First report of hepatobiliary Mycobacterium avium infection developing obstructive jaundice in a patient with neutralizing anti-interferon-gamma autoantibodies.

This study describes a patient who experienced hepatobiliary Mycobacterium avium infection associated with neutralizing anti-interferon gamma (IFN-γ) autoantibodies during treatment for disseminated M. avium disease. Hepatobiliary M. avium infection should be considered in jaundiced patients with neutralizing anti-IFN-γ autoantibodies, including those receiving antimycobacterial therapy for disseminated M. avium disease.

A new approach for estimating the density of liquids.

We propose a novel approach with which to estimate the density of liquids. The approach is based on the assumption that the systems would be structurally similar when viewed at around the length scale (inverse wavenumber) of the first peak of the structure factor, unless their thermodynamic states differ significantly. The assumption was implemented via a similarity transformation to the radial distribution function to extract the density from the structure factor of a reference state with a known density. The method was first tested using two model liquids, and could predict the densities within an error of several percent unless the state in question differed significantly from the reference state. The method was then applied to related real liquids, and satisfactory results were obtained for predicted densities. The possibility of applying the method to amorphous materials is discussed.

IL-17 eliminates therapeutic effects of oral tolerance in murine airway allergic inflammation.

BACKGROUND: Oral tolerance is a classically used strategy for antigen-specific systemic immunotherapy. However, the roles of IL-17 in modification of oral tolerance are not yet understood. OBJECTIVE: To define the effects of IL-17 on the modification of oral tolerance, the effects of transfer of Th17 cells, administration of IL-17 or anti-IL-17 antibody (αIL-17Ab) to a murine allergic airway inflammation model were investigated. METHODS: Mice sensitized to and challenged with OVA, received OVA feeding, followed by OVA challenges. Transfer of Th17 cells, administration of IL-17 or αIL-17Ab were executed during OVA feeding. Airway hyperresponsiveness (AHR), airway inflammation, Th2 cytokine response and lung pathology were assessed. RESULTS: Administration of IL-17 as well as transfer of Th17 cells aggravated AHR and airway allergic inflammation as compared with the findings in mice subjected to OVA feeding alone, whereas administration of αIL-17Ab ameliorated AHR and airway eosinophilia. The effects of Th17 transfer were presumably attributable to augmentation of endogenous IL-6 production in gut. The number of Foxp3-positive regulatory T (Treg) cells in lungs and Payer's patches was increased in the OVA fed mice, whereas the number of these cells was decreased in the mice subjected to OVA feeding + Th17 cell transfer. Neutralization of IL-6 by monoclonal antibody in the mice subjected to OVA feeding + transfer of Th17 cells restored the effects of oral tolerance. CONCLUSIONS AND CLINICAL RELEVANCE: These data suggest that IL-17 may inhibit the induction of tolerance to antigen through, at least in part augmenting IL-6 production, thereby suppressing the expansion of Treg cells.

A prostacyclin agonist with thromboxane inhibitory activity for airway allergic inflammation in mice.

BACKGROUND: ONO-1301 is a novel drug that acts as a prostacyclin agonist with thromboxane A(2) (TxA(2)) synthase inhibitory activity. We investigated the effect of ONO-1301 on development of airway allergic inflammation. METHODS: Mice sensitized and challenged to ovalbumin (OVA) received ONO-1301, OKY-046 (TxA(2) synthase inhibitor), beraprost, a prostacyclin receptor (IP) agonist, ONO-1301 plus CAY10449 (selective IP antagonist) or vehicle during the challenge period. Twenty-four hours after the OVA challenge, airway hyperresponsiveness (AHR) to methacholine was assessed and bronchoalveolar lavage was performed. Lung specimens were excised for goblet cell staining and analysis of lung dendritic cells (DCs). Bone marrow-derived dendritic cells (BMDCs) were generated, in the presence or absence of drugs, for analysis of DC function. RESULTS: Mice that received ONO-1301 showed significantly lower AHR, airway eosinophilia, T-helper type 2 cytokine levels, mucus production and lung DCs numbers than vehicle-treated mice. These effects of ONO-1301 were mostly reversed by CAY10449. BMDCs treated with ONO-1301 alone showed lower DC functions, such as expression of costimulatory factors or stimulation to spleen T cells. CONCLUSIONS: These data suggest that ONO-1301 may suppress AHR and airway allergic inflammation through modulation of DCs, mainly mediated through the IP receptor. This agent may be effective as an anti-inflammatory drug in the treatment of asthma.

Interobserver agreement in endoscopic evaluation of reflux esophagitis using a modified Los Angeles classification incorporating grades N and M: a validation study in a cohort of Japanese endoscopists.

The Los Angeles classification system is the most widely employed criteria associated with the greatest interobserver agreement among endoscopists. In Japan, the Los Angeles classification system has been modified (modified LA system) to include minimal changes as a distinct grade of reflux esophagitis, rather than as auxiliary findings. This adds a further grading M defined as minimal changes to the mucosa, such as erythema and/or whitish turbidity. The modified LA system has come to be used widely in Japan. However, there have been few reports to date that have evaluated the interobserver agreement in diagnosis when using the modified LA classification system incorporating these minimal changes as an additional grade. A total of 100 endoscopists from university hospitals and community hospitals, as well as private practices in the Osaka-Kobe area participated in the study. A total of 30 video clips of 30-40 seconds duration, mostly showing the esophagocardiac junction, were created and shown to 100 endoscopists using a video projector. The participating endoscopists completed a questionnaire regarding their clinical experience and rated the reflux esophagitis as shown in the video clips using the modified LA classification system. Agreement was assessed employing kappa (kappa) statistics for multiple raters. The kappa-value for all 91 endoscopists was 0.094, with a standard error of 0.002, indicating poor interobserver agreement. The endoscopists showed the best agreement on diagnosing grade A esophagitis (0.167), and the poorest agreement when diagnosing grade M esophagitis (0.033). The kappa-values for the diagnoses of grades N, M, and A esophagitis on identical video pairs were 0.275-0.315, with a standard error of 0.083-0.091, indicating fair intraobserver reproducibility among the endoscopists. The study results consistently indicate poor agreement regarding diagnoses as well as fair reproducibility of these diagnoses by endoscopists using the modified LA classification system, regardless of age, type of practice, past endoscopic experience, or current workload. However, grade M reflux esophagitis may not necessarily be irrelevant, as it may suggest an early form of reflux disease or an entirely new form of reflux esophagitis. Further research is required to elucidate the pathophysiological basis of minimal change esophagitis.

Local adaptation and population differentiation at the interleukin 13 and interleukin 4 loci.

A 25.6 kb region at chromosome 5q31, covering the entire human interleukin 13 (IL-13) and interleukin 4 (IL-4) genes, has been reported to be associated with bronchial asthma. We have examined nucleotide variations at this locus in African, European American, and Japanese populations, using 120 diallelic variants. A block of strong linkage disequilibrium (LD) (mid R:D'mid R:>0.7) spans a 10 kb region containing IL-4 in European American and Japanese populations, and is present but less clear in African samples. Two major haplotypes at IL-4 account for >80% of haplotypes in European Americans and Japanese. These haplotypes are common and quite diverged from each other and the ancestral haplotype, resulting in highly significant deviations from neutrality. F(ST) statistics show that European American and Japanese populations are unusually distinct at the IL-4 locus. The most common haplotype in the European American population is much less common in the Japanese population, and vice versa. This implies that natural selection has acted on IL-4 haplotypes differently in different populations. This selected variation at IL-4 may account for some genetic variance underlying susceptibility to asthma and other allergic diseases. The strong LD observed in the IL-4 region may allow more efficient disease-association studies using this locus.

Successful eradication of Helicobacter pylori prevents relapse of peptic ulcer disease.

BACKGROUND: The NIH consensus conference in 1994 recommended that all patients with peptic ulcers should be tested and treated for Helicobacter pylori. Recent studies have shown that the eradication of H. pylori is associated with a significant reduction in the relapse rate of peptic ulcers, but there are few reports about long-term outcome. AIMS: To evaluate the relapse rate of peptic ulcer in the long-term follow-up of patients after H. pylori eradication therapy. PATIENTS AND METHODS: Patients infected with H. pylori (445; 88 duodenal ulcer, 357 gastric ulcer) were randomly divided into three groups. In group A, patients received 'conventional treatment' including acid decreasing therapy with a histamine H2-receptor antagonist or proton pump inhibitor (PPI). In group B, patients received 'dual therapy' including one antibiotic plus acid-decreasing therapy. In group C, patients received 'triple therapy' with PPI plus amoxicillin and clarithromycin. Eradication of H. pylori infection was assessed by histology of biopsy specimens from both the antrum and body corpus at 4 weeks, and 6 and 12 months after stopping therapy. Endoscopy was performed at intervals of 6 months for 5 years. RESULTS: Intention-to-treat eradication rates for the duodenal ulcer patients were 0% for group A, 46% for group B and 80% for group C; eradication rates for the gastric ulcer patients were 0%, 33% and 83% respectively. No recurrence was noted in the duodenal ulcer patients and only 4% of gastric ulcers recurred after successful eradication during follow-up for 5 years. In contrast, in patients with persistent H. pylori infection all DU and 92% of gastric ulcers recurred. CONCLUSION: Eradication of H. pylori infection changes the natural course of peptic ulcer.

[The relation between resistance to change and preference in pigeons with concurrent chained schedules].

Two experiments were conducted to investigate the relation between resistance to change and preference. Four pigeons responded in concurrent chained schedules in which variable-interval (VI) 60-s schedules were arranged in the initial link. In Experiment 1, VI and fixed-interval (FI) schedules of equal mean reinforcement rates were arranged in the terminal link. Response rates were higher in the initial link leading to VI terminal link. Under the prefeeding test, the initial-link response rates leading to VI terminal link were more resistant to change than were those leading to FI terminal link, but under the extinction test there were no consistent differences between the two initial-link response rates. In Experiment 2, FI value of the terminal link was manipulated so that pigeons maintained approximately equal responding in the initial link. The two initial-link response rates showed equal resistance to change under the prefeeding and extinction tests. Thus, the data suggest that although the use of extinction as a manipulation to study resistance to change is questioned, resistance to change and preference are different measures of a single object.

Branch retinal vein occlusion in the right eye and retinal hemorrhage in the left in a patient with classical Tsutsugamushi disease.

PURPOSE: To report branch retinal vein occlusion and retinal hemorrhages associated with tsutsugamushi disease. METHODS: Case report of a 60-year-old woman who complained of fever, chills, headache, lymphadenopathy, and blurred vision in the right eye following an insect bite to the lower right forehead. RESULTS: Serological findings showed elevated titers for the strains of Rickettsia tsutsugamushi. Ophthalmologic examination disclosed bilateral conjunctival injection, flame-shaped hemorrhage in her right fundus, and scattered hemorrhage in her left fundus. Fluorescein angiography demonstrated dye leakage and dilation of capillaries. CONCLUSIONS: Branch retinal vein occlusion associated with classical tsutsugamushi disease, as demonstrated in our patient, may be rare.

Experimental gastric carcinogenesis related to Helicobacter pylori.

In this paper, we present our research on the lipid A of Helicobacter pylori, an experimental study using the Mongolian gerbil model and experimental carcinogenesis using the mouse model to evaluate roles of host factors and bacterial factors which are related to the pathogenicity of Helicobacter pylori including gastric carcinogenesis. Future study on bacterial factors and host factors may give more insight into the role of Helicobacter pylori in gastric carcinogenesis.

Effect of cobalt ion on radical intensity and cytotoxic activity of antioxidants.

The effect of CoCl2 on the cytotoxic activity of various antioxidants against human oral tumor cell lines (HSC-2, HSG) and normal human gingival fibroblasts (HGF) was investigated. Noncytotoxic concentrations of CoCl2 significantly reduced the cytotoxic activity of sodium ascorbate, gallic acid, epigallocatechin gallate (EGCG), curcumin and dopamine, but not that of sodium 5,6-benzylidene-L-ascorbate (SBA) and benzaldehyde. Among these compounds, benzaldehyde showed the most prominent tumor-specific cytotoxic action. ESR spectroscopy showed that these antioxidants produced radicals under alkaline condition and that their radical intensity was transiently enhanced and finally disappeared by addition of CoCl2. Antioxidants which are sensitive to CoCl2 generally had higher cytotoxic activity and oxidation potential (measured by NO monitor) and addition of CoCl2 significantly reduced their oxidation potential. The present study suggests that cobalt ion stimulates the oxidation of antioxidants to their inactive products.

Influence of Helicobacter pylori infection on development of stress-induced gastric mucosal injury.

Immediately after the Great Hanshin Earthquake in Kobe in 1995, the recurrence rate of peptic ulcer in patients infected with Helicobacter pylori was higher than that in patients in whom H. pylori had been eradicated. We evaluated the influence of H. pylori infection on stress-induced gastric mucosal injury in Mongolian gerbils and C57BL/6 mice. These animals were immersed in water for 30, 120, and 720 min 12 weeks after inoculation with H. pylori, and then killed to assess gastric mucosal damage, and to measure cytokine production (interleukin [IL]-1beta, IL-4, IL-6, and IL-10; interferon [IFN]-gamma; and tumor necrosis factor [TNF]-alpha) in the gastric tissue of the mice. The stress treatment for 30 min resulted in a significantly higher bleeding rate and bleeding index among infected gerbils and mice compared with results in uninfected animals. Conversely, the bleeding and ulcer indexes were significantly higher in uninfected gerbils after 720 min of the stress treatment than in infected gerbils. Prior to the stress treatment, gastric IL-1beta and IFN-gamma production was significantly higher in the infected group than in the uninfected group. After 120 min of the stress treatment, TNF-alpha production was increased in the infected group, and IL-1beta and IL-10 production was increased in the uninfected group. However, the production of these cytokines showed no change at 30 min of the stress treatment. These results suggest that H. pylori infection influences the development of gastric mucosal injury in the early phase of stress exposure; cytokines do not play a major role in this process.

[Epidemiological study for infection with H. pylori in Japan compared with that in USA, Europe and Asian Pacific area].

The prevalence of infection with H. pylori in developed countries was about 20%, on the other hand in developing countries it reached over 80%. In developed countries 40% of infants already had anti-H. pylori antibody and the prevalence of infection rapidly increased and then reached the peak (80%) in teenager. In contrast in developed countries the rate of infection with H. pylori was below 20% in teenager and gradually increased by age (1% per 1 year). In our country an unique pattern of the prevalence of infection with H. pylori was observed. The rate of infection with H. pylori in young person was low and increased with 1% per 1 year (developed countries pattern). However, middle-aged person had higher rate of infection of H. pylori (over 85%) (developing countries pattern). These results suggested H. pylori infection would be closely associated with childhood living conditions than current living (including socioeconomic) status. From this point of view, the prevention for infection with H. pylori in childhood will be most important to prevent the gastroduodenal disease related with H. pylori in the future.

Comparison of pathologic changes in Helicobacter pylori-infected Mongolian gerbils and humans.

Helicobacter pylori has been recognized as a pathogen causing gastroduodenal disease, with adequate evidence to prove this relation in clinical research. Available animal models, however, were inadequate until 1995, when a new animal model of H. pylori infection was established using Mongolian gerbils. In this study we compared pathological changes in seven H. pylori-infected Mongolian gerbils with ulcers to five patients with gastric ulcer who underwent operation. All of the animals showed positive reactions for both H. pylori culture and serum anti-H. pylori antibody titer. All human subjects had H. pylori on the mucosal surface. Thus, inflammatory cell infiltration in the pyloric gland area was observed throughout almost all layers in the animals. In contrast, inflammation was observed in the surface layer of the mucosa in the pyloric gland area in the human subjects. Lymph follicle formation was observed more often in humans than in the animals. Inflammation of the fundic gland area in both groups was weaker than of the pyloric gland area and was observed within the mucosa. Histological changes observed in both groups were chronic active gastritis, lymph follicles, and intestinal metaplasia in the stomach. H. pylori-associated gastritis in humans is characterized by erosion, inflammation with neutrophil infiltration, lymph follicles, intestinal metaplasia, and atrophy. These findings are similar to those in this animal model. Thus, H. pylori infection might participate in the pathogenesis of gastroduodenal mucosal damage. In conclusion, the Mongolian gerbil is a good animal model for H. pylori-associated gastric diseases, and it might be useful for investigating the pathogenesis of H. pylori infection.

Pathological changes in glandular stomach of Helicobacter pylori-infected Mongolian gerbil model.

We have established a Helicobacter pylori-infected Mongolian gerbil model, following Hirayama's method, to clarify gastric diseases associated with H. pylori infection. We administered the culture broth of H. pylori ATCC 43504 orally to 8-week-old male Mongolian gerbils. After H. pylori inoculation, the gerbils were fed in a vinyl isolator. Subsequently, over the course of 48 weeks, they were killed for histopathological examination, H. pylori culture, and serum antibody measurement. H. pylori colonization in the glandular stomach was seen in all the infected gerbils, but only a few H. pylori were detected histologically. The serum antibody titer in the H. pylori-inoculated group increased gradually in comparison with controls. Acute inflammation, immature epithelium, and erosion were observed 2 weeks after H. pylori infection. Chronic inflammation was noted from 4 weeks after H. pylori infection. We also found intestinal metaplasia and gastric ulcers from 12 and 24 weeks after inoculation, respectively. Some histological findings were similar to those in humans, but the chronic inflammation in the gerbils was present mainly in the deep mucosa and submucosa. This appears to be a good animal model for H. pylori-associated gastric diseases and it may be useful for investigating the pathogenesis of H. pylori infection.

Pathologic changes in the glandular stomach and duodenum in an H. pylori-infected Mongolian gerbil model.

We have established a Helicobacter pylori-infected Mongolian gerbil model following Hirayama's method to investigate gastric diseases associated with H. pylori infection. We orally administered the culture broth of H. pylori ATCC 43504 to 8-week-old male Mongolian gerbils. After this, the gerbils were fed in a vinyl isolator. Subsequently, over the course of 48 weeks some of them were sacrificed for histopathologic examination and H. pylori culture. H. pylori colonization in the glandular stomach was seen in all the infected gerbils but only a few H. pylori were detected histologically. Acute inflammation, immature epithelium, and erosion were observed 2 weeks after H. pylori infection. Chronic inflammation was noted from 4 weeks after H. pylori infection. In addition, we found intestinal metaplasia and gastric ulcers from 12 and 24 weeks, respectively. There was mild to moderate inflammation in the duodenum but no ulcerative lesions or gastric metaplasia were observed. Some histologic findings were similar to those in humans, but inflammation occurred mainly in the deep mucosa and submucosa. This is a good animal model for H. pylori-associated gastric diseases but not for duodenal ulcers or gastric metaplasia. It might be useful for investigating the pathogenesis of H. pylori infection in the stomach.

The endotoxin of Helicobacter pylori is a modulator of host-dependent gastritis.

Atrophic gastritis caused by Helicobacter pylori is the precursor lesion in the development of intestinal-type gastric adenocarcinoma. In animal models, atrophic gastritis induced by Helicobacter felis has been shown to be host dependent, developing in some mouse strains and not in others. The lipopolysaccharide (LPS) of H. pylori has been suggested to play a role in the induction of gastritis. The goal of this study was to compare the inflammation induced by long-term infection of the C3H/He and the C3H/HeJ strains of mice with H. felis. C3H/HeJ mice are unresponsive to LPS. Six months after infection, severe atrophic gastritis had developed in the body mucosae of all infected C3H/He mice, with replacement of parietal and chief cells. Atrophy was associated with a loss of the H. felis from the antral mucosa. In contrast, no atrophy was seen in the infected C3H/HeJ non-LPS responder animals, and heavy colonization of the antrum remained. There were no significant differences between both the quantitative and qualitative serum immunoglobulin G (IgG) and salivary IgA levels in both strains of mice. The main difference between the two strains of long-term-infected mice was a lack of macrophage infiltration in the lamina propria. Immunization induced good protective immunity to challenge with viable H. felis. Helicobacter-induced, host-dependent gastritis is likely to be cell mediated. The C3H/He and C3H/HeJ mouse model provides an excellent opportunity to investigate the cellular basis of atrophic gastritis.