features of MDF. These histological characteristics are reported to be associated with the development of CRC. Therefore, our results indicate that MDF might represent preneoplastic lesions in human colorectal carcinogenesis., (© 2011 Japanese Cancer Association.)

Objective: The ideal medication for the treatment of acid-related diseases, e.g., peptic ulcers, stress-related gastric bleeding, functional dyspepsia, and gastroesophageal reflux disease, should have a rapid onset of action to promote hemostasis and relieve the symptoms. The aim of our study was to investigate the inhibitory effects on gastric acid secretion of a single oral administration of a proton pump inhibitor, omeprazole 20 mg, and an H(2)-receptor antagonist, roxatidine 75 mg., Methods: Ten Helicobacter pylori-negative male subjects participated in this randomized, two-way crossover study. Intragastric pH was monitored continuously for 6 h after single oral administration of omeprazole 20 mg and roxatidine 75 mg. Each administration was separated by a 7-d washout period., Results: During the 6-h study period, the average pH after administration of roxatidine was higher than that after administration of omeprazole (median: 4.45 vs. 2.65; P=0.0367). Also during the 6-h study period, a longer duration of maintenance at pH above 2, 5, and 6 was observed after administration of roxatidine 75 mg than after administration of omeprazole 20 mg (median: 90.6% vs. 55.2%, P=0.0284; 43.7% vs. 10.6%, P=0.0125; 40.3% vs. 3.3%, P=0.0125; respectively)., Conclusions: In Helicobacter pylori-negative healthy male subjects, oral administration of roxatidine 75 mg increased the intragastric pH more rapidly than that of omeprazole 20 mg.

Background and Aim: Diverticular hemorrhage is the common cause of lower gastrointestinal bleeding, and its incidence has been increasing in Japan. However, the exact cause of diverticular hemorrhage is not well understood. We investigated the risk factors for diverticular hemorrhage., Methods: We selected 103 patients with diverticular hemorrhage as cases and patients with colonic diverticulosis without a history of bleeding were selected as control subjects, exactly matched for age and gender. We collected the data from the medical records of each of the patients, such as those related to the comorbidities, medications and findings of colonoscopy, and conducted a matched case-control study to analyze the risk factors for diverticular hemorrhage., Results: Both groups were composed of 75 men and 28 women. The median age of the patients in both groups was 72.0 years (47.0-87.0). The body weight (p = 0.0065), body mass index (p = 0.006), prevalence of hypertension (p = 0.0242), prevalence of ischemic heart disease (p = 0.0015), and frequency of use of low-dose aspirin (p = 0.042) were significantly different between the two groups. The percentage of patients with bilateral diverticula, that is, diverticula on both the right and left hemicolon, was significantly higher in the diverticular hemorrhage group (p = 0.0011). Multiple regression analysis identified only the diverticular location as being significantly associated with the risk of diverticular hemorrhage (p = 0.0021)., Conclusions: Only the diverticular location (bilateral) was found to be an independent risk factor for diverticular hemorrhage., (Copyright © 2012 S. Karger AG, Basel.)