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Background: In recent studies, the involvement of mast cells in the pathogenesis of Helicobacter pylori infection was suggested. In the present study, using isolated canine gastric mucosal mast cells, we undertook to elucidate the effects of interleukin-8 (IL-8) and H. pylori on histamine release from these cells.Methods: Enriched canine gastric mucosal mast cells (50% target cells) were incubated in Hanks medium with IL-8, or water extract or sonicate of H. pylori for 15 min at 37 degrees C. The content of histamine in the supernatants and the cell pellets after centrifugation was assayed with a histamine radioimmunoassay (RIA) kit.Results: IL-8 (50 ng/ml) and concanavalin A (20 microg/ml) significantly increased histamine release from enriched gastric mucosal mast cells. Dose-dependent stimulation of histamine release by IL-8 (5-50 ng/ml) was also seen. Water extract and sonicate of H. pylori (10(8) bacteria) increased histamine release from mast cells. A concentration-dependent stimulation of histamine release by water extract or sonicate was also seen. The maximal response of histamine release was seen at the highest concentration of the water extract or sonicate.Conclusions: The results indicated that IL-8 and H. pylori had stimulatory effects on histamine release from canine gastric mucosal mast cells. The results imply that IL-8 and soluble factors of H. pylori may accelerate inflammation of the gastric mucosa via histamine release from mast cells. [ABSTRACT FROM AUTHOR]

The mechanisms by which Dai-kenchu-to (TJ-100), a kampo medicine, enhances gastrointestinal motility was investigated using isolated guinea pig ileum. TJ-100 induced contractions accompanied by autonomous contraction at a concentration of more than 3 x 10(-4) g/ml in a dose-related manner. The TJ-100-induced ileal contraction was suppressed by atropine and tetrodotoxin, but not by hexamethonium. This effect was partially suppressed in the presence of high concentrations of ICS 205-930, a serotonin 4 (5-HT4) receptor antagonist. In addition, TJ-100 showed an acetylcholine (ACh)-releasing action in the smooth muscle tissues of ileum. These results suggest that contractile response induced by TJ-100 is partially mediated by ACh released from the cholinergic nerve endings and that 5-HT4 receptors would be involved in the effect of TJ-100. [ABSTRACT FROM AUTHOR]

Endogenous prostaglandin E2 has been indicated to have an important role in preventing gastric mucosal damage from noxious agents (i.e., in adaptive cytoprotection). However, the response of endogenous prostaglandin E2 to a mild irritant is controversial. In this study, we attempted to determine whether pretreatment with a low concentration of ethanol could induce endogenous prostaglandin E2 production by isolated canine fundic mucosal cells and to identify cells that are responsible for an increase of prostaglandin E2 production. Canine fundic mucosa was digested by collagenase, dispase, and EDTA. The cells were separated into five fractions with an elutriator rotor. Pretreatment with 5% ethanol induced a significant increase of prostagladin E2 release only from the secondary small-sized cell fraction, which was rich in mast cells and endocrine cells, and not from the other four fractions. Further cell separation by density gradient centrifugation revealed that the mast cell-enriched fraction (54%) was responsible for the increase of prostaglandin E2 release induced by the pretreatment with 5% ethanol. The results suggest that mast cells of the gastric mucosa play an important role in the production of endogenous prostaglandin E2 in adaptive cytoprotection. [ABSTRACT FROM AUTHOR]

Recent studies have demonstrated a relationship between cytokines and gastric acid secretion. However, details of the mechanism underlying that relationship have not been elucidated. For this study, an in vivo experiment was undertaken to investigate the possibility that IL-8 would be involved in the mechanism of gastric acid secretion. Gastric lumen-perfused rats were prepared and the stomachs were perfused with a saline solution. The effluent was collected at 15-min intervals and assayed for titratable acid against 0.01 M NaOH. IL-8 (200 ng/rat) given intravenously did not influence basal acid output in rats. However, when IL-8 was administered by injection during continuous tetragastrin infusion (4 microg/kg/hr) acid output increased significantly (P < 0.01). The acid output during the first hour following IL-8 injection was 43.6% higher than prior to the injection. Acid output during the second hour was lower than during the first hour. However, successive injection of IL-8 again increased tetragastrin-stimulated acid output by 23.4% (P < 0.05). IL-8 injection did not change histamine-stimulated acid output. The results indicate that IL-8 has the effect of enhancing gastrin-stimulated acid secretion and might have an important role in the pathophysiology of gastric acid secretion in vivo. [ABSTRACT FROM AUTHOR]

Background: Rikkunshito (RKT), a traditional Japanese medicine, can relieve epigastric discomfort and anorexia in patients with functional dyspepsia. RKT enhances the orexigenic hormone, ghrelin. Ghrelin regulates food motivation by stimulating the appetite control center in the hypothalamus and the brain mesolimbic dopaminergic pathway (MDPW). However, the effect of RKT on MDPW remains unclear. Here, we aimed to investigate the central neural mechanisms underlying the orexigenic effects of RKT, focusing on the MDPW., Methods: We examined the effects of RKT on food intake and neuronal c-Fos expression in restraint stress- and cholecystokinin octapeptide-induced anorexia in male rats., Key Results: RKT treatment significantly restored stress- and cholecystokinin octapeptide-induced decreased food intake. RKT increased c-Fos expression in the ventral tegmental area (VTA), especially in tyrosine hydroxylase-immunoreactive neurons, and nucleus accumbens (NAc). The effects of RKT were suppressed by the ghrelin receptor antagonist [D-Lys 3 ]-GHRP-6. RKT increased the number of c-Fos/orexin-double-positive neurons in the lateral hypothalamus (LH), which project to the VTA. The orexin receptor antagonist, SB334867, suppressed RKT-induced increase in food intake and c-Fos expression in the LH, VTA, and NAc. RKT increased c-Fos expression in the arcuate nucleus and nucleus of the solitary tract of the medulla, which was inhibited by [D-Lys 3 ]-GHRP-6., Conclusions & Inferences: RKT may restore appetite in subjects with anorexia through ghrelin- and orexin-dependent activation of neurons regulating the brain appetite control network, including the hypothalamus and MDPW., (© 2024 The Author(s). Neurogastroenterology & Motility published by John Wiley & Sons Ltd.)

Background: We have proposed that cognitive resilience (CR) counteracts brain damage from Alzheimer's disease (AD) or AD-related dementias such that older individuals who harbor neurodegenerative disease burden sufficient to cause dementia remain cognitively normal. However, CR traditionally is considered a binary trait, capturing only the most extreme examples, and is often inconsistently defined., Methods: This study addressed existing discrepancies and shortcomings of the current CR definition by proposing a framework for defining CR as a continuous variable for each neuropsychological test. The linear equations clarified CR's relationship to closely related terms, including cognitive function, reserve, compensation, and damage. Primarily, resilience is defined as a function of cognitive performance and damage from neuropathologic damage. As such, the study utilized data from 844 individuals (age = 79 ± 12, 44% female) in the National Alzheimer's Coordinating Center cohort that met our inclusion criteria of comprehensive lesion rankings for 17 neuropathologic features and complete neuropsychological test results. Machine learning models and GWAS then were used to identify medical and genetic factors that are associated with CR., Results: CR varied across five cognitive assessments and was greater in female participants, associated with longer survival, and weakly associated with educational attainment or APOE ε4 allele. In contrast, damage was strongly associated with APOE ε4 allele (P value < 0.0001). Major predictors of CR were cardiovascular health and social interactions, as well as the absence of behavioral symptoms., Conclusions: Our framework explicitly decoupled the effects of CR from neuropathologic damage. Characterizations and genetic association study of these two components suggest that the underlying CR mechanism has minimal overlap with the disease mechanism. Moreover, the identified medical features associated with CR suggest modifiable features to counteract clinical expression of damage and maintain cognitive function in older individuals., (© 2023. The Author(s).)

Alzheimer's disease (AD) is the most common cause of dementia with advancing age as its strongest risk factor. AD neuropathologic change (ADNC) is known to be associated with numerous DNA methylation changes in the human brain, but the oldest old (> 90 years) have so far been underrepresented in epigenetic studies of ADNC. Our study participants were individuals aged over 90 years (n = 47) from The 90+ Study. We analyzed DNA methylation from bulk samples in eight precisely dissected regions of the human brain: middle frontal gyrus, cingulate gyrus, entorhinal cortex, dentate gyrus, CA1, substantia nigra, locus coeruleus and cerebellar cortex. We deconvolved our bulk data into cell-type-specific (CTS) signals using computational methods. CTS methylation differences were analyzed across different levels of ADNC. The highest amount of ADNC related methylation differences was found in the dentate gyrus, a region that has so far been underrepresented in large scale multi-omic studies. In neurons of the dentate gyrus, DNA methylation significantly differed with increased burden of amyloid beta (Aβ) plaques at 5897 promoter regions of protein-coding genes. Amongst these, higher Aβ plaque burden was associated with promoter hypomethylation of the Presenilin enhancer 2 (PEN-2) gene, one of the rate limiting genes in the formation of gamma-secretase, a multicomponent complex that is responsible in part for the endoproteolytic cleavage of amyloid precursor protein into Aβ peptides. In addition to novel ADNC related DNA methylation changes, we present the most detailed array-based methylation survey of the old aged human brain to date. Our open-sourced dataset can serve as a brain region reference panel for future studies and help advance research in aging and neurodegenerative diseases., (© 2022. The Author(s).)

Cholecystokinin (CCK) had been the first gastrointestinal hormone known to exert anorexic effects. CCK had been inferred to contribute to the onset of functional dyspepsia (FD) symptoms. To understand the pathophysiology of FD, the roles of stress have to be clarified. In this study, we aimed to clarify the influence of stress on the action of cholecystokinin (CCK) on appetite and gastric emptying. Using rats, stress was simulated by giving restraint stress or intraperitoneal injection of the stress-related peptide hormone urocortin 1 (UCN1). The effects of CCK and restraint stress, alone or in combination, on food intake and gastric motility were examined, and c-Fos expression in the neurons of appetite control network in the central nervous system was assessed by immunohistochemical staining. CCK inhibited food intake and gastric emptying in a dose-dependent manner. Food intake for 1 h was significantly lower with UCN1 (2 nmol/kg) than with the saline control. Restraint stress amplified the suppressive effects of CCK on food intake for 1 h and on gastric emptying. With regard to brain function, the CCK induced c-Fos expression in the neurons of the nucleus tractus solitarius and paraventricular nucleus of the hypothalamus was markedly and significantly amplified by the addition of restraint stress with CCK. The results suggested that stress might amplify the anorexic effects of CCK through activation of the nuclei that comprise the brain neuronal network for satiation; this might play a role in the pathogenesis of the postprandial distress syndromes of functional dyspepsia.

Background: Magnifying endoscopy has demonstrated dramatic morphologic changes in the surface microvasculature of superficial esophageal squamous cell carcinoma (ESCC) according to the depth of invasion. We investigated the mechanism of angiogenesis in early-stage ESCC by examining the expression of vascular endothelial growth factor (VEGF)-A and chondromodulin (ChM)-1., Methods: Using 41 samples of superficial esophageal cancer (EP and LPM 19 cases, MM or deeper 22 cases) and 7 samples of regenerative squamous epithelium, the expression of VEGF-A and ChM-1 was examined in relation to the histological grade or morphology of the surface microvasculature demonstrated by magnifying endoscopy (types A, B, and C correspond to types A, B1, and B2 and B3 of the magnifying endoscopic classification of the Japan Esophageal Society, respectively). We also investigated the correlation between CD31-positive microvessel density (MVD) and VEGF-A or ChM-1 expression., Results: In normal squamous epithelium, regenerative squamous epithelium, EP and LPM cancer, and MM or deeper cancer, the positivity rates for VEGF-A and ChM-1 were 0%, 85.7%, 52.6% and 90.9%, respectively, and 48.5%, 71.4%, 73.7% and 23.8%, respectively. The VEGF-A and ChM-1 positivity rates in type B or type C vasculature were 70.0% and 76.2%, respectively, and 75.0% and 19.0%, respectively. The expression of neither VEGF-A nor ChM-1 in cancer cells was correlated with MVD (P = 0.19 and 0.68, respectively), whereas that of VEGF-A in stromal mononuclear cells (SMCs) was significantly correlated with MVD (P = 0.04)., Conclusion: Angiogenesis at the early stage of ESCC progression is configured by the balance between accelerator (angiogenic factors from both cancer cells and SMCs) and brake (angiogenic inhibitor) factors.

Background: Transabdominal ultrasound is a promising technique to evaluate inflammatory bowel disease. Several studies have demonstrated a relationship between ultrasound findings and colonic inflammation. However, the applicability of transabdominal ultrasound in patients with ulcerative colitis (UC) has not been elucidated. The aim of this study was to clarify the relationship between the transabdominal ultrasound findings and endoscopic activity in patients with UC., Methods: Patients with active and underwent transabdominal ultrasound and colonoscopy were enrolled in this retrospective single-center analysis. Blood flow in the bowel wall was evaluated by power Doppler ultrasound. Both the thickness and stratification of the bowel wall were assessed by B-mode ultrasound imaging. The endpoints were the correlations between the ultrasound appearances (i.e., blood flow, thickness, and stratification of the bowel wall) and endoscopic activity (endoscopic Mayo Score)., Results: There were 34 lesions in 26 patients evaluated. Blood flow and thickness of the bowel wall were positively significantly correlated with the endoscopic Mayo Scores (r=0.43, p=0.011 and r=0.503, p=0.002, respectively). According to the bowel stratification, the endoscopic Mayo Scores were significantly higher in unclear and diminished bowel wall stratifications than in the clear bowel wall stratifications (p<0.001 and p<0.001, respectively). When focusing on the endoscopic Mayo Scores of three lesions, blood flow was lower in ulcer lesions with a diameter of ≥10mm than in those with a diameter of <10mm., Conclusion: All transabdominal ultrasound findings of bowel blood flow, wall thickness, and wall stratification reflected colonic inflammation.

We investigated whether vasoactive intestinal peptide (VIP) and/or prostaglandins contribute to peripheral corticotropin-releasing factor (CRF)-induced CRF 1 receptor-mediated stimulation of colonic motor function and diarrhea in rats. The VIP antagonist, [4Cl-D-Phe 6 , Leu 17 ]VIP injected intraperitoneally completely prevented CRF (10 µg/kg ip)-induced fecal output and diarrhea occurring within the first hour after injection, whereas pretreatment with the prostaglandins synthesis inhibitor, indomethacin, had no effect. In submucosal plexus neurons, CRF induced significant c-Fos expression most prominently in the terminal ileum compared with duodenum and jejunum, whereas no c-Fos was observed in the proximal colon. c-Fos expression in ileal submucosa was colocalized in 93.4% of VIP-positive neurons and 31.1% of non-VIP-labeled neurons. CRF 1 receptor immunoreactivity was found on the VIP neurons. In myenteric neurons, CRF induced only a few c-Fos-positive neurons in the ileum and a robust expression in the proximal colon (17.5 ± 2.4 vs. 0.4 ± 0.3 cells/ganglion in vehicle). The VIP antagonist prevented intraperitoneal CRF-induced c-Fos induction in the ileal submucosal plexus and proximal colon myenteric plexus. At 60 min after injection, CRF decreased VIP levels in the terminal ileum compared with saline (0.8 ± 0.3 vs. 2.5 ± 0.7 ng/g), whereas VIP mRNA level detected by qPCR was not changed. These data indicate that intraperitoneal CRF activates intestinal submucosal VIP neurons most prominently in the ileum and myenteric neurons in the colon. It also implicates VIP signaling as part of underlying mechanisms driving the acute colonic secretomotor response to a peripheral injection of CRF, whereas prostaglandins do not play a role. NEW & NOTEWORTHY Corticotropin-releasing factor (CRF) in the gut plays a physiological role in the stimulation of lower gut secretomotor function induced by stress. We showed that vasoactive intestinal peptide (VIP)-immunoreactive neurons in the ileal submucosal plexus expressed CRF 1 receptor and were prominently activated by CRF, unlike colonic submucosal neurons. VIP antagonist abrogated CRF-induced ileal submucosal and colonic myenteric activation along with functional responses (defecation and diarrhea). These data point to VIP signaling in ileum and colon as downstream effectors of CRF.

Background: Ulcerative proctitis, one of the disease types of ulcerative colitis, is considered one of the initial manifestations of ulcerative colitis. Prevention of aggravation of ulcerative proctitis is important for improving the prognosis of ulcerative colitis. Here we reviewed the epidemiology, diagnosis, and management of ulcerative proctitis., Summary: The number of patients with ulcerative proctitis is increasing. Disease extension occurs in many patients with ulcerative proctitis. Differential diagnosis from other chronic proctitis is important and should be performed based on the clinical history and endoscopical and histological features. Mesalazine suppository has been the first-line therapy for patients with ulcerative proctitis because of its high effectiveness and safety. Topical treatment of ulcerative proctitis, particularly using mesalazine suppository has been underused in clinical practice. Key Messages: Mesalazine suppositories are more effective than dose intensification of oral mesalazine for relapsed patients with maintenance dose of oral mesalazine. However, low adherence to rectal mesalazine has hindered remission in patients with ulcerative proctitis., (© 2018 S. Karger AG, Basel.)

Background: Idiopathic acute-on-chronic inflammation in the gastrointestinal tract is an etiology of inflammatory bowel disease (IBD). Granulocyte and monocyte adsorptive apheresis (GMA) is a nonpharmacological treatment tool for patients with IBD. Here, we present a review of the positioning and possibilities of GMA for patients with IBD., Summary: GMA decreases inflammatory cytokines and upregulates regulatory T cells. Intensive GMA is significantly more effective than weekly GMA in patients with IBD. The frequency of GMA sessions per week positively correlates with treatment effects. GMA can be safely used in pregnant women and children because of its low adverse event rates. Maintenance therapy and rescue therapy for loss of response of anti-tumor necrosis factor (TNF)-α antibodies are effective. Optimal patients who responded to combination therapy with infliximab and GMA showed aggravation characteristics against infliximab treatment at week 4. Key Message: Prospective randomized blinded studies using a sham column should be performed for the loss of response against anti-TNF-α antibodies., (© 2018 S. Karger AG, Basel.)

Background: The relationship between thymidine phosphorylase (TP) and angiogenesis at the early stage of esophageal squamous cell carcinoma has been unclear., Methods: Using 14 samples of normal squamous epithelium, 11 samples of low-grade intraepithelial neoplasia, and 64 samples of superficial esophageal cancer, microvessel density (MVD) was estimated using immunostaining for CD34 and CD105. TP expression was also evaluated in both cancer cells and stromal monocytic cells (SMCs). We then investigated the correlation between MVD and TP expression in both cancer cells and SMCs., Results: On the basis of the above parameters, MVD was significantly higher in cancerous lesions than in normal squamous epithelium. In terms of CD34 and CD105 expression, MVD showed a gradual increase from normal squamous epithelium, to low-grade intraepithelial neoplasia, and then to M1 and M2 cancer, and M3 or deeper cancer. M1 and M2 cancer showed overexpression of TP in both cancer cells and SMCs. There was no significant correlation between TP expression in cancer cells and MVD estimated from CD34 (rS = 0.16, P = 0.21) or CD105 (rS = 0.05, P = 0.68) expression. Significant correlations were found between TP expression in SMCs and CD34-related (rS = 0.46, P < 0.001) and CD105-related (rS = 0.34, P < 0.01) MVD. In M3 or deeper cancers, there were no significant correlations between TP expression in cancer cells or SMCs and venous invasion, lymphatic invasion, and lymph node metastasis., Conclusion: TP expression is activated in both cancer cells and stromal monocytic cells at the very early stage of ESCC progression. TP expression in SMCs, rather than in cancer cells, is significantly correlated with angiogenesis.

The Baeyer-Villiger oxidation is a key transformation for sustainable chemical synthesis, especially when H 2 O 2 and solid materials are employed as oxidant and catalyst, respectively. 4-substituted cycloketones, which are readily available from renewables, present excellent platforms for Baeyer-Villiger upgrading. Such substrates exhibit substantially higher levels of activity and produce lactones at higher levels of lactone selectivity at all values of substrate conversion, relative to non-substituted cyclohexanone. For 4-isopropyl cyclohexanone, which is readily available from β-pinene, continuous upgrading was evaluated in a plug-flow reactor. Excellent selectivity (85 % at 65 % conversion), stability, and productivity were observed over 56 h, with over 1000 turnovers (mol product per mol Sn) being achieved with no loss of activity. A maximum space-time yield that was almost twice that for non-substituted cyclohexanone was also obtained for this substrate [1173 vs. 607 g(product) kg(catalyst) -1  cm -3  h -1 ]. The lactone produced is also shown to be of suitable quality for ring opening polymerization. In addition to demonstrating the viability of the Sn-β/H 2 O 2 system to produce renewable lactone monomers suitable for polymer applications, the substituted alkyl cyclohexanones studied also help to elucidate steric, electronic, and thermodynamic elements of this transformation in greater detail than previously achieved., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Patients with Parkinson's disease (PD) usually experience distress related not only to motor dysfunction, but also to nonmotor symptoms, including gastrointestinal dysfunction., Objective: The purpose of this pilot study was to evaluate the efficacy and safety profile of a traditional Japanese medicine, rikkunshito (RKT), used for the treatment of gastrointestinal symptoms, associated with anorexia and dyspepsia, in patients with PD., Methods: Patients were randomly assigned to either Group A (4-week treatment period with 7.5 g/d RKT followed by a 4-week off-treatment period) or Group B (4-week off-treatment period followed by a 4-week treatment period with 7.5 g/d RKT). Appetite, quality of life for gastrointestinal symptoms, and depression were assessed using a visual analog scale, the Gastrointestinal Symptom Rating Scale and the Self-Rating Depression Scale, respectively. The gastric emptying examination and assay of plasma acylated ghrelin level were performed using the 13 C-acetate breath test and commercially available assay kits, respectively., Results: RKT treatment produced a significant increase in the appetite score (1.84 [2.34]; P < 0.05), compared to a decrease in the score over the off-treatment period (-1.36 [2.94]). The mean score for abdominal pain, on the Gastrointestinal Symptom Rating Scale, and for self-reported depression, on the Self-Rating Depression Scale, also decreased significantly with RKT treatment ( P < 0.05), compared with the off-treatment period scores. No effect of RKT on plasma acylated ghrelin level and rate of gastric emptying was identified., Conclusions: RKT may improve anorexia in patients with PD. The positive effects of RKT on depression and anorexia may improve the overall quality of life of these patients. The benefits of RKT identified in our pilot study will need to be confirmed in a randomized, double-blind, controlled trial. UMIN Clinical Trial Registry identifier: UMIN000009626.

We herein describe a case of somatostatinoma coexisting with a gastrointestinal stromal tumor (GIST) in the duodenum of an 81-year-old woman with Von Recklinghausen's disease (VRD) and common bile duct stone who presented with diarrhea of three months in duration. Gastroduodenoscopy revealed an ulcer on the second part of the duodenum. A 2.1-cm enhancing tumor was observed to extend from the ulcer on an abdominal computed tomography scan. Subtotal stomach-preserving pancreaticoduodenectomy revealed a somatostatinoma on the papilla of the vater and duodenal GIST. There have been only eight reports on VRD associated with ampullary somatostatinoma and GIST. An awareness of this possibility in patients with gastrointestinal lesions is necessary for proper treatment and patient management.

Aim: To optimize the therapeutic efficacy of NS3/4A protease inhibitors, a multicenter prospective study was performed according to an algorithm based on the Adherence, IL-28B Gene Allele and Viral Response Trial (AG & RGT)., Methods: A total of 340 patients with genotype 1b hepatitis C virus (HCV) showing serum RNA levels of >5 log were enrolled. The duration of ribavirin/pegylated interferon (PEG IFN)-α-2b therapy was prolonged to 48 weeks in patients with unfavorable IL28B alleles showing adherence rates of less than 80% for either drug during the first 12 weeks even if RVR had been achieved, and in those in whom cEVR, but not RVR, was achieved; furthermore, to 72 weeks in those showing partial early viral response., Results: The therapeutic outcomes were assessed in 282 patients, and the therapy was set to complete at 24 weeks in 181 patients (64%) and to prolong to 48 weeks or 72 weeks in 71 patients (25%). The former group showed a SVR rate of 84%, while the latter group showed an SVR rate of 69% with a relapse rate of 7%. The SVR rate was 33% in the 30 patients (11%) in whom the therapy had to be discontinued in less than 12 weeks. Thus, the results of intention-to-treat analysis revealed an overall SVR rate of 75%. Multivariate analysis identified prolongation of the duration of therapy as a significant factor associated with SVR., Conclusion: Triple therapy yielded a high SVR rate in the AG & RGT trial via attenuation of viral relapse by prolonged ribavirin/PEG IFN-α-2b administration. © 2015 The Japan Society of Hepatology., (© 2015 The Japan Society of Hepatology.)

For patients with ulcerative colitis, adherence to 5-aminosalicylic acid (5-ASA) is generally expected to ensure better maintenance of remission. Over the past 2 years, we have conducted a questionnaire survey in our hospital of 120 outpatients with quiescent ulcerative colitis to assess their adherence to oral 5-ASA. Of them, 112 patients responded. The overall adherence rate was 57%; however, the adherence rate for 5-ASA taken once a day was 95%, which was significantly higher than that for 5-ASA taken twice or three times a day (50%; P=0.00044). Univariate analysis revealed that the factors associated with high adherence included the following: type of 5-ASA derivative, intake of fewer drugs being at a time, and once-daily intake of 5-ASA. However, once-daily intake of 5-ASA was the only factor found to have a statistically significant effect using multivariate analysis. The adherence rate improved from 23% to 100% when the prescription for 5-ASA was changed from two or three times daily to once daily (P=0.000054).

Abdominal surgery inhibits food intake and induces c-Fos expression in the hypothalamic and medullary nuclei in rats. Rikkunshito (RKT), a Kampo medicine improves anorexia. We assessed the alterations in meal microstructure and c-Fos expression in brain nuclei induced by abdominal surgery and the modulation by RKT in mice. RKT or vehicle was gavaged daily for 1 week. On day 8 mice had no access to food for 6-7 h and were treated twice with RKT or vehicle. Abdominal surgery (laparotomy-cecum palpation) was performed 1-2 h before the dark phase. The food intake and meal structures were monitored using an automated monitoring system for mice. Brain sections were processed for c-Fos immunoreactivity (ir) 2-h after abdominal surgery. Abdominal surgery significantly reduced bouts, meal frequency, size and duration, and time spent on meals, and increased inter-meal interval and satiety ratio resulting in 92-86% suppression of food intake at 2-24 h post-surgery compared with control group (no surgery). RKT significantly increased bouts, meal duration and the cumulative 12-h food intake by 11%. Abdominal surgery increased c-Fos in the prelimbic, cingulate and insular cortexes, and autonomic nuclei, such as the bed nucleus of the stria terminalis, central amygdala, hypothalamic supraoptic (SON), paraventricular and arcuate nuclei, Edinger-Westphal nucleus (E-W), lateral periaqueduct gray (PAG), lateral parabrachial nucleus, locus coeruleus, ventrolateral medulla and nucleus tractus solitarius (NTS). RKT induced a small increase in c-Fos-ir neurons in the SON and E-W of control mice, and in mice with surgery there was an increase in the lateral PAG and a decrease in the NTS. These findings indicate that abdominal surgery inhibits food intake by increasing both satiation (meal duration) and satiety (meal interval) and activates brain circuits involved in pain, feeding behavior and stress that may underlie the alterations of meal pattern and food intake inhibition. RKT improves food consumption post-surgically that may involve modulation of pain pathway.

Background and Aim: An intention-to-treat prospective randomized study was carried out to compare the potentiation of antiviral efficacies between cholecalciferol, non-activated vitamin D3 supplement, and alfacalcidol, activated 1α-Hydroxyvitamin D3 [1α (OH)-vitamin D3]., Methods: Chronic hepatitis patients with genotype 1b hepatitis C virus (HCV) infection showing serum HCV-RNA levels greater than 5 Log IU/mL received oral administration of cholecalciferol (2000 IU/day) or alfacalcidol (0.5 μg/day) for 4 weeks, and then they were given pegylated interferon (Peg-IFN)-α2a plus ribavirin therapy in combination with either vitamin D3 for 48 or 72 weeks according to the response-guided manner., Results: A total of 36 patients were evaluated. Serum 25-hydroxyvitamin D3 [25(OH)-D3] levels were increased only in patients in the cholecalciferol group during the lead-in vitamin D administration, and the levels at 4 weeks were higher in these patients than in those in the alfacalcidol group (P < 0.001), while serum 1α,25-dihydroxyvitamin D3 [1α,25(OH)2 -D3] levels were not different between both groups. Rapid virological response was obtained in six (33%) patients in the cholecalciferol group; the ratio was higher than that in the alfacalcidol group (one patient; 6%, P < 0.05). Serum HCV-RNA level decline at 4 weeks of combined Peg-IFN-α2a plus ribavirin therapy compared with the baseline levels were greater in the cholecalciferol group (4.6 Log IU/mL) than in the alfacalcidol group (3.5 Log IU/mL) (P < 0.05), when four patients showing null response to the therapy was excluded. However, both complete early virological response and sustained viral response rates were not different between both groups., Conclusion: Cholecalciferol produced superior potentiation of the antiviral activity than alfacalcidol only during the initial periods of combined Peg-IFN-α2a plus ribavirin therapy through upregulation of serum 25(OH)-D3 levels., (© 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)

Aim: To evaluate the efficacy and safety of single-step endoscopic placement of self-expandable metallic stents (SEMS) for treatment of obstructive jaundice., Methods: A retrospective study was performed among 90 patients who underwent transpapillary biliary metallic stent placement for malignant biliary obstruction (MBO) between April 2005 and October 2012. The diagnosis of primary disease and MBO was based on abdominal ultrasound, computed tomography, magnetic resonance imaging, endoscopic ultrasound, endoscopic retrograde cholangiopancreatography with brush cytology, biopsy, and/or a combination of these modalities. The type of SEMS (covered or non-covered, 8 mm or 10 mm in diameter) was determined by the endoscopist. Ninety patients were divided into two groups: group 1 (49 patients) who underwent a single-step SEMS placement and group 2 (41 patients) who underwent a two-step SEMS placement. The technical success rate, complication rate, stent patency, and patient survival rate were compared between the groups. In addition, to identify the clinical prognostic factors associated with patient survival, the following variables were evaluated in Cox-regression analysis: gender, age, etiology of MBO (pancreatic cancer or non-pancreatic cancer), clinical stage (IVb; with distant metastases or IVa >; without distant metastases), chemotherapy (with or without), patency of the stent, and the use of single-step or two-step SEMS., Results: Immediate technical success was achieved in 93.9% (46/49) in group 1 and in 95.1% (39/41) in group 2, with no significant difference (P = 1.0). Similarly, there was no difference in the complication rates between the groups (group 1, 4.1% and group 2, 4.9%; P = 0.62). Stent failure was observed in 10 cases in group 1 (20.4%) and in 16 cases in group 2 (39.0%). The patency of stent and patient survival revealed no difference between the two groups with Kaplan-Meier analysis, with a mean patency of 111 ± 17 d in group 1 and 137 ± 19 d in group 2 (P = 0.91), and a mean survival of 178 ± 35 d in group 1 and 222 ± 23 d in group 2 (P = 0.57). On the contrary, the number of days of hospitalization associated with first-time SEMS placement in group 1 was shorter when compared with that number in group 2 (28 vs 39 d; P < 0.05). Multivariate analysis revealed that a clinical stage of IVa > (P = 0.0055), chemotherapy (P = 0.0048), and no patency of the stent (P = 0.011) were independent prognostic factors associated with patient survival., Conclusion: Our results showed that single-step endoscopic metal stent placement was safe and effective for treating obstructive jaundice secondary to various inoperable malignancies.

Using immunohistochemical staining, the present study was conducted to examine whether cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS) affect angiogenesis in early-stage esophageal squamous cell carcinoma (ESCC). We also analyzed the correlation between these two factors. Cyclooxygenase 2, iNOS, and angiogenesis in early-stage ESCC are unclear. Using 10 samples of normal squamous epithelium, 7 samples of low-grade intraepithelial neoplasia (LGIN), and 45 samples of superficial esophageal cancer, we observed the expression of COX-2 and iNOS. We then investigated the COX-2 and iNOS immunoreactivity scores and the correlation between COX-2 or iNOS scores and microvessel density (MVD) using CD34 or CD105. The intensity of COX-2 or iNOS expression differed significantly according to histological type (P < 0.001). The scores of COX-2 and iNOS were lowest for normal squamous epithelium, followed in ascending order by LGIN, carcinoma in situ and tumor invading the lamina propria mucosae (M1-M2 cancer); and tumor invading the muscularis mucosa (M3) or deeper cancer. The differences were significant (P < 0.001). Cancers classified M1-M2 (P < 0.01 and P < 0.05, respectively); M3; or deeper cancer (P < 0.01) had significantly higher COX-2 and iNOS scores than normal squamous epithelium. There was a significant correlation between COX-2 and iNOS scores (P < 0.001, rs = 0.51). Correlations between COX-2 score and CD34-positive MVD or CD105-positive MVD were significant (rs = 0.53, P < 0.001; rs = 0.62, P < 0.001, respectively). Inducible nitric oxide synthase score was also significantly correlated with CD34 MVD and CD105 MVD (rs = 0.45, P < 0.001; rs = 0.60, P < 0.001, respectively). Chemoprevention of COX-2 or iNOS activity may blunt the development of ESCC from precancerous lesions.

General interest in functional gastrointestinal disorders is increasing among Japanese doctors as well as patients. This increase can be attributed to a number of factors, including recent increased interest in quality of life and advances in our understanding of the pathophysiology of gastrointestinal disease. Japan recently became the world's first country to list "functional dyspepsia" as a disease name for national insurance billing purposes. However, recognition and understanding of functional dyspepsia (FD) remain poor, and no standard treatment strategy has yet been established. Accordingly, the Japanese Society of Gastroenterology (JSGE) developed an evidence-based clinical practice guideline for FD, consisting of five sections: concept, definition, and epidemiology; pathophysiology; diagnosis; treatment; and prognosis and complications. This article summarizes the Japanese guideline, with particular focus on the treatment section. Once a patient is diagnosed with FD, the doctor should carefully explain the pathophysiology and benign nature of this condition, establish a good doctor-patient relationship, and then provide advice for daily living (diet and lifestyle modifications, explanations, and reassurance). The proposed pharmacological treatment is divided into two steps: initial treatment including an acid inhibitory drug (H2RA or PPI) or prokinetics, (strong recommendation); second-line treatment including anxiolytics, antidepressants, and Japanese traditional medicine (weak recommendation). H. pylori eradication, strongly recommended with a high evidence level, is positioned separately from other treatment flows. Conditions that do not respond to these treatment regimens are regarded as refractory FD. Patients will be further examined for other organic disorders or will be referred to specialists using other approaches such as psychosomatic treatment.

The autonomic nervous system (ANS) conveys neuronal input from the brain to the stomach. We investigated mechanisms through which urocortin 1 (UCN1) injected intracerebroventricularly (ICV, 300 pmol/rat) inhibits circulating ghrelin in rats. This was achieved by assessing (1) the induction of c-fos gene expression as a marker of neuronal activation in specific hypothalamic and caudal brainstem regulating ANS; (2) the influence of vagotomy and pharmacological blockade of central and peripheral α- and β-adrenergic receptor (AR) on ICV UCN1-induced reduction of plasma ghrelin levels (determined by ELISA); and (3) the relevance of this pathway in the feeding response to a fast in rats. UCN1 increased c-fos mRNA expression in key brain sites influencing sympathetic activity namely the hypothalamic paraventricular and ventromedial nuclei, locus coeruleus, nucleus of the solitary tract, and rostral ventrolateral medulla, by 16-, 29-, 6-, 37-, and 13-fold, respectively. In contrast, the dorsal motor nucleus of the vagus had little c-fos mRNA expression and ICV UCN1 induced a similar reduction in acylated ghrelin in the sham-operated (31%) and vagotomized (41%) rats. An intraperitoneal (IP) injection of either a non-selective α- or selective α2-AR antagonist reduced, while a selective α2-AR agonist enhanced ICV UCN1-induced suppression of plasma acylated ghrelin levels. In addition, IP injection of a non-selective β- or selective β1-AR agonist blocked, and selective β1-AR antagonist augmented, the ghrelin response to ICV UCN1. The IP injections of a selective α1- or non-selective β or β2-AR antagonists, or any of the pretreatments given ICV had no effect. ICV UCN1 reduced the 2-h food intake in response to a fast by 80%, and this effect was partially prevented by a selective α2-AR antagonist. These data suggest that ICV UCN1 reduces plasma ghrelin mainly through the brain sympathetic component of the ANS and peripheral AR specifically α2-AR activation and inactivation of β1-AR. The α2-AR pathway contributes to the associated reduction in food intake., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

We previously reported that ghrelin prevented l-dopa (LD)-induced inhibition of gastric emptying (GE) of a non-nutrient solution in rats. Parkinson's disease treatment involves the combined administration of l-dopa with the enzyme l-amino acid decarboxylase inhibitor, carbidopa (CD) to reduce peripheral formation of dopamine. We investigated the effect LD/CD given orogastrically (og) on GE of a non-nutrient or nutrient meal and whether og pretreatment with rikkunshito, a kampo medicine clinically used to treat gastroparesis, influenced LD/CD effect on GE and postprandial antral and duodenal motility in conscious rats. LD/CD (20/2 mgkg(-1)) decreased significantly GE to 26.3 ± 6.0% compared to 61.2 ± 3.2% in og vehicle monitored 20-min after a non-nutrient meal and to 41.9 ± 5.8% compared to 72.9 ± 5.2% in og vehicle monitored 60 min after a nutrient meal. Rikkunshito (0.5 or 1.0 g kg(-1)) reduced the LD/CD (20/2 mg kg(-1)) inhibition of GE of non-nutrient meal (36.9 ± 7.4% and 46.6 ± 4.8% respectively vs. 12.1 ± 7.4% in og vehicle plus LD/CD) while having no effect alone (56.6 ± 8.5%). The ghrelin antagonist, [d-Lys(3)]-GHRP-6 (1 mg kg(-1)) injected intraperitoneally partially reversed rikkunshito preventive effect on LD/CD-inhibited GE. Rikkunshito (1.0 g kg(-1)) blocked LD/CD (20/2 mg kg(-1))-induced delayed GE of a nutrient meal and the reduction of postprandial antral motility. In 6-hydroxydopamine-induced Parkinson's disease rat model, rikkunshito (1.0 g kg(-1), og) also prevented LD/CD-inhibited gastric emptying of a nutrient meal and enhanced fasting plasma levels of acylated ghrelin. These data indicate that oral rikkunshito alleviates the delayed GE induced by LD/CD in naïve and PD rat model in part through ghrelin-related mechanisms., (Copyright © 2014 Elsevier Inc. All rights reserved.)