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Background Significance of monitoring adalimumab trough levels and anti-adalimumab antibodies ( AAA) for disease outcome in Crohn's disease ( CD) patients remained unclear. Aim To evaluate the association of adalimumab trough levels and AAA at week 26 with clinical remission at week 52, the effect of azathiopurine on AAA and factors influencing trough levels in CD patients in the DIAMOND trial. Methods We performed this study using adalimumab trough levels, AAA at week 26 and 6-thioguanine nucleotide ( TGN) in red blood cells at week 12. A multiple regression model and receiver operating analysis was performed to identify factors influencing adalimumab trough levels and AAA, and adalimumab thresholds for predicting disease activity. Results There was a significant difference of adalimumab trough level at week 26 between patients with disease remission and without at week 52 (7.7 ± 3.3 μg/ mL vs 5.4 ± 4.3 μg/ mL: P <.001). Adalimumab trough level of 5.0 μg/ mL yielded optimal sensitivity and specificity for remission prediction (80.2% and 55.6%, respectively). AAA development at week 26 significantly affected remission at week 52 ( P = .021), which was strongly associated with adalimumab trough levels. Female gender and increasing body weight were independently associated with low adalimumab trough levels, and female gender was associated with AAA development. A cut-off 6 TGN level of >222.5 p mol/8 ×108 RBCs yielded sensitivity (100%) and specificity (60.6%) for AAA negativity. Conclusion Adalimumab trough levels and AAA occurrence were significantly associated with clinical remission. Higher 6 TGN affected AAA negativity. The combination therapy is beneficial in some relevant aspects for CD patients. ( UMIN Registration No. 000005146) [ABSTRACT FROM AUTHOR]

Masticatory function is significantly lower in individuals with malocclusion than in those with normal occlusion. Although several studies suggest that masticatory function influences gastrointestinal digestive function, the relationship between malocclusion and gastrointestinal symptoms has not been studied extensively. We hypothesised that insufficient masticatory function would increase the functional burden of the stomach and have some influence on the gastrointestinal system. The purpose of this study was to investigate masticatory function and gastric emptying rate in subjects with malocclusion. Eleven healthy dentate female volunteers and eleven female patients with maloc-clusion underwent a 13C-acetate breath test with a liquid meal. Maximum 13 CO2 exhalation time ( Tmax) was compared statistically between both groups. Masticatory function was assessed by colour-changeable chewing gum. In addition, the frequency scale for the symptoms of gastroeso-phageal reflux disease ( FSSG) and questionnaires on food intake were given to both groups. The mean Tmax of the malocclusion group was significantly longer than that of the normal occlusion group ( P = 0·007). Masticatory performance, measured by colour-changeable gum and questionnaires, was significantly lower in the malocclusion group than in the normal occlusion group ( P = 0·023, P = 0·003). There was no significant difference in the FSSG results between the two groups ( P = 0·262). This study suggested that there was a correlation between malocclusion and gastric emptying function in women. [ABSTRACT FROM AUTHOR]

Background Mesalazine suppositories are recommended and widely used as the standard therapy in induction and maintenance of remission for proctitis. Aim To evaluate the efficacy of mesalazine suppositories in patients with ulcerative colitis ( UC) and rectal inflammation; and in patient groups categorised by the extent of lesions. Methods This study was a phase III multicentre, randomised, double-blind, placebo-controlled, parallel-group study. Mild-to-moderate UC patients with rectal inflammation were randomly assigned either a 1 g mesalazine or placebo suppository. The suppository was administered in the rectum once daily for 4 weeks. The primary efficacy end point was the rate of endoscopic remission (mucosal score of 0 or 1) after 4 weeks. Results The endoscopic remission rates after 4 weeks in the mesalazine and placebo suppository groups were 81.5% and 29.7%, respectively, and the superiority of mesalazine to placebo was confirmed ( P < 0.0001, chi-squared test). For proctitis, the endoscopic remission rates after 4 weeks were 83.8% and 36.1% in the mesalazine and placebo suppository groups, respectively, and the corresponding rates for all other types of UC were 78.6% and 21.4%, respectively. The superiority of mesalazine to placebo was confirmed in both subgroups ( P < 0.0001, Fisher's exact test). The percentage of patients without bleeding was significantly higher in the mesalazine group than the placebo group from Day 3 of treatment ( P = 0.0001, Fisher's exact test). Conclusions The effectiveness of mesalazine suppositories in all types of UC patients with rectal inflammation was confirmed for the first time in a double-blind, placebo-controlled, parallel-group study (Japic CTI- 111421). [ABSTRACT FROM AUTHOR]

Background Streptozotocin ( STZ) is known to induce type I diabetes and the loss of the interstitial cells of Cajal ( ICC). However, the regulation of heme oxygenase-1 ( HO-1) expression, which is reported to protect ICC, has not yet been elucidated in this model. The aim of this study was to investigate the alterations of HO-1 expression and clarify the mechanism of ICC loss in the stomach using the rat model of STZ-induced diabetes. Methods Streptozotocin (65 mg kg−1) was intraperitoneally administered to 8-week-old female Wistar rats. Cobalt protoporphyrin (Co PP), an HO-1 inducer, was administered subcutaneously once a week after the STZ injection. The expressions of HO-1 and the receptor tyrosine kinase c-Kit (a marker for ICC) proteins were investigated by western blot analysis and immunofluorescence staining. Key Results Expression of c-Kit, particularly in the gastric antrum, was significantly decreased at 8 weeks, not at 1 week, compared to those of the control group. Significantly increased induction of HO-1 expression, especially in the gastric corpus but not in the antrum, was observed in the STZ group at 8 weeks after the STZ injection relative to control. Co PP administration significantly up-regulated HO-1 expression in the STZ diabetic group and significantly restored the previously reduced ICC in the gastric antrum. Conclusions & Inferences Up-regulation of HO-1 expression in the STZ diabetic model was limited to the gastric corpus and impaired up-regulation of HO-1 expression in the gastric antrum likely induced the disruption of the ICC network. [ABSTRACT FROM AUTHOR]

Background Overactive bladder syndrome (OAB) is defined as a symptom complex comprising urgency, with or without urge incontinence, and usually frequency and nocturia. The association between irritable bowel syndrome (IBS) and bladder symptoms has been reported. This study is designed to investigate whether functional dyspepsia (FD), like IBS, is associated with OAB. Methods A web surveys containing questions about OAB, FD, IBS, and demographics were completed by 5494 public individuals (2302 men and 3192 women) who have no history of severe illness. The prevalence and overlap of OAB, FD, and IBS were examined. Key Results Among participants with FD, 20.5% could also be diagnosed with OAB (odds ratio [OR]: 2.85; 95% confidence interval [CI]: 2.21-3.67). Although concomitant FD and IBS were more strongly associated with OAB (OR: 4.34; 95% CI: 2.81-6.73), OAB was also highly prevalent among participants with FD but without IBS (OR: 3.09; 95% CI: 2.29-4.18). Among participants with FD, an overlapping OAB condition was more prevalent in those with both postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS) (OR: 3.75; 95% CI: 2.48-5.67) than in those with PDS or EPS alone. Among participants with OAB, the severity of bladder symptoms was greater in participants with dyspeptic symptoms than without them. Conclusions & Inferences Overactive bladder syndrome is common among FD patients, even if they do not have IBS. To improve FD patients' quality of life, it will be important to provide management for OAB. [ABSTRACT FROM AUTHOR]

Background Functional dyspepsia (FD) is a heterogeneous disease, and categorized into postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS). However, many FD patients have overlap of both PDS and EPS. The present study was designed to examine whether FD could be categorized based on the presence of concomitant gastrointestinal symptoms. Methods A web survey comprised of the Gastrointestinal Symptom Rating Scale (GSRS), Rome III criteria of FD, and demographic information was sent to public participants who have no history of severe illness. Factor and cluster analyses were conducted to identify sub-categories of FD based on GSRS. Key Results A total of 8038 participants completed the survey. A total of 563 participants met the criteria for FD, whereas 6635 participants did not have dyspepsia symptoms. The remainder had either organic disease (377) or uninvestigated dyspepsia (463). The cluster analysis categorized participants as constipation predominant (cluster C), diarrhea predominant (cluster D), or having neither diarrhea nor constipation (cluster nCnD). Cluster C and D were significantly associated with the presence of FD [odds ratio (OR) 2.57, 95% confidence interval (CI) 2.06-3.21; OR 2.80; 95% CI 2.27-3.45, respectively]. In FD, especially in PDS cases, the scores of upper gastrointestinal symptoms were higher in cluster C or D than in cluster nCnD. Conclusions & Inferences The severity of dyspepsia symptoms is associated with the presence of bowel symptoms especially in PDS. This novel categorization of FD based on concomitant constipation or diarrhea may improve classification of patients. [ABSTRACT FROM AUTHOR]

Background Metabolic syndrome and obesity are known risk factors for gastro-esophageal reflux disease (GERD), especially for erosive esophagitis. Although non-erosive reflux disease (NERD) is probably associated with obesity or other metabolic syndrome, there is little direct evidence to support this assertion. Methods Workers in Keio University who underwent a general health examination between September 2006 and August 2007 were enrolled. Reflux symptom questionnaires were administered and metabolic parameters were obtained. The severity of gastro-esophageal reflux (GER) was scored using a validated scale of videoesophagography. Key Results Two hundred and eighty-three subjects (243 men and 40 women; mean age 49.8 ± 6.9 years) with no radiographic evidence of erosive esophagitis were enrolled. The severity of GER was worse among men than among women, whereas the severity of reflux symptoms was worse among women. The severity of GER was associated with age and serum triglyceride levels in men, and with the serum low-density lipoprotein cholesterol levels in women. The severity of reflux symptoms, however, was not associated with metabolic parameters. There were more women than men with reflux symptoms but without GER (‘presumed’ functional heartburn group), compared with subjects with neither GER nor reflux symptoms. In men, the presence of both reflux symptoms and GER (‘presumed’ NERD group) was associated with the serum triglyceride levels. Conclusions & Inferences While NERD is associated with serum lipid levels, functional heartburn is not. The prevalence of GER was greater among men; conversely, the prevalence of functional heartburn was greater among women. [ABSTRACT FROM AUTHOR]

Acotiamide hydrochloride is a novel upper gastrointestinal (GI) motility modulator and stress regulator currently being developed for the treatment of functional dyspepsia (FD). The mechanism underlying the enhancement of GI motility by this agent has been proposed to be based on its muscarinic antagonism and inhibitory effects on acetylcholinesterase activity. Pathophysiological studies showed that acotiamide significantly improved both delayed gastric emptying and feeding inhibition in restraint stress-induced model, but did not affect both normal gastric emptying and feeding in intact animals, indicating that acotiamide exerted effects only on the impaired gastric emptying and feeding behavior. According to the clinical pilot study in Europe, acotiamide, at the dose of 100 mg t.i.d., showed to improve the symptoms and quality of life of patients with FD, indicating the need for larger scale symptomatic studies on the efficacy of acotiamide in patients with FD. The recent phase II studies conducted in Japan presented in this issue of the journal also confirmed that acotiamide, at the optimal dose of 100 mg, has potential therapeutic efficacy, especially for meal-related FD symptoms. Although a phase III study is on going, acotiamide is now expected as a novel treatment option for FD. [ABSTRACT FROM AUTHOR]

Background Gastrointestinal tract is one of the most susceptible organ systems to ischaemia. Not only mucosal injury but also alterations of the intestinal motility and loss of interstitial cells of Cajal (ICC) have been reported in response to ischaemia and reperfusion (I/R). However, there are few reports on the changes in the gastric motility after gastric I/R. The present study was designed to investigate the alterations in gastric emptying, the ICC and enteric nerves that regulate smooth muscle function in response to gastric I/R. Methods Seven-week-old male Wistar rats were exposed to gastric I/R, and the gastric emptying rates at 12 and 48 h after I/R were evaluated by the phenol red method. Expressions of gene product of c-kit receptor tyrosine kinase (c-Kit), a marker of ICC, and of neuronal proteins were also examined. Key Results Gastric emptying was transiently delayed at 12 h after I/R, but returned to normal by 48 h. Expression of c-Kit protein as assessed by Western blotting and immunofluorescent staining of the smooth muscle layer, as well as expression of the mRNA of stem cell factor, the ligand for c-Kit, were reduced at both 12 and 48 h after I/R. The expression of neuronal nitric oxide synthase (nNOS) protein as assessed by Western blotting and immunofluorescent staining was also decreased at 12 h after I/R, but was restored to normal by 48 h. Conclusions & Inferences Gastric I/R evokes transient gastroparesis with delayed gastric emptying, associated with disruption of the ICC network and nNOS-positive neurons. [ABSTRACT FROM AUTHOR]

Management of functional gastrointestinal disorders is hindered by both poor efficacy and adverse effects of traditional pharmacological therapy. Herbal medicine may be an attractive alternative based on the perception of its ‘natural’ approach and low risk of side effects; however, the lack of standardization of drug components has limited the ability to perform rigorous clinical studies in Western countries. Japanese herbal medicine (JHM) is a standardized form of herbal medicine with regards to the quality and quantities of ingredients. While extensively studied and widely used in Asia, there is a paucity of data upon which physicians in other parts of the world may draw conclusions regarding the effectiveness of herbal medicine for gastrointestinal disorders. The aim of this study was to summarize the most recent developments in JHM for treatment of functional gastrointestinal disorders. Animal and human studies were systematically reviewed to identify published data of JHM used for treatment of gastrointestinal disorders. The herbal components of JHM were examined. Results describing the physiological and clinical effects of JHM were abstracted, with an emphasis on functional gastrointestinal disorders. JHM are associated with a variety of beneficial physiological on the gastrointestinal system. Patient-based clinical outcomes are improved in several conditions. Rikkunnshi-to reduces symptoms and reverses physiological abnormalities associated with functional dyspepsia, while dai-kenchu-to improves symptoms of postoperative ileus and constipation in children. This updated summary of JHM in the field of gastrointestinal disorders illustrates the potential for herbal medication to serve a valuable role in the management of patients with functional gastrointestinal disorders. [ABSTRACT FROM AUTHOR]

Objective To assess the safety and efficacy of lecithinized superoxide dismutase (PC-SOD) in patients with ulcerative colitis (UC). Method PC-SOD was injected once daily at doses of 40 mg ( n = 22) and 80 mg ( n = 20) for a total treatment period of 4 weeks. Efficacy was assessed by UC-Disease Activity Index (DAI) total score. All side effects were recorded and investigated. Results At 4 weeks, the UC-DAI total score was significantly decreased vs baseline in both the 40 mg and 80 mg groups. It was confirmed that PC-SOD 80 mg was, at least, not significantly superior to PC-SOD 40 mg. Twenty incidences of side effects were noted in 12 (54.55%) of 22 patients in the 40 mg group, while there were three incidences of side effects in two (10.00%) of 20 patients in the 80 mg group. None of these side effects was severe. Thus it was concluded that the test drug is safe when given at daily dosages of 40 mg and 80 mg. Conclusion In this pilot study PC-SOD improved UC more rapidly than previously existing drugs. A double blind, placebo-controlled clinical trial of PC-SOD 40 mg/day is required to confirm the efficacy of this agent against UC. [ABSTRACT FROM AUTHOR]

Objective The aim of this study was to investigate the clinical outcome of laparoscopic surgery for Crohn's disease and clarify the indications using the Vienna Classification. Method Between September 1994 and July 2004, 107 patients with Crohn's disease underwent 124 procedures. Of these, 91 laparoscopic procedures formed the basis of this study. The Vienna Classification, which consists of three subgroups – age at diagnosis (A1-2), location (L1-4) and behaviour (B1-3) – was applied to compare the conversion to open surgery and incidence of postoperative complications. Results Conversion to open surgery was necessary in 12 (13.2%) patients. Major and minor postoperative complications occurred in five (5.5%) and 13 (19.8%) patients respectively. The conversion rate, major and total complications in the B3L3/4 subgroup were significantly greater than in the other subgroups. Multivariate analysis showed that B3L3/4 was the only predictive factor for all complications. However, the incidence of major and all complications in the B3L3/4 subgroup did not differ between the open and laparoscopic surgery groups. Conclusion Laparoscopic surgery for Crohn's disease is the procedure of choice for all uncomplicated cases (B2L1-4, B3L1/2). For patients in the complicated group (B3L3/4), laparoscopy is also feasible and justified; however, the surgeon must be aware of the propensity for higher rate of conversion. [ABSTRACT FROM AUTHOR]

Expression of sonic hedgehog (Shh), a morphogen for the gastric fundic glands, is reduced in the atrophic mucosa that develops in association with Helicobacter pylori infection, resulting in impaired differentiation of the fundic gland cells, increased expression of trefoil factor family 2 (TFF2) and the formation of spasmolytic polypeptide (SP)-expressing metaplasia (SPEM), a preneoplastic lesion. However, it is still unresolved whether H. pylori-induced inflammation and the resultant reduction in parietal cell number or reduced parietal cell function per se reduces Shh expression. The present study was designed to clarify the expression of Shh and TFF2 in the context of parietal cell dysfunction in the absence of inflammation, using histamine H2 receptor-knockout (H2R-null) mice and an acid exposure model. Age-matched H2R-null mice and wild-type (WT) mice were used. The expression of Shh and TFF2 mRNA was quantified by quantitative RT-PCR. Immunohistochemistry was also performed to detect the expression of Shh, TFF2 and cell markers. To study the effects of acid exposure, HCl solution was administered to the animals. The H2R-null mice exhibited higher gastric pH, increased TFF2 expression and reduced Shh expression. Impaired mucous neck-to-zymogenic cell differentiation was observed in the H2R-null mice. Furthermore, Shh expression increased in the presence of gastric acid and showed a significant correlation with gastric surface pH. In conclusion, our results suggest that persistent parietal cell dysfunction alone (suppressed gastric acid secretion), in the absence of inflammation or parietal cell loss caused by H. pylori infection, may be sufficient to down-regulate Shh expression in TFF2-overexpressing preneoplastic lesions of the gastric fundus. Since exposure to acid restored fundic Shh expression, appropriate gastric acid secretion may play an important role in the morphogen dynamics involved in the maintenance of gastric fundic gland homeostasis. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background Hepatitis C virus (HCV) easily undergoes genomic changes, especially in the hypervariable region (HVR) in the N-terminus of the E2/NS1 region. The quasispecies nature of HCV may have important biological implications in relation to viral persistence; however, the relationship between disease activity of chronic HCV infection and development of the genomic complexity have yielded conflicting results. We explored the changes in the complexity of the HVR-1 in the natural course of chronic HCV infection with and without elevation of serum alanine transaminase (ALT) levels. Materials and methods Ten patients with chronic hepatitis C proven by liver biopsy, who showed persistent elevation of the serum ALT levels, and 15 patients with chronic HCV infection and persistently normal serum ALT levels (PNAL) were enrolled in this study. The number of the HCV quasispecies was determined twice for each patient at an interval of mean 2·5 years by fluorescence single-strand conformation polymorphism and sequence analysis. Results There was no significant difference in the changes in the number of quasispecies during the follow-up period between chronic hepatitis C and PNAL. There was also no significant difference in the change in the number of variable nucleotides sites between the two groups. In these patients, the number of quasispecies and the diversity of HVR-1 were correlated with platelet counts and serum hyaluronic acid levels previously shown to be associated with disease progression. Conclusion Our results suggested that the disease activity is not always related to the generation of the HVR-1 quasispecies complexity. [ABSTRACT FROM AUTHOR]

Background Ghrelin, a recently discovered peptide hormone, has been shown to be produced mainly by the A-like cells of the gastric mucosa. Ghrelin not only stimulates growth hormone (GH) release but also promotes gastric motility. While the effect of ghrelin on the gastric acid secretion in rats has been reported, no such reports appeared to date from studies in humans. Aim To investigate the effect of ghrelin administration on the gastric pH in humans, using a novel wireless pH capsule (Bravo, Medtronic, Shoreview, MN, USA). Methods Four healthy volunteers (male; average age, 35.0 years; Helicobacter pylori-negative) were enrolled. The pH capsule was attached endoscopically to the gastric mucosa and the data were transmitted to a portable receiver. Thirty minutes after a stabilization period, synthetic ghrelin (5 μg/kg body weight) was injected intravenously into the subjects and the data were monitored for more than 120 min while the subjects lay supine. Results The average minimum gastric pH in four cases (1.2 ± 0.10) was significantly decreased after injection of ghrelin, as compared with the basal pH value (1.8 ± 0.06). The serum gastrin level, however, showed no change after the ghrelin injection. Conclusion These results suggest that exogenous ghrelin could enhance gastric acid secretion in humans. [ABSTRACT FROM AUTHOR]

Background Ghrelin is a novel appetite-promoting peptide secreted primarily from the A-like cells in the gastric fundic mucosa. As gastric inflammation caused by Helicobacter pylori infection extends, the number of ghrelin-producing A-like cells is diminished and gastric ghrelin content decreases significantly. We previously reported that plasma levels of ghrelin, which correlated well with the serum levels of pepsinogen (PG) I and PG I/II ratio, decreased as gastric mucosal atrophy increased in non-ulcerogenic conditions and that plasma ghrelin level increased in rats with cysteamine-induced duodenal ulcer. Aim To investigate the plasma levels of ghrelin in patients with peptic ulcer disease. Patients and Methods Two hundred and eighty-six patients with epigastric symptoms, who underwent upper gastrointestinal endoscopy, were enrolled. Blood samples were collected after a 12-h fast before endoscopy. Patients were divided into four groups, namely chronic gastritis with high PG ( n = 197), chronic gastritis with low PG ( n = 58), duodenal ulcer ( n = 14) and gastric ulcer ( n = 17) and plasma concentrations of total and active ghrelin as well as serum concentrations of PG I and PG II were measured by radioimmunoassay. Six patients with duodenal ulcer and seven with gastric ulcer were also examined after ulcer healing. Results Plasma ghrelin levels were significantly higher in patients with duodenal ulcer or gastric ulcer than in those without ulcers. Elevated plasma total ghrelin levels did not significantly change after the healing of ulcers. Conclusions Plasma ghrelin levels were significantly higher in patients with peptic ulcer than in those with gastritis without ulcer. This finding suggests a possible relationship between mucosal injury susceptibility and elevated fasting plasma ghrelin. [ABSTRACT FROM AUTHOR]

Background Although resistance of Helicobacter pylori to metronidazole had been reported to be associated with mutations in the rdxA or the frxA gene, recent studies have indicated that they may contribute little to metronidazole resistance. Aim To clarify the roles of these genes in metronidazole resistance, we examined them in strains that were not eradicated by first-line eradication therapy. Patients and methods A total of 132 patients (92 males, 40 females, average age: 53.8 years old) who underwent upper gastrointestinal endoscopy after unsuccessful first-line H. pylori eradication were enrolled. Antibiotic susceptibility to metronidazole was investigated using the agar dilution method. The H. pylori rdxA and frxA genes were then sequenced. Results In the metronidazole-resistant strains, the sensitivity of detection of frameshift mutations in the rdxA gene was 44%. A significant association between the presence of frameshift mutations in the rdxA gene and resistance to metronidazole was observed. No significant association between frameshift mutations in the frxA gene and resistance to metronidazole was observed. Conclusion Mutation in the rdxA gene was sufficient, but not necessary to confer resistance to metronidazole in H. pylori. Mutation in the frxA gene was not necessary for resistance to metronidazole in H. pylori. [ABSTRACT FROM AUTHOR]

Background Ghrelin, growth-hormone-releasing peptide, has been reported to accelerate food intake and gastrointestinal motility. Aim The present study was designed to investigate the plasma ghrelin levels in patients with functional dyspepsia (FD). Patients and Methods Ninety-seven patients, who showed no evidence of peptic ulcer disease or gastrointestinal cancer on upper gastrointestinal endoscopy, were recruited. Seventeen patients who had no gastrointestinal symptoms were recruited as controls. Forty-seven patients were diagnosed to be suffering from FD, based on the Rome II criteria. The FD patients were further subdivided into those with ulcer-like FD, dysmotility-like FD and non-specific-type FD, based on their Gastrointestinal Symptom Rating Scale (GSRS) scores. Fourteen patients were categorized as having gastro-oesophageal reflux disease, and 19 patients were excluded as having the irritable bowel syndrome, based on the GSRS. The plasma ghrelin levels were measured by radioimmunoassay. Results The plasma ghrelin levels were significantly higher in FD patients, especially in those with dysmotility-like FD, as compared with those in controls. The plasma ghrelin levels were also correlated well with the indigestion scores. Conclusion Plasma ghrelin levels are significantly higher in patients with dysmotility-like FD, suggesting that this parameter could become useful as a novel supportive marker for the diagnosis of FD. [ABSTRACT FROM AUTHOR]

Aim To examine whether Helicobacter pylori induces structural chromosomal aberrations, such as loss of heterozygosity (LOH) and microsatellite instability (MSI) in the infected gastric mucosa. Methods Subjects were 13 patients with H. pylori-positive and 9 with H. pylori-negative gastric cancer and 20 patients with H. pylori-positive and 4 patients with H. pylori-negative chronic gastritis. Gastric mucosal tissues were endoscopically sampled from each subject. Each sample was checked for structural chromosomal aberrations (LOH and MSI) by PCR and microsatellite analysis, using a total of 31 primers corresponding to the regions containing the major genes of chromosomes 1q, 5q, 7q, 17p, 17q, 18q and 21q. Results All tissue samples obtained from cancer-affected regions of the stomach had structural chromosomal aberrations (LOH or MSI), irrespective of H. pylori infection. The degree of structural chromosomal aberration was greater in poorly differentiated than well-differentiated adenocarcinoma. In addition, structural chromosomal aberrations were also found in a few samples obtained from the chronic atrophic gastritis group, irrespective of H. pylori infection. Conclusions It seems unlikely that H. pylori serves as a direct promoter of gastric cancer, and H. pylori-positive chronic gastritis may not always be a precancerous state. [ABSTRACT FROM AUTHOR]

Background The [13C]-ethanol breath test (EBT) has been proposed as a novel non-invasive laboratory test to detect the degradation of ethanol into CO2. However, this method has not yet been evaluated clinically. Aim To investigate the factors that influence [13C]-EBT. Methods Twenty-six healthy volunteers were instructed to drink 100 mL of beer (4 g ethanol) containing 100 μL of [13C]-ethanol. Breath samples were collected every 15 min before and after the intake of ethanol solution and 13CO2-enrichment was measured using mass spectrometry. CO2 excretion was then calculated, and the results were evaluated using kinetic parameters ( Tmax, Cmax, AUC). Results Tmax (min) was significantly shorter in men than in women but not Cmax and AUC. Infection with H. pylori had no impact on all kinetic parameters. Genetic alcohol dehydrogenase (ADH) polymorphisms did not affect 13CO2 excretion, but Cmax (11.1 ± 3.4% dose/h, n = 16) and AUC (10.5 ± 3.4% dose) were slightly increased in aldehyde dehydrogenase (ALDH)-deficient individuals (heterozygote of ALDH2*2) (13.2 ± 3.2 and 12.9 ± 4.5, respectively; n = 10). Conclusions [13C]-EBT is capable of assessing the metabolic processing of 100 mL beer in a non-invasive way. Kinetic parameters are partially influenced by ALDH polymorphism but not by gender, H. pylori infection or ADH polymorphism. [ABSTRACT FROM AUTHOR]

Background Many reports have described coinfection of Helicobacter pylori and other bacteria in the gastric mucosa in humans. However, relatively few have reported the relation of coinfection with pathological characteristics. Aim To culture and identify bacteria other than H. pylori from the gastric mucosa of 64 patients undergoing scheduled gastric biopsy for various gastric conditions. The relation of coinfection with the pathological changes was also investigated. Methods From colonies showing characteristics different to those of H. pylori, bacteria were identified by the 16S rRNA gene sequence using FASTA. Cluster analysis was performed using GENETYX-MAC and a phylogenetic tree was constructed using the UPGMA method. The correlation of pathological observation and the existence of identified bacteria and H. pylori were also analysed. Results Forty-eight per cent of patients were positive to H. pylori, and 27% were positive to Neisseria species. Coinfection of the two bacterial existences was significantly linked. DNA sequencing studies revealed these Neisseria strains to coincide mostly with Neisseria subflava. With regard to the interaction of pathological characteristics, Neisseria and H. pylori coinfection was closely related to lymph follicle formation. Conclusions Coinfection of H. pylori and N. subflava was found to be closely related to lymph follicle formation. [ABSTRACT FROM AUTHOR]

: There are no management criteria for optimum out-patient care in mild-to-moderate acute colonic diverticulitis.: To enable such patients to be managed in an out-patient setting, by establishing criteria and treatment protocols.: We conducted an open trial and follow-up study from 1997 to 2002. On the basis of ultrasonography, we defined and categorized mild-to-moderate acute colonic diverticulitis ranging from limited inflammation within diverticulum to an abscess< 2 cm in diameter. Subjects were treated as out-patients and followed a 10-day treatment protocol consisting of an oral antibiotic and a sports drink for the first 3 days. Physical examination and laboratory testing helped determine whether or not a patient could resume a liquid diet on day 4, and a regular diet on day 7.: Of the 70 patients, 68 were successfully treated. Two patients required hospitalization. Of the 65 patients who were tracked over several months [median (intraquarter range) = 30.8 (11.9–44.2) months], 16 had one or more clinical recurrences. The medical cost per episode was 80% lower than in-patient treatment.: Patients with mild-to-moderate acute colonic diverticulitis can be safely and successfully treated as out-patients using this protocol. [ABSTRACT FROM AUTHOR]

Recently, chicken egg yolk was recognized as an inexpensive antibody source, and the therapeutic usefulness of egg yolk immunoglobulin Y (IgY) in oral passive immunization has been investigated. Although multiple antibiotic treatments eradicate most Helicobacter pylori ( H. pylori) infections, therapy fails in 10–15% of cases due to the development of drug resistance. Consequently, it is important that new, more broadly based therapies for the treatment of H. pylori infection should be identified. The present study evaluated the effect, on H. pylori infection, of IgY prepared from egg yolk of hens immunized with H. pylori urease (anti-HpU IgY). Seventeen asymptomatic volunteers diagnosed as H. pylori-positive by the 13C-urea breath test (UBT) were orally administered anti-HpU IgY for 4 weeks. Four weeks later, UBT values were significantly decreased although no case showed H. pylori eradication. An H. pylori-positive 53-year-old female gastritis patient administered anti-HpU IgY plus lansoprazole for 8 weeks showed a decrease in serum pepsinogen (PG) I and UBT values as well as an increase in the PG I/II ratio. In conclusion, anti-HpU IgY may mitigate H. pylori-associated gastritis and partially attenuate gastric urease activity. Furthermore, anti-HpU IgY combined with antacids appears to ameliorate gastric inflammation. These encouraging results may represent a novel approach to the management of H. pylori-associated gastroduodenal disease. [ABSTRACT FROM AUTHOR]

Examines the pathogenicity of hrpX genes present in Xanthomonas campestris. Use of Southern blot analysis in examining hrpX genes; Role of hrpX genes in preventing the recognition of Xanthomonas; Activation of loci in hrp clusters.

The article presents the medical case report of a patient with a history of anorexia who ingested 13.2 g of aspirin with suicidal intent. Harmonic flash echo imaging was used to demonstrate increased gastric blood flow after the ingestion of an overdose of aspirin. It is stated that outcome of the diagnosis raise the possibility that changes in gastric transmural blood flow after ischemic or other events can be monitored by noninvasive methods such as harmonic flash echo imaging.

Background: Intestinal ultrasound (IUS) is a non-invasive tool for evaluating transmural inflammation in Crohn's disease (CD). However, its utility is constrained by operator dependency and limited accessibility., Aims: To explore the feasibility of serum biomarkers-specifically leucine-rich alpha-2 glycoprotein (LRG)-as an alternative to IUS for assessing transmural inflammation., Methods: This retrospective, single-centre study included patients with CD who underwent IUS and measurements of LRG and C-reactive protein (CRP). We assessed correlations between biomarkers and five IUS scores (Limberg score, Bowel Ultrasound Score (BUSS), International Bowel Ultrasound Segmental Activity Score (IBUS-SAS), Simple Ultrasound Score (Simple-US) and Simple Ultrasound Score for Crohn's Disease (SUS-CD)) using receiver operator characteristic curve analysis and Spearman's rank correlation coefficient. We conducted subgroup analyses for patients in clinical remission., Results: We analysed 213 IUS examinations performed on 97 patients; 170 (80%) IUS were during clinical remission. The area under the curve for LRG for each IUS score (0.76, 0.80, 0.77, 0.75 and 0.69, respectively) was superior to that of CRP and was statistically significant, particularly for LS, BUSS, IBUS-SAS and Simple-US (p < 0.001, p = 0.018, p < 0.001 and p < 0.001, respectively). Predictive values remained consistent among patients in remission. LRG demonstrated excellent correlation with IUS scores in both the overall patient population and those in remission., Conclusion: LRG showed a robust correlation with IUS scores, suggesting its potential as a novel indicator for targeting transmural healing in patients with CD., (© 2024 John Wiley & Sons Ltd.)

The tumor microenvironment of hepatoblastoma (HB), the most common pediatric liver tumor, predominantly exhibits a myeloid immune landscape. in which tumor-associated macrophages (TAMs) are considered the core component. The crosstalk between TAMs and HB cells markedly influences tumor behavior. TAM-derived factors are involved in tumor proliferation and vascular invasion. On the other hand, HB cell secretome attracts, stimulates, and reprograms TAMs to be immunosuppressive in favor of tumor invasion, rather than their innate role in combating tumor growth, such crosstalk sometimes forms bidirectional feedback loops, making the tumor more virulent and resistant to routine therapeutics. Consequently, TAMs are the common denominator of most suggested HB immunotherapeutic strategies. Macrophage immune checkpoint inhibitors, macrophage-mediated antibody-dependent cellular phagocytosis, and the novel chimeric antigen receptor macrophage therapy (CAR Mφ) are currently under trial. In this review, we will summarize the significance of TAMs and their potential role as a therapeutic target in HB., (© 2024 The Societies and John Wiley & Sons Australia, Ltd.)

Background: Endoscopic healing (EH) is a therapeutic target in ulcerative colitis (UC). However, even patients who have achieved EH relapse frequently., Aims: To investigate the association between recent steroid use and relapse risk in UC patients with EH., Methods: This multi-centre cohort study included 1212 UC patients with confirmed EH (Mayo endoscopic subscore ≤1). We excluded patients with current systemic steroid use or history of advanced therapy. We divided patients into a recent steroid group (last systemic steroid use within 1 year; n = 59) and a non-recent or steroid-naïve group (n = 1153). We followed the patients for 2 years to evaluate relapse, defined as induction of systemic steroids or advanced therapy. We used logistic regression to estimate the odds ratio (OR) of relapse., Results: Relapse occurred in 28.8% of the recent steroid group and 5.6% of the non-recent/steroid-naïve group (multi-variable-adjusted OR 5.53 [95% CI 2.85-10.7]). The risk of relapse decreased with time since the last steroid use: 28.8% for less than 1 year after steroid therapy, 22.9% for 1 year, 16.0% for 2 years and 7.9% beyond 3 years, approaching 4.0% in steroid-naïve patients. (p trend  <0.001)., Conclusions: Even for patients with UC who achieved EH, the risk of relapse remains high following recent steroid therapy. Physicians need to consider the duration since last steroid use to stratify the relapse risk in UC patients with EH., (© 2024 John Wiley & Sons Ltd.)

Background: The increasing incidence of older-onset ulcerative colitis (UC), which has a higher risk of surgery, is a global health issue. However, data regarding intravenous steroid treatment, one of the important treatment options to avoid surgery, for older-onset UC is lacking., Aims: To evaluate the association between onset age and effectiveness of intravenous steroids in UC., Methods: This retrospective multicentre (27 facilities) cohort study included moderate-to-severe hospitalised UC patients who underwent their first intravenous steroids between April 2014 and July 2019. The primary outcome was clinical remission at day 30, using two-item patient-reported outcome scoring. The key secondary outcomes were risks of surgery and adverse events (death, infection and venous thrombosis) within 90 days. A modified Poisson regression model was used for analysis., Results: Overall, 467 UC patients (384 younger-onset and 83 older-onset) were enrolled. Clinical remission at day 30 was observed in 252 (65.6%) among younger-onset patients and 43 (51.8%) among older-onset patients (adjusted risk difference, -21.7% [95% CI, -36.1% to -7.2%]; adjusted risk ratio [ARR], 0.74 [95% CI, 0.59 to 0.93]). The risks of surgery and adverse events were higher in older-onset UC (20.5% vs. 3.1%; ARR, 8.92 [95% CI, 4.13 to 19.27], 25.3% vs. 9.1%; ARR, 2.19 [95% CI, 1.22 to 3.92], respectively). Four deaths occurred, all involving older-onset UC. The risks of infection and venous thrombosis were also higher in older-onset UC (18.1% vs. 8.6%, 7.2% vs. 0.5%, respectively)., Conclusions: Older-onset was associated with a lower effectiveness of intravenous steroids with higher risks of surgery and adverse events in UC., (© 2022 John Wiley & Sons Ltd.)

Background: Bowel ultrasonography is a non-invasive imaging tool that can repeatedly monitor ulcerative colitis (UC) activity., Aim: This study aimed to determine whether early transabdominal or transperineal ultrasonography changes can predict subsequent clinical response to induction therapy in patients with UC., Methods: This single-centre prospective study explored ultrasonographic predictors for clinical remission (patient-reported outcome-2 ≤ 1 with no rectal bleeding subscore) at week 8 in patients with active UC who underwent induction therapy, in comparison with faecal calprotectin and C-reactive protein (measured at baseline, week 1 and week 8). Predictive factors were assessed using multivariable regression models and receiver-operating-characteristic curve analysis., Results: A total of 100 patients were analysed, of which 54 achieved remission at week 8. Baseline biomarker and ultrasonographic-parameter values were not predictive of remission. Contrastingly, change from baseline to week 1 in rectal bowel wall thickness measured using transperineal ultrasonography was an independent predictor of remission by week 8 (adjusted odds ratio is associated with a 1-mm decrease: 1.90 [95% confidence interval, 1.22-2.95]). In a subgroup analysis of the patients who did not achieve remission in 1 week, the predictive value of change in rectal bowel wall thickness remained high (AUC = 0.77 [95% confidence interval, 0.61-0.88])., Conclusion: Improvement in rectal bowel wall thickness measured using transperineal ultrasonography at week 1 predicts treatment success and potentially facilitates decision making during the early course of induction therapy in UC., (© 2022 John Wiley & Sons Ltd.)

Background: Transabdominal ultrasound is useful to assess inflammation in patients with ulcerative colitis (UC); however, the assessment of the rectum is challenging and a barrier for its widespread use., Aim: To evaluate if transperineal ultrasound is useful for predicting endoscopic and histological findings of the rectum in UC., Methods: Fifty-three consecutive adults with UC who required colonoscopy were included and transperineal ultrasound was performed in combination with transabdominal ultrasound within a week before or after colonoscopy with rectal biopsy. Mayo endoscopic subscore (MES) ≤1 was defined as endoscopic healing and Geboes score <2.1, Robarts histopathology index ≤6, and Nancy index ≤1 were defined as histological healing. Limberg score and bowel wall thickness were recorded with transperineal ultrasound. Faecal calprotectin was also measured., Results: Excellent correlation was confirmed between colonoscopy and transabdominal ultrasound in all segments except for the rectum. Rectal bowel wall thickness and Limberg score in transperineal ultrasound well correlated with rectal MES and histological indices. Bowel wall thickness ≤4 mm predicted endoscopic (Area under the curve [AUC] = 0.90) and histological (AUC = 0.87-0.89) healing. In multivariable logistic regression analysis, only bowel wall thickness in transperineal ultrasound was a significant independent predictor for rectal endoscopic and histologic healing (P < 0.05) and the predictability was better than faecal calprotectin., Conclusions: Transperineal ultrasound predicts endoscopic and histological healing of the rectum. The combination of transperineal ultrasound with transabdominal ultrasound visualises the entire colorectum and is an ideal modality for the treat-to-target strategy. Clinical Trials Registry number UMIN000033611 (https://upload.umin.ac.jp/cgi-open-bin/ctr&#95;e/ctr&#95;view.cgi?recptno=R000038323)., (© 2020 John Wiley & Sons Ltd.)

Background: The clinical significance of Helicobacter pylori antibody titer has been controversial, and the association between the extent of gastric atrophy or acid secretion and H. pylori antibody concentration has not been elucidated., Materials and Methods: Serum pepsinogen, H. pylori antibody concentration, and fasting gastric pH (as an indicator of acid secretion) were measured in 231 patients undergoing upper gastrointestinal endoscopy. "Atrophic" pepsinogen was defined as pepsinogen-I < 70 ng/mL and pepsinogen-I/II ratio < 3. Other levels of pepsinogen were defined as "normal". Fasting gastric pH was analyzed in subjects stratified by pepsinogen level and by H. pylori antibody concentration., Results: Helicobacter pylori antibody concentration showed no significant relationship with fasting gastric pH when all subjects were analyzed together. In H. pylori-seronegative subjects, fasting gastric pH was within the normal range, irrespective of the extent of mucosal atrophy. In H. pylori-seropositive subjects, H. pylori antibody concentration was positively correlated with fasting gastric pH in subjects with "normal" pepsinogen, but inversely correlated in those with "atrophic" pepsinogen. Particularly in subjects with low H. pylori antibody concentration and atrophic mucosa, a group reportedly at high risk of noncardia cancer, the most impaired acid secretion was shown among subjects with atrophic mucosa., Conclusions:   The relationship between acid secretion and H. pylori antibody concentration differs depending on the presence of mucosal atrophy. Our findings provide a possible rationalization for measuring both serum pepsinogen levels and H. pylori antibody concentration in gastric cancer screening., (© 2011 Blackwell Publishing Ltd.)

Background: Aquaporins (AQPs) are key regulators not only of water transport in the cytoplasm but also of angiogenesis. Although AQPs in the normal hepatobiliary system have been studied in mammals, little is known about the localization and changes of AQPs in the hepatic microvascular system including sinusoids in cirrhotic liver, which might contribute to portal hypertension., Aims: We designed this study to examine the localization of AQP1 in human cirrhotic liver., Methods: Surgical wedge biopsy specimens were obtained from non-cirrhotic portions of human livers (normal control) and from cirrhotic livers (LC) (Child A-LC and Child C-LC). Immunostaining, Western blotting, in situ hybridization (ISH) and laser-captured microdissection (LCM) were conducted., Results: In control liver tissue, AQP1 was localized mainly in the portal venules, hepatic arterioles and bile ducts in the portal tract, although AQP1 was detected only slightly in the sinusoids. In cirrhotic liver tissue, AQP1 expression was evident, aberrantly observed on periportal sinusoidal endothelial cells corresponding to the capillarized sinusoids, on the proliferated arterial capillaries opening into the sinusoid in the generating hepatic nodule and on proliferated bile ductules at the peripheral edge of nodules and fibrotic septa. In cirrhotic liver, overexpression of AQP1 at protein and mRNA levels was demonstrated, respectively, using Western blot and ISH. AQP-1 of mRNA level in sinusoid was confirmed using LCM., Conclusions: Aberrant expressions of AQP1 in periportal sinusoidal regions in human cirrhotic liver indicate the proliferation of arterial capillaries directly connected to the sinusoids, contributing to microvascular resistance in cirrhosis., (© 2011 John Wiley & Sons A/S.)

Objective: Aberrant leukocyte migration has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Lemon grass is a natural herb that contains citral, which suppresses lymphocyte expression of gut homing molecules by inhibiting retinoic acid formation. We therefore hypothesized that lemon grass intake could ameliorate excess migration of leukocytes to the inflamed intestine in chronic ileitis., Methods: Migration of fluorescence-labeled T cells to microvessels in the ileal mucosa of SAMP1/Yit mice was monitored using intravital microscopy. In some mice, lemon grass solution was administered for two weeks. For evaluation of the effects on chronic ileitis, mice were treated with lemon grass for 26 weeks., Results: Surface expression of beta7 and CCR9 on T lymphocytes was stronger in SAMP1/Yit mice than in AKR/J mice. Lemon grass treatment attenuated the surface expression of beta7-integrin and CCR9. The number of adherent lymphocytes to microvessels in chronic inflamed ileum was significantly few when lymphocytes were isolated from lemon grass treated mice. Long-term lemon grass treatment improved ileitis in SAMP1/Yit mice, which was assessed by body weight, histological changes and the infiltration of beta7-positive cells., Conclusion: Lemon grass ameliorated ileitis through decreasing lymphocyte migration by inhibiting beta7-expression, suggesting its therapeutic usefulness for IBD.

Background: We previously reported that an NAD-dependent in situ retinoic acid supply system, which comprises some isoforms of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) and provides retinoic acid from retinol via a 2-step oxidation process, exists in the rat esophagus. Herein, their isoforms responsible for the pathway and its localization in the rat esophagus was examined., Methods: The expressions of mRNAs of various isoforms of ADH and ALDH were examined in the fraction mainly comprising mucosal layer of the rat esophagus by RT-PCR. Expression levels of Class IV ADH and ALDH 1A1 were compared between the fractions and that mainly comprising muscle layer of the rat esophagus by quantitative PCR. The catalytic activities producing retinoic acid from retinal were compared between the 2 fractions and its optimum pH was also determined., Results: Classes I, III, and IV ADHs and ALDHs 1A1 and 3A1 were predominant isoforms in the rat esophageal mucosa. The expression levels of mRNA of Class IV ADH and ALDH 3A1 were significantly higher in the mucosal than in the muscle layer. Consistently, the catalytic activities producing retinoic acid from retinal were significantly higher in the former than the latter. The optimum pH of the process was 9.0., Conclusions: Considering the affinities for retinol and retinal of ADHs and ALDHs expressed in the rat esophagus, the NAD-dependent in situ retinoic acid supply system in the rat esophagus is thought to comprise Class IV ADH and ALDH 1A1. In the rat esophagus, the system exists predominantly in the mucosal layer.

Microcirculation is one of the susceptible targets in the pathogenesis of disorders caused by exogenous pathogens, such as the well-known bacterium, Helicobacter pylori (Hp). While extensive studies have been published on the kinetics of Hp infection, only a few have dealt with the microcirculatory aspects of Hp-induced disorders. This review summarizes the recent developments in the elucidation of the pathophysiology of disorders caused by Hp infection, focusing on the microcirculatory aspect. Animal and human studies were systematically reviewed to identify published data on the microcirculatory aspects of Hp infection. This updated summary of the microcirculatory aspects of Hp-induced disorders illustrates potential approaches that might be used to clarify the pathophysiology of the gastric and extragastric sequelae of Hp infection and the therapeutic strategies that could be adopted.

gamma-Glutamylcysteine synthetase-glutathione synthetase (gammaGCS-GS) is a bifunctional enzyme that catalyzes two consecutive steps of ATP-dependent peptide formation in glutathione biosynthesis. Streptococcus agalactiae gammaGCS-GS is a target for the development of potential therapeutic agents. gammaGCS-GS was crystallized using the sitting-drop vapour-diffusion method. The crystals grew to dimensions of 0.3 x 0.2 x 0.2 mm under reducing conditions with 5 mM TCEP. X-ray data were collected to 2.8 A resolution from a tetragonal crystal that belonged to space group I4(1).

Background/aims: Rho guanidine triphosphatases (GTPases) are major regulators of cell migration. We investigated the cytoskeleton and Rho GTPases during cell migration and morphogenesis processes in isolated rat liver sinusoidal endothelial cells (LSECs) cultured on Matrigel while stimulated by the vascular endothelial growth factor (VEGF)., Methods: To obtain primary monolayers, LSECs were cultured on Matrigel for 5-17 h with or without VEGF. Sinusoidal endothelial fenestrae (SEF) morphology was observed using scanning electron microscopy and transmission electron microscopy. RhoA, Rac1 and phosphorylated myosin light-chain kinase, Rho-binding domain of Rhotekin and the p21-binding domain of p21-activated protein kinase were analysed using Western blotting., Results: The LSECs showed cellular protrusions and or cords of aligned cells resembling primitive capillary-like structures, with SEF contraction. Time course analyses of Rac1 activation matched specific morphological changes. Rac1 activity increased progressively to 17 h in cells cultured without VEGF, but markedly increased at 7 h in the presence of VEGF. RhoA activity was slightly elevated at 5 h. The levels of endogenous caveolin-1 (CAV-1) expression increased in a time-dependent manner, reaching a peak at 7 h. CAV-1 expression occurred immediately before the formation of the capillary-like tube. Moreover, treatment with VEGF regulated CAV-1 expression in LSECs., Conclusions: Spatial activation of Rac1 is involved in the formation of a capillary-like tubular network accompanying SEF contraction in LSECs, implying that endothelial migration and adhesion are necessary for LSECs tubular formation in the liver. CAV-1 might play an important positive role in the regulation of LSEC tubular formation.

Mpr1 is an enzyme that catalyzes the N-acetylation of the toxic L-azetidine-2-carboxylic acid (AZC). Recently, Mpr1 has been shown to reduce levels of intracellular reactive oxygen species (ROS) under oxidative stress. The natural substrate involved in the ROS elimination in vivo is still unknown. Mpr1 has been purified and crystallized in space groups P1 and P3(1)12. X-ray data were collected to 1.9 A resolution from a trigonal crystal soaked with AZC.

Background/aims: Liver injury results in the activation of hepatic stellate cells (HSCs), which in turn produce matrix metalloproteinase (MMP) in response to pro-inflammatory cytokines for tissue remodelling. This study explored the transcriptional induction of the MMP-1 gene by tumour necrosis factor-alpha (TNF-alpha) in HSCs., Methods: The LI90 human HSC line was used in the present study. Gelatin zymography, enzyme-linked immunosorbent assay, Northern blotting and gene promoter-reporter assays were used to analyse the induction of MMP-1 protein, mRNA expression and gene transcription respectively. Deletional or site-directed mutations were introduced into the promoter region and transiently transfected into LI90 cells to determine the cis-acting elements necessary for TNF-alpha inducibility. Gel shift mobility assays were used to determine the transcriptional factors involved in the TNF-alpha responsiveness., Results: TNF-alpha upregulated MMP-1 protein and mRNA expression in a dose-dependent manner. A time-course experiment revealed a rapid induction of MMP-1 mRNA expression after TNF-alpha treatment. Mutation in a putative nuclear factor (NF)-kappaB-binding site at -2541 bp almost completely abolished the TNF-alpha response to MMP-1 gene-promoter activity, suggesting transcriptional regulation of MMP-1 expression by TNF-alpha via this site. Electrophoretic mobility shift assay and supershift assays indicated that this transcriptional regulation was regulated via the p50/p50 homodimer of NF-kappaB., Conclusions: MMP-1 gene expression might be induced by TNF-alpha via the p50/p50 homodimer of NF-kappaB in activated human HSCs.

Two methods of TSS diagnosis were evaluated: comparison of symptoms with clinical criteria and monitoring for evidence of selective activation of Vbeta2(+) T cells by the causative toxin, TSS toxin-1 (TSST-1). Ten patients with acute and systemic febrile infections caused by Staphylococcus aureus were monitored for increase in TSST-1-reactive Vbeta2(+) T cells during their clinical courses. Nine of the ten patients were diagnosed with TSS based on evidence of selective activation of Vbeta2(+) T cells by TSST-1; however, clinical symptoms met the clinical criteria for TSS in only six of these nine patients. In the remaining patient, clinical symptoms met the clinical criteria, but selective activation of Vbeta2(+) T cells was not observed. Time taken to reach the diagnosis of TSS could be significantly shortened by utilizing the findings from tracing Vbeta2(+) T cells. In vitro studies showed that TSST-1- reactive T cells from TSS patients were anergic in the early phase of their illness. Examining selective activation of Vbeta2(+) T cells could be a useful tool to supplement clinical criteria for early diagnosis of TSS.

Objective: Although it is known that the chemokines CXCL12 and CCL20 are expressed in the intestine, their contribution to lymphocyte homing has not been investigated in detail. The authors investigated whether the CXCL12-CXCR4 and CCL20-CCR6 systems are involved in T lymphocyte-endothelial interaction in microvessels of the small and large intestines., Methods: Labeled lamina proprial lymphocytes (LPLs) were administered to mice, and their adhesion to microvessels of normal and TNF-alpha -induced inflamed intestinal mucosa was observed under an intravital microscope. Antibodies against CXCL12, CCL-20, or CCL-25 were administered prior to lymphocyte administration, and in some experiments CXCR4 or CCR6 on LPLs was desensitized with an excess amount of chemokine., Results: LPLs adhered to microvessels of the ileum and colon, and TNF-alpha induced a significant accumulation at both sites. Blocking of the CXCL12-CXCR4 system significantly inhibited the LPL adhesion in the ileum and colon under both normal and TNF-alpha -treated conditions. However, blocking of the CCL20-CCR6 system significantly attenuated LPL adhesion only under a TNF-alpha -treated condition. There was an additive inhibitory effect on LPL adherence by CXCL12 and CCL20 blocking in TNF-alpha -induced inflamed intestines. There was also an additive function of the CCL25-CCR9 system in LPL accumulation in the small intestine., Conclusion: Several chemokine systems may play significant roles cooperatively in vivo in LPL adherence to microvessels of intestinal mucosa.

Tranexamic acid is one of the widely used antifibrinolytic agents. In spite of its effective inhibitory activity against plasminogen, thromboembolic adverse events caused by tranexamic acid are rare. We encountered three recipients of allogeneic hematopoietic stem cell transplantation (HSCT) who developed hepatic veno-occlusive disease (VOD) shortly after the administration of tranexamic acid. Hepatic VOD was resolved completely in all patients with the discontinuation of the drug, and with supportive measures with or without intravenous tissue plasminogen activator administration. These findings suggest that administration of tranexamic acid could be one of the possible risk factors for developing hepatic VOD in HSCT recipients., (2007 Wiley-Liss, Inc)

Background/aims: We previously reported that endothelin (ET)-1 may be involved in the contraction of hepatic sinusoidal endothelial fenestrae (SEF). Rho has emerged as an important regulator of the actin cytoskeleton and consequently cell morphology. To clarify the role of ET receptors [endothelin A receptor (ETAR) and endothelin B receptor (ETBR)] in ET-1-induced defenestration, we studied the size of hepatic SEF under various experimental conditions., Methods: Liver sinusoidal endothelial cells (LSECs) isolated from rat livers by collagenase perfusion were cultured and divided into four groups: control, ET-1 (10(-6) -10(-10) M)-treated, ET-1+selective ETAR antagonist (BQ610)-treated and ET-1+ETBR antagonist (BQ788)-treated groups. SEF morphology was observed by scanning electron microscopy. Protein expressions of ETAR and ETBR, Rho A and phosphorylated myosin light-chain kinase were analyzed by Western blotting. F-actin stress fiber formation was observed by confocal microscopy. Active Rho was measured by Ren's modification. Intracellular free Ca2+ concentration ([Ca2+]i) was measured by fluorescence digital imaging using fura-2 AM by Aqua cosmos., Results: ET-1 induced a reduction in the number and size of SEF. ETAR antagonist pretreatment inhibited defenestration induced by low ET-1 concentrations (10(-8) -10(-10) M), whereas ETBR antagonist pretreatment did not block defenestration at low to high ET-1 concentrations (10(-6) -10(-10) M). F-actin stress fibers, Rho A levels and phosphorylated myosin light-chain kinase levels remained the same in various treatments. Active Rho was not detected in control and various treatments. ET-1 did not increase [Ca2+]i. Western blot showed prominent ETBR but scarce ETAR protein expression in LSECs., Conclusions: The present findings demonstrated that ETBR- and ETAR-induced contractile mechanisms are not involved in ET-1-induced defenestration, and that Rho is also not activated. Therefore, ET-1 induces hepatic defenestration by mechanisms other than receptor-mediated contraction.

Background: Recently, the incidence of alcoholic liver disease (ALD) has been increasing in Japan; this associated with an increase in alcoholic beverage consumption. Multiple organ failures are frequently observed in patients with severe alcoholic hepatitis (AH), most of whom have a poor prognosis similar to fulminant hepatitis; as well numbers of severe AH patients appear to be increasing. Although prognosis of fulminant hepatitis in Japan has been recently improved by intensive treatments such as plasma exchange (PE) that of severe AH has not changed. The objective of this study was to determine whether there was any factor that could determine the prognosis of severe AH., Methods: We carried out nation-wide survey by asking hospitals certified by the Japanese Society of Gastroenterology and hospitals related to ours hospital for the current status of patients seen with severe alcoholic hepatitis since 1998. We investigated correlations between various factors including blood laboratory data, presence of other organ failure, and prognosis., Results: Mortality of patients with severe AH was high (66.4%). The ratio of female patients with severe AH (26%) was higher than that for other ALD (approximately 10%). Mean age was older (Alive: 44 +/- 11; Dead: 50 +/- 11 years old), white blood cell (WBC) counts were higher (11600 +/- 5200; 21800 +/- 13400/microl), red blood cell counts were lower (320 +/- 95; 265 +/- 72 x 10/microl) and prothrombin time (PT) was prolonged (36.2 +/- 10.4; 29.1 +/- 9.4%, respectively) in patients who had died than in patients who had survived. However, as all differences diminished after carrying out PE, we analyzed data in patients without PE. The results were similar to those in all patients. Prevalence of infection, gastrointestinal (GI) bleeding and disseminated intravascular coagulation (DIC) was higher in patients who had died. Although intensive treatments such as PE, hemodialysis, and anticoagulation therapy did not change the prognosis of severe AH, PE improved the prognosis of patients without either GI bleeding or DIC. WBC counts were also slightly higher in patients who had died after carrying out PE. Two cases had been cured by granulocytapheresis (GCAP) CONCLUSIONS: PE can compensate for and reduce the risk due to prolonged PT in patients with severe AH. These results suggest that the patients with markedly elevated WBC counts, prolonged PT, or anemia should, if possible, be treated at an earlier stage with an intensive treatment such as PE, hemodialysis, or anticoagulation therapy before infection, GI bleeding or DIC occurs. Further, GCAP might be useful for severe AH patients with higher WBC counts.

Background: Previous work with metformin has shown that this antidiabetic agent improves nonalcoholic fatty liver in ob/ob mice. AMP-activated protein kinase (AMPK) is one of the major cellular regulators of lipid and glucose metabolism, and reportedly mediates the beneficial metabolic effects of metformin. In this study, we examined the effects of 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR), an AMPK activator, on an experimental model of ethanol-induced hepatic steatosis., Methods: Rats were randomly divided into three groups: (A) rats fed ethanol-containing liquid diet for six weeks; (B) rats pair-fed ethanol-containing liquid diet for six weeks, during the last three weeks of which they were subcutaneously injected with 0.5 mg AICAR/g body weight per day; (C) rats pair-fed isocaloric liquid diet without ethanol for six weeks. At the end of the six-week period, the animals were sacrificed. Serum and liver specimens were analyzed using biochemical and histologic methods, as well as real-time PCR., Results: Chronic ethanol feeding resulted in fatty liver both histologically and biochemically, whereas AICAR administration attenuated the degree of change in the liver. AICAR also decreased the hepatic sterol regulatory factor binding protein-1c (SREBP-1c) and reduced fatty acid synthase (FAS) expression; these changes led to reduced triglyceride synthesis in rat livers. Furthermore, detection of 4-hydroxy-2-nonenal (4-HNE)-protein adducts showed that the AICAR treatment also decreased the products of lipid peroxidation., Conclusion: In this preclinical rat model, AICAR, an AMPK activator, appears to protect the liver from fatty changes associated with chronic alcohol use. As such, AICAR may have a role in the treatment and prevention of alcohol-induced fatty liver.

Background and Aim: Helicobacter pylori is known to be a major pathogenic factor in the development of gastritis, peptic ulcer disease and gastric cancer. Recently, chicken egg yolk immunoglobulin Y (IgY) has been recognized as an inexpensive antibody source for passive immunization against gastrointestinal infections. The present study was designed to investigate the effect of anti-urease IgY on H. pylori infection in Mongolian gerbils., Methods: H. pylori-infected Mongolian gerbils were administered a diet containing anti-urease IgY, with or without famotidine (F). After 10 weeks, bacterial culture and measurement of the gastric mucosal myeloperoxidase (MPO) activity were performed. In a second experiment, another group of gerbils was started on a diet containing F + IgY a week prior to H. pylori inoculation. After 9 weeks, these animals were examined., Results: In the H. pylori-infected gerbils, there were no significant differences in the level of H. pylori colonization among the different dietary and control groups. However, the MPO activity was significantly decreased in the H. pylori group administered the F + IgY diet compared with that in the H. pylori group administered the IgY, F, or control diet. Furthermore, in the gerbils administered the F + IgY diet prior to the bacterial inoculation, inhibition of H. pylori colonization and suppression of the elevated gastric mucosal MPO activity were observed., Conclusions: Oral administration of urease-specific IgY not only inhibited H. pylori disease activity in H. pylori-infected gerbils, but also prevented H. pylori colonization in those not yet infected. These encouraging results may pave the way for a novel therapeutic and prophylactic approach in the management of H. pylori-associated gastroduodenal disease.

Aim: We evaluated the usefulness of Doppler ultrasonography (DUS) for the analysis of tumor hemodynamics in small hepatocellular carcinoma (HCC)., Methods: We compared Doppler ultrasound (DUS) findings with angiography-assisted computed tomography (Angio-CT) such as CT during arterial portography and during hepatic arteriography in the evaluation of the intratumoral hemodynamics, and with pathologic findings in 45 small HCC nodules (< or =3.0 cm in diameter) of 43 patients. DUS flow pattern of each nodule was categorized into three types: afferent continuous flow (Type 1), afferent pulsatile flow with afferent continuous flow (Type 2), and afferent pulsatile flow without afferent continuous flow (Type 3). Intratumoral blood supply was determined by Angio-CT, and pathologic findings were evaluated on resected or biopsied specimen., Results: Based on Angio-CT findings, Type 1 nodules showed decreased arterial blood supply (ABS) without decreased portal blood supply (PBS). Type 2 nodules showed unchanged ABS but decreased PBS. Type 3 nodules showed both increased ABS and decreased PBS. DUS findings well represented blood supply of HCC evaluated by Angio-CT. In addition, all Type 1 and 2 nodules were well-differentiated HCC, and all Type 3 nodules were moderately or poorly differentiated HCC; DUS findings well reflected differentiation of HCC., Conclusions: DUS is a non-invasive imaging method and can be used for the evaluation of the stage of malignancy of small HCC.