Language：Japanese   Publisher：(一社)日本ヘリコバクター学会  

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Helicobacter pylori infection is an important risk factor for developing gastric cancer. However, only a few H. pylori-infected people develop gastric cancer. Thus, other risk factors aside from H. pylori infection may be involved in gastric cancer development. This study aimed to investigate whether the nitrate-reducing bacteria isolated from patients with atrophic gastritis caused by H. pylori infection are risk factors for developing atrophic gastritis and gastric neoplasia. Nitrate-reducing bacteria were isolated from patients with atrophic gastritis caused by H. pylori infection. Among the isolated bacteria, Actinomyces oris, Actinomyces odontolyticus, Rothia dentocariosa, and Rothia mucilaginosa were used in the subsequent experiments. Cytokine inducibility was evaluated in monocytic cells, and mitogen-activated protein kinase (MAPK) activity and cell cycle were assessed in the gastric epithelial cells. The cytotoxicities and neutrophil-inducing abilities of the Actinomyces and Rothia species were enhanced when cocultured with H. pylori. Th1/Th2-related cytokines were also expressed, but their expression levels differed depending on the bacterial species. Moreover, H. pylori and Actinomyces activated MAPK (ERK and p38) and affected cell cycle progression. Some nitrate-reducing bacteria cocultured with H. pylori may promote inflammation and atrophy by inducing cytokine production. In addition, the MAPK activation and cell cycle progression caused by these bacteria can contribute to gastric cancer development.

DOI： 10.3390/microorganisms10122495

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Language：Japanese   Publisher：(一社)日本ヘリコバクター学会  

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Language：Japanese   Publisher：(一社)日本ヘリコバクター学会  

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Language：Japanese   Publisher：(一社)日本ヘリコバクター学会  

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BACKGROUND: Eradication treatment for Helicobacter pylori gastritis is covered by national health insurance since 2013 in Japan. However, eradication failure due to the increase of antimicrobial resistance has become a serious problem. The present study aims to establish a reference panel of Japanese H. pylori strains for antimicrobial susceptibility testing. METHOD: A total of 28 strains were collected from 4 medical facilities in Japan. Antimicrobial susceptibility tests (ASTs) to clarithromycin (CLR), amoxicillin (AMX), and metronidazole (MNZ), were used to select standard reference strains. Complete genome sequences were also determined. RESULTS: Three H. pylori strains (JSHR3, JSHR6 and JSHR31) were selected as standard reference strains by the Japanese Society for Helicobacter Research (JSHR). The minimum inhibitory concentrations (MICs) of the antibiotics against these 3 strains by agar dilution method with Brucella-based horse-serum-containing agar medium were as follows: JSHR3 (CLR 16 μg/ml, AMX 0.032 μg/ml and MNZ 4 μg/ml), JSHR6 (CLR 0.016 μg/ml, AMX 0.032 μg/ml and MNZ 4 μg/ml), and JSHR31 (CLR 16 μg/ml, AMX 1 μg/ml and MNZ 64 μg/ml). CONCLUSIONS: A reference panel of H. pylori JSHR strains was established. The panel consisted of JSHR6, which was antibiotic-susceptible, JSHR3, which was CLR-resistant, and JSHR31, which was multi-resistant. This reference panel will be essential for standardized ASTs before the optimal drugs are selected for eradication treatment.

DOI： 10.1111/hel.12874

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The statistical correlation between the number of oral streptococci and the results of ATP bioluminescence assay was examined and compared with the results from Streptococcus plate counts and an oral bacteria quantification system. Because a significant correlation was found between ATP (RLU) and the number of bacteria in the oral bacteria quantification system for all seven types of oral streptococci examined, ATP would reflect a conditions of oral hygiene. However, using this assay, it was observed it may be difficult to correctly evaluate bacteria that form aggregates. Furthermore, even a small number of bacteria (below 105 CFU/mL) , which cannot be measured by the oral bacteria quantification system, could be estimated by using ATP bioluminescence assay. It was suggested that this assay could be used for quantitative evaluation of the effect of oral cleaning.

DOI： 10.4265/bio.27.229

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Language：Japanese   Publisher：(一社)日本ヘリコバクター学会  

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Language：Japanese   Publisher：(一社)日本ヘリコバクター学会  

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Elizabethkingia anophelis is a pathogen that can cause a life-threatening infection in immunocompromised patients. The first case of E. anophelis infection was reported in 2013; subsequently, an increase in its incidence has been reported globally. Additionally, a mortality rate of more than 30% was observed in the US outbreak of 2015. To date, the pathogenic mechanisms underlying E. anophelis infection, such as toxin production, remain unclear. Since tissue macrophages act as the first line of defense against pathogens, in the present study the interactions between E. anophelis and a macrophage-like cell line RAW 264.7 were examined. Although E. anophelis showed no cytotoxicity toward RAW 264.7 macrophages, the infection inhibited LPS-induced morphological changes and activation of differentiation markers for the polarization of RAW 264.7 macrophages toward an M1-like phenotype. However, when the cell contact was restricted using Transwell inserts or bacterial culture supernatants were used instead of live bacteria, no such inhibition was observed. Moreover, it was shown that E. anophelis evaded phagocytosis. Overall, the results suggest that E. anophelis infection inhibits the differentiation of RAW 264.7 macrophages to a pro-inflammatory phenotype in a contact-dependent manner.

DOI： 10.1111/1348-0421.12888

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The infection caused by Helicobacter pylori is associated with several diseases, including gastric cancer. Several methods for the diagnosis of H. pylori infection exist, including endoscopy, the urea breath test, and the fecal antigen test, which is the serum antibody titer test that is often used since it is a simple and highly sensitive test. In this context, this study aims to find the association between different antibody reactivities and the organization of bacterial genomes. Next-generation sequences were performed to determine the genome sequences of four strains of antigens with different reactivity. The search was performed on the common genes, with the homology analysis conducted using a genome ring and dot plot analysis. The two antigens of the highly reactive strains showed a high gene homology, and Western blots for CagA and VacA also showed high expression levels of proteins. In the poorly responsive antigen strains, it was found that the inversion occurred around the vacA gene in the genome. The structure of bacterial genomes might contribute to the poor reactivity exhibited by the antibodies of patients. In the future, an accurate serodiagnosis could be performed by using a strain with few gene mutations of the antigen used for the antibody titer test of H. pylori.

DOI： 10.3390/toxins13070467

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Language：Japanese   Publisher：日本細菌学会  

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Language：English   Publisher：日本細菌学会  

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Background: Helicobacter pylori infection poses a risk of the occurrence of gastrointestinal diseases, such as gastric cancer. Its incidence rate is significantly reduced by eradication, and thereby, eradication therapy is generally performed. Disulfiram is an oral prescription drug mainly used for the treatment of alcohol dependence. In recent years, reports have been made on its anticancer and antibacterial effects, and thus, it has recently become an interesting subject. This study aimed to examine the antibacterial activity of disulfiram, investigate the presence or absence of its antibacterial activity on H. pylori, and determine whether it could be a new bactericidal drug against drug-resistant H. pylori. Materials and Methods: Drug-sensitive strains of H. pylori and amoxicillin-resistant, clarithromycin-resistant, and metronidazole-resistant strains were used, and a growth inhibition test of H. pylori using disulfiram was performed. Furthermore, the expression of urease, vacuolating cytotoxin A (VacA), and CagA, the virulence proteins of H. pylori, was quantitatively analyzed using the Western blotting method. In addition, for H. pylori used in this study, the 16SrDNA sequence, a ribosomal gene involved in protein production, was analyzed to examine the presence or absence of gene mutation. Results: Disulfiram suppressed the growth of 7 out of 12 H. pylori strains at 1 µg/mL, and no correlation was observed between their susceptibility/resistance to current eradication antimicrobial drugs and disulfiram resistance. Disulfiram reduced the expression levels of urease, VacA, and CagA proteins. H. pylori, which showed resistance to disulfiram, tended to have fewer gene deletions/insertions in the 16S rDNA sequence; however, no specific mutation was detected. Conclusion: Disulfiram has a bactericidal effect on H. pylori at low concentrations, suggesting that it can be used as a supplement for current H. pylori eradication drugs.

DOI： 10.2147/IDR.S299177

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We examined the hospital-wide incidence of methicillin-resistant Staphylococcus contamination in a hospital environment to predict the risk of the nosocomial spread of infection. Samples were also taken different surfaces and medical equipment in a general hospital ward and a staff station. The isolates were identified bacterial strains and analyzed by PCR for detection of the mecA gene and staphylococcal cassette chromosome mec (SCCmec) types (I-V). Overall, out of 146 isolates that were screened, 15.7% of the samples in the hospital wards were contaminated with Staphylococcus aureus and 74.7% were isolated with coagulase-negative Staphylococci (CNS). The methicillin-resistant mecA gene was detected in all oxacillin-resistant S. aureus, and 89% of oxacillin-resistant CNS was identified as methicillin-resistant S. aureus (MRSA) and MRCNS respectively. All S. aureus and CNS from the hospital wards with MRSA patients were detected as MRSA and MRCNS. A widespread distribution of MRSA and MRCNS was detected in the Cuff. The majority of the MRSA and MRCNS isolates in this study were SCCmec type V, which are a community-acquired infection type. The increased incidence and prevalence of community-acquired MRSA and MRCNS, as well as hospital-acquired MRSA, should be recognized as serious healthcare problems.

DOI： 10.4265/bio.26.137

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Language：Japanese   Publisher：日本防菌防黴学会  

健常人の尿沈渣標本中に,ステルンハイマー染色にて青色の顆粒状物質が出現することがある。この物質の成分や出現背景等に関して詳細は明らかとなっていないため,検討を行った。その結果,顆粒状物質は,健常な女性15名中8名(53%)に出現していた。SDS-PAGEによる電気泳動では,15名中11名(73%)に75KDaの単一のバンドを認め,質量分析にてTamm-Horsfall protein(THP)(Uromodulin)と同定された。THPは尿路細菌叢が存在した10名中9名(90%)で検出され,尿路に細菌や真菌が存在しなかった4名中3名(75%)では検出されなかった。また,顆粒状物質が出現していた8名中,THPと尿路細菌叢の両方を認めたのは4名(50%)であった。明らかな傾向を統計学的に証明できなかったが,顆粒状物質は,THPや尿路細菌叢と同時に検出される場合があることから,何らかの自然免疫学的な応答に関与している可能性が示された。今後,検体採取条件を再検討し,この関連性について検証する必要がある。(著者抄録)

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BACKGROUND AND AIMS: Eradication of Helicobacter pylori reduces the risk of gastric cancer. In this study, we investigated the risk beyond 10 years after eradication of H. pylori. METHODS: We conducted a retrospective cohort study of 2737 patients who had yearly endoscopic follow-up after cure of H. pylori infection. For comparison of gastric cancer risk in the second decade of follow-up with that in the first decade, we calculated standardized incidence ratios (SIRs) by dividing the number of observed cases of gastric cancer in the second decade of follow-up by that of expected cases which was estimated using the incidence rate ratio of age in the first decade. RESULTS: During the follow-up for as long as 21.4 years (mean 7.1 years), gastric cancer developed in 68 patients (0.35% per year). The SIRs for diffuse-type gastric cancer was infinity (0 expected case and 4 observed cases) in patients with mild gastric mucosal atrophy and 10.9 (95% confidence interval 4.53-26.1) with moderate atrophy, whereas no significant increase of SIRs was observed in intestinal-type cancer regardless of the grade of baseline gastric atrophy or in diffuse-type cancer in patients with severe atrophy even though who had the highest risk. CONCLUSIONS: The longer the follow-up, the greater the risk of developing diffuse-type gastric cancer becomes in patients with mild-to-moderate gastric atrophy at baseline. Endoscopic surveillance should be continued beyond 10 years after cure of H. pylori irrespective of the severity of gastric atrophy.

DOI： 10.1007/s00535-019-01639-w

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In the original publication of the article, the figure 3 was published with errors. The corrected figure 3 should appear as in this correction.

DOI： 10.1007/s00535-019-01654-x

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Castleman-Kojima disease, also known as idiopathic multicentric Castleman disease with TAFRO syndrome (iMCD-TAFRO), is a recently recognized systemic inflammatory disorder with a characteristic series of clinical symptoms, including thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (R), and organomegaly (O). Patients with iMCD-TAFRO often develop severe abdominal pain, elevated alkaline phosphatase levels, and systemic inflammation, but the etiological factors are unknown. To investigate the potential role of bacterial infection in the pathogenesis of iMCD-TAFRO, we performed polymerase chain reaction (PCR) for the bacterial 16S rRNA gene with DNA extracted from liver specimens of three patients with iMCD-TAFRO, four patients with amyotrophic lateral sclerosis, and seven patients with inflammatory conditions. Sequencing of the PCR product showed 99% DNA sequence identity with Campylobacter jejuni in all three patients with iMCD-TAFRO and in two patients with inflammatory conditions. Immunohistochemical and electron microscopy analyses could not identify C. jejuni in patients with iMCD-TAFRO. The findings indicated that C. jejuni infection is not the pathological cause of iMCD-TAFRO; however, this ubiquitous bacterium may play a role in uncontrolled systemic hypercytokinemia, possibly through the development of cross-reactive autoantibodies.

DOI： 10.1111/pin.12856

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Language：Japanese   Publisher：(一社)日本環境感染学会  

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This study was to survey the capturing rate in Japanese dental clinics of the Lasioderma serricorne (cigarette beetles) , and to evaluate the beetle's potential as a carrier for transmission of nosocomial pathogens. L. serricorne imagoes were captured in pheromone traps in 14 Japanese dental clinics in August and September 2012 and 2013, and their numbers recorded. Polymerase chain reaction (PCR) for the bacterial antibiotic-resistant genes mecA, vanA, vanB, blaIMP, and blaVIM was performed on the captured L. serricorne imagoes. Bacterial species in the captured specimens were identified by 16S rRNA PCR and sequencing analysis. The L. serricorne imagoes were captured from 10 dental clinics (71.4%) . We failed to detect the presence of nosocomial antibiotic-resistant pathogens in L. serricorne imagoes. The bacterial species detected most commonly in the imagoes was Wolbachia sp., an intracellular proteobacterium infecting certain insect species. Monitoring of insects including L. serricorne should be incorporated into regiment of the infection control.

DOI： 10.4265/bio.24.117

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Background: Eradication effectively prevents Helicobacter pylori-associated diseases; however, H. pylori antibiotic resistance has increased throughout Japan and worldwide. This study aimed to assess rates of resistance to antibiotics; amoxicillin, clarithromycin and metronidazole in a University Hospital in Japan. Materials and methods: H. pylori (208 strains) were isolated from patients at the Okayama University Hospital in Japan. The minimum inhibitory concentrations (MIC) were determined using the mean values of the E-test to determine the antimicrobial susceptibilities of the strains. Sequencing and gene analysis were performed to analyze resistance genes to clarithromycin and amoxicillin. Results: Rates of amoxicillin, clarithromycin, and metronidazole resistance were 13%, 48%, and 49%, respectively. Genetic analysis indicated that the A2143G point mutation in 23S rDNA is closely associated with the MIC of clarithromycin. The MIC in amoxicillin-resistant strains increased with an increase in the number of PBP1A amino acids mutations. Conclusion: Genetic analysis for resistant strains is not clinically effective in cases of amoxicillin resistance. Numerous bacteria with already high antibiotic resistance rates have been isolated in large hospitals such as a University Hospital. For effective eradication therapy, MIC measurement should be considered via several methods.

DOI： 10.2147/IDR.S196452

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Background: Helicobacter pylori infection is associated with the incidence of gastric cancer. Endoscopic resection has been developed as a proper technique to treat early stage of gastric cancer. However, some patients develop recurrent gastric cancer within 5 years after endoscopic treatment. The aim of the present study is to explore a biomarker for detecting people who has high risk of gastric cancer recurrence. Methods: We analyzed the Interleukin-10 (IL-10) single nucleotide polymorphism (SNP) and IgG subclass responses to the bacteria in patients with early gastric cancer and recurrent gastric cancer. Results: Patients with hetero-type in the 1082 SNP and CC genotype in the 592 SNP were at high risk of recurrence of gastric cancer. In patients with genotype carrying high risk of recurrence, IgG1 level tended to be higher than that in patients with other genotypes. Conclusions: Dominance of T helper 2 (Th2) immunity controlled by IL-10 cytokine may be associated with H. pylori-associated gastric cancer recurrence.

DOI： 10.1186/s13027-019-0221-1

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(NPO)バイオテクノロジー標準化支援協会  

入院患者や要介護者を対象に用いられている吸い飲み内残余飲料の微生物汚染状況について実験的な予備調査を実施した。吸い飲み内試料はミネラルウォーター、緑茶、経口補水液、果汁飲料を用いて、pHと糖度を測定した。ブラッシング後に吸い飲みで飲用した後、吸い飲み内に残余した各飲料を28℃で2時間および5時間保管した。保管後、残余飲料の微生物数(口腔内細菌数および真菌数)を計測した。さらに、緑茶を用いて食事中に飲用した後、吸い飲み内に残余した緑茶の微生物数を計測し、ブラッシング後に飲用した吸い飲み内の残余緑茶の微生物数と比較した。吸い飲み内の残余飲料すべてに、口腔内細菌(主にStreptococci)と口腔内真菌(主にCandida species)の混入が認められた(25 to 2,827 CFU/mL)。ミネラルウォーター、緑茶では、口腔微生物数が保管2時間後で最も多くなった。また、食事中に飲用した吸い飲み内の残余緑茶には口腔内微生物がより多く混入し、保管5時間後も微生物数の減少はみられなかった。口腔内の清掃・衛生管理状態は吸い飲みの微生物汚染状況に影響を与える。吸い飲みの十分な洗浄・消毒など、適切な衛生管理が重要である。(著者抄録)

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：W.B. Saunders Ltd  

Aerosol and splatter produced during dental treatments (ultrasonic scaling and professional mechanical tooth cleaning) are potential sources of infection. Contamination patterns on the mask, goggles, chest and gowned right arm of operators, and on the goggles of patients before and after dental treatments were investigated using ATP bioluminescence analysis. Contamination on every surface tested increased significantly after dental treatment. Maximum contamination was found on the goggles of patients. Aerosol and splatter produced during dental treatments therefore have the potential to spread infection to operators and patients. ATP bioluminescence is a useful tool for monitoring surface contamination.

DOI： 10.1016/j.jhin.2018.03.002

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The bacterium Vibrio alginolyticus, an opportunistic pathogen in humans, has a type III secretion system (T3SS) that is responsible for its cytotoxicity toward eukaryotic cells. The effector of T3SS that is responsible for the cytotoxicity had not been identified. Here we demonstrate that VepA, a homolog of the T3SS effector in V. parahaemolyticus, is required for cytotoxicity in V. alginolyticus. VepA induces lysosomal membrane permeabilization, and it allows the leakage of only small molecules into the cytosol. Our findings revealed that VepA induces cathepsin-independent cell death in mammalian cells. The ferrous ion, one of the small molecules in the lysosome contents, appears to be involved in the cell death caused by V. alginolyticus VepA.

DOI： 10.18926/AMO/56068

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Language：English   Publisher：(一社)日本リンパ網内系学会  

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Helicobacter pylori infections cause gastritis and affect systemic immune responses; however, no direct association between immune cells and stomach bacteria has yet been reported. The present study investigated DEC205-mediated phagocytosis of H. pylori and the role of DEC205-positive macrophages in the human gastric mucosa. DEC205 mediated phagocytosis of H. pylori was detected immunocytochemically in PMA-stimulated macrophages differentiated from NOMO1 cells. Expression of DEC205 mRNA in peripheral blood mononuclear cells (PBMCs) from H. pylori-infected patients was analyzed following stimulation with H. pylori cell lysate. We found that anti-DEC205 antibodies inhibited phagocytosis of H. pylori. The number of cells double-positive for DEC205 and CD14 in human gastric mucosa was higher in H. pylori-infected patients. DEC205-positive macrophages invaded the extracellular space between epithelial cells within gastric pits. In addition, DEC205 mRNA expression was upregulated in human PBMCs stimulated with H. pylori lysate. These findings suggest DEC205-expressing macrophages are important for recognition of H. pylori in human gastric mucosa, which affects systemic immunity.

DOI： 10.18632/oncotarget.24574

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DOI： 10.1016/j.cgh.2018.03.030

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Language：English   Publisher：日本細菌学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Multicentric Castleman disease (MCD) is a heterogeneous lymphoproliferative disorder. It is characterized by inflammatory symptoms, and interleukin (IL)-6 contributes to the disease pathogenesis. Human herpesvirus 8 (HHV-8) often drives hypercytokinemia in MCD, although the etiology of HHV-8-negative MCD is idiopathic (iMCD). A distinct subtype of iMCD that shares a constellation of clinical features including thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (R), and organomegaly (O) has been reported as TAFRO-iMCD, however the differences in cytokine profiles between TAFRO-iMCD and iMCD have not been established. We retrospectively compared levels of serum interferon gamma-induced protein 10 kDa (IP-10), platelet-derived growth factor (PDGF)-AA, interleukin (IL)-10, and other cytokines between 11 cases of TAFRO-iMCD, 6 cases of plasma cell type iMCD, and 21 healthy controls. During flare-ups, patients with TAFRO-iMCD had significantly higher serum IP-10 and tended to have lower PDGF-AA levels than the other 2 groups. In addition, serum IL-10, IL-23, and vascular endothelial growth factor-A were elevated in both TAFRO-iMCD and iMCD. Elevated serum IP-10 is associated with inflammatory diseases including infectious diseases. There was a strong correlation between high serum IP-10 and the presence of TAFRO-iMCD, suggesting that IP-10 might be involved in the pathogenesis of TAFRO-iMCD.

DOI： 10.1038/srep42316

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Bacterial contamination of dental unit waterlines (DUWLs) was evaluated using ATP bioluminescence analysis and a conventional culture method. Water samples (N=44) from DUWLs were investigated for heterotrophic bacteria by culture on R2A agar, which gave counts ranging from 1.4×103 to 2.7×105 cfu/mL. The ATP bioluminescence results for DUWL samples ranged from 6 to 1189 relative light units and could be obtained within 1min; these correlated well with the culture results (r=0.727-0.855). We conclude that the results of the ATP bioluminescence assay accurately reflect the results of conventional culture-based testing. This method is potentially useful for rapid and simple monitoring of DUWL bacterial contamination.

DOI： 10.1016/j.jhin.2016.08.001

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Multicentric Castleman disease (MCD) describes a heterogeneous group of disorders involving systemic inflammation, characteristic lymph node histopathology, and multi-organ dysfunction because of pathologic hypercytokinemia. Whereas Human Herpes Virus-8 (HHV-8) drives the hypercytokinemia in a cohort of immunocompromised patients, the etiology of HHV-8-negative MCD is idiopathic (iMCD). Recently, a limited series of iMCD cases in Japan sharing a constellation of clinical features, including thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (R), and organomegaly (O) has been described as TAFRO syndrome. Herein, we report clinicopathological findings on 25 patients (14 males and 11 females; 23 Japanese-born and two US-born), the largest TAFRO syndrome case series, including the first report of cases from the USA. The median age of onset was 50 years old (range: 23-72). The frequency of each feature was as follows: thrombocytopenia (21/25), anasarca (24/25), fever (21/25), organomegaly (25/25), and reticulin fibrosis (13/16). These patients frequently demonstrated abdominal pain, elevated serum alkaline phosphatase levels, and acute kidney failure. Surprisingly, none of the cases demonstrated marked hypergammoglobulinemia, which is frequently reported in iMCD. Lymph node biopsies revealed atrophic germinal centers with enlarged nuclei of endothelial cells and proliferation of endothelial venules in interfollicular zone. 23 of 25 cases were treated initially with corticosteroids; 12 patients responded poorly and required further therapy. Three patients died during the observation period (median: 9 months) because of disease progression or infections. TAFRO syndrome is a unique subtype of iMCD that demonstrates characteristic clinicopathological findings. Further study to clarify prognosis, pathophysiology, and appropriate treatment is needed. (C) 2015 Wiley Periodicals, Inc.

DOI： 10.1002/ajh.24242

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Geranylgeranylacetone (GGA) is used to treat patients suffering from peptic ulcers and gastritis. We examined the effect of GGA on Helicobacter pylori, which is a causative factor of gastrointestinal diseases. Previously, we have reported that GGA binds specifically to the molecular chaperone HSP70. In this paper, we report that GGA bounds to H. pylori HSP70 (product of the DnaK gene) with 26-times higher affinity than to human HSP70, and induced large conformational changes as observed from surface plasmon resonance and circular dichroism. Binding of GGA suppressed the activity of the H. pylori chaperone. GGA also altered several characteristics of H. pylori cells. GGA-treated cells elicited enhanced interleukin-8 production by gastric cancer cell lines and potentiated susceptibility to complement as compared to untreated cells. GGA also caused morphological alterations in H. pylori as reflected in fewer coccoid-like cells, suggesting that GGA converts H. pylori to an actively dividing, spiral state (vegetative form) from a non-growing, coccoid state. This morphological conversion by GGA resulted in accelerated growth of H. pylori. These results suggest a model in which GGA sensitizes H. pylori to antibiotic treatment by converting the cells to an actively growing state.

DOI： 10.1038/srep13738

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Language：Japanese   Publisher：日本歯科衛生学会  

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Vibrio vulnificus is the causative agent of primary septicemia, wound infection and gastroenteritis in immunocompromised people. In this study, signature-tagged mutagenesis (STM) was applied to identify the virulence genes of V. vulnificus. Using STM, 6,480 mutants in total were constructed and divided into 81 sets (INPUT pools); each mutant in a set was assigned a different tag. Each INPUT pool was intraperitoneally injected into iron-overloaded mice, and in vivo surviving mutants were collected from blood samples from the heart (OUTPUT pools). From the genomic DNA of mixed INPUT or OUTPUT pools, digoxigenin-labeled DNA probes against the tagged region were prepared and used for dot hybridization. Thirty tentatively attenuated mutants, which were hybridized clearly with INPUT probes but barely with OUTPUT probes, were negatively selected. Lethal doses of 11 of the 30 mutants were reduced to more than 1/100; of these, the lethal doses of 2 were reduced to as low as 1/100,000. Transposon-inserted genes in the 11 attenuated mutants were those for IMP dehydrogenase, UDP-N-acetylglucosamine-2-epimerase, aspartokinase, phosphoribosylformylglycinamidine cyclo-ligase, malate Na (+) symporter and hypothetical protein. When mice were immunized with an attenuated mutant strain into which IMP dehydrogenase had been inserted with a transposon, they were protected against V. vulnificus infection. In this study, we demonstrated that the STM method can be used to search for the virulence genes of V. vulnificus.

DOI： 10.1292/jvms.14-0655

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

We previously reported that eradication of Helicobacter pylori in our cohort of patients with peptic ulcer disease reduced their risk of developing gastric cancer to approximately one-third after a mean follow-up period of 3.4 years (up to 8.6 years). We have now followed these patients for a longer period.
A total of 1,222 consecutive patients with peptic ulcer diseases who completed more than 1-year follow-up after receiving H. pylori eradication therapy were followed with annual endoscopic surveillance for a mean of 9.9 years (as long as 17.4 years).
H. pylori infection was judged cured in 1,030 patients (eradication-success group) but persisted in 192 (eradication-failure group) after initial eradication therapy. In the eradication-failure group, 114 patients received re-treatment at a mean of 4.4 years after the start of follow-up, and 105 of these were cured of infection. Gastric cancer developed in 21 of the 1,030 patients in the eradication-success group and in nine of the 192 in the failure group (p = 0.04). The risk of developing gastric cancer in the eradication-success group (0.21 %/year) was significantly lower than that in the failure group (0.45 %, p = 0.049). The longest interval between the initial H. pylori eradication and the occurrence of gastric cancer was 14.5 years in the eradication-success group and 13.7 years in the eradication-failure group.
A prophylactic effect for gastric cancer persists for more than 10 years after H. pylori eradication therapy, but we should be aware that cancer can develop even after that interval.

DOI： 10.1007/s00535-014-1004-5

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Other Link： http://search.jamas.or.jp/link/ui/2015203332

Language：Japanese   Publisher：(一社)日本環境感染学会  

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Language：Japanese   Publisher：(一社)日本環境感染学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Helicobacter pylori, a pathogen responsible for gastric and duodenal diseases, absorbs various steroid compounds into the cell membrane even though some are toxic to this bacterium. An earlier study by our group has demonstrated that progesterone is bactericidal to H. pylori. In this study, we newly synthesized a steroid compound, 17 alpha-hydroxyprogesterone linoleic acid ester (17hPL), to examine antibacterial activity against H. pylori. As expected, 17hPL acted as a bactericidal agent to H. pylori and had no effect on the survival of other common bacterial species. This steroidal substance interacted with phosphatidylethanolamine (PE) on the outer membrane of H. pylori to induce the release of PE from the bacterial cell membrane and to ultimately lyse the bacterial cells. One of the hormonal effects of progesterone is the inhibition of nitric oxide (NO) production from mouse macrophages activated by lipopolysaccharide (LPS). We therefore examined the inhibition effect of 17hPL on the NO production of RAW 264.7 cells, a murine macrophage-like cell line, stimulated with LPS and demonstrated that 17hPL is relatively weaker in its capability to inhibit NO production in LPS-activated cells than progesterone. These results suggest the possibility that 17hPL could be an oral medicine for selectively treating patients infected with H. pylori. (C) 2013 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.jsbmb.2013.10.023

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Language：Japanese   Publisher：(一社)日本環境感染学会  

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Language：Japanese   Publishing type：Research paper (scientific journal)  

Since discovery of Helicobacter pylori, more than 30 species non-H. pylori Helicobacter spp. (NHPH) have been reported. Those NHPH were now classified into gastric Helicobacter spp. and enterohepatic Helicobacter spp.(EHS). Gastric NHPH show tight spiral and long shape in the gastric mucosa, and we can distinguish from H. pylori by light microscope. Some gastric NHPH may be zoonosis and cause gastritis in human. H. hepaticus and H. cinaedi belongs in EHS were detected in human diseases. H. hepaticus may be associated with hepatobiliary diseases in humans. Surprisingly, it was reported that H. cinaedi infection was associated with atrial arrhythmias and atherosclerosis. Many NHPH will be recognized as human pathogen in the future.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

Atrophy of the gastric mucosa is a precursor of intestinal-type gastric cancer, and Helicobacter pylori infection causes atrophic gastritis. The aim of this study was to determine whether the genetic diversity of H. pylori virulence genes is associated with the development and progression of gastric atrophy in humans. We isolated and cultured H. pylori strains from patients with gastric ulcer and duodenal ulcer accompanied by atrophic gastritis in background mucosa. H. pylori strains were stored at -80 degrees C prior to the experiments being carried out. We analyzed iceA, babA, vacA, cagA, and cagE genes by PCR. The cagA gene was analyzed through sequencing of the C-terminal region containing the EPIYA motif, which is related to tyrosine phosphorylation. Severe atrophy was observed in patients with gastric ulcer. The major phenotype of the vacA gene was slc/ml (93%). The cagA gene was detected in all strains. The cagE gene was not detected in 2 and 5 strains from the mild cases and severe cases, respectively. The major cagA EPIYA motif, which is amino acids repeat in the C terminus, was the A-B-D type (44 of 58 strains). The virulence genes were not statistically associated with the severity of atrophy in the background gastric mucosa in humans. Not only identification of bacterial virulence factors but also studies of the host response will be necessary to investigate the progression of gastric atrophy and subsequent cancer development in humans.

DOI： 10.18926/AMO/49667

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC MICROBIOLOGY  

The glucosylation of free cholesterol (FC) by Helicobacter pylori cells has various biological significances for the survival of this bacterium. H. pylori cells with glucosylated FC are capable of evading host immune systems, such as phagocytosis by macrophages and activation of antigen-specific T cells, and surviving in the gastric mucosal tissues for long periods. An additional role of cholesterol glucosylation in the survival of H. pylori which is distinct from the role of escaping the host immune system, however, has yet to be identified. This study demonstrated that 7-dehydrocholesterol (7dFC), an FC precursor, is a toxic compound fatal to H. pylori cells, but the cell membrane of H. pylori is capable of absorbing this toxic sterol via glucosylation. In contrast to the case with 7dFC, no toxicity to H. pylori cells was detected from the glucosylated 7dFC. In addition, cgt gene mutant H. pylori cells that cannot glucosylate cholesterols had higher susceptibility to the toxic action of 7dFC than wild-type H. pylori cells. These results indicate that the cgt gene product of H. pylori serves to detoxify the sterol fatal to this bacterium and to permit this toxic sterol as a cell membrane lipid component. In summary, this study defined a novel role of cholesterol glucosylation in H. pylori.

DOI： 10.1128/JB.01495-12

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER TOKYO  

We previously reported that the reinfection rate with Helicobacter pylori in Japan was low despite a high prevalence of infection. In the present study, we extended our previous work to more accurately determine the reinfection rate.
We enrolled 1625 patients (219 women and 1406 men, mean age 50.8 years) who had received H. pylori eradication therapy. After documentation of eradication, bacterial culture and urea breath test were carried out yearly. H. pylori strains were analyzed by using random amplification of polymorphic DNA fingerprinting.
A total of 1609 patients were followed for up to 12.5 years (mean 4.7 years); H. pylori became re-positive in 26 patients. In 13 of the 26 patients, H. pylori became positive at the first-year follow up. Stored H. pylori isolates were available for analysis from ten of the 13 patients; four of the isolates were genetically different from the initial strain, but the other six were identical to the initial strain. In the other 13 patients, H. pylori became positive at later follow up (mean 4.8 years; range 1.8-8.0 years). In all of the four of these patients whose isolates could be analyzed, the H. pylori strains were different from the initial strain. Assuming that reinfection occurred in the four patients positive for different strains of H. pylori at the first-year follow up and in the 13 positive at later follow up, the reinfection rate was 0.22% per year.
When probable recrudescence (H. pylori positivity with identical strains) was excluded, the reinfection rate of H. pylori in this Japanese population was very low, but we note that reinfection can occur over many years.

DOI： 10.1007/s00535-012-0536-9

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

Cultured Clostridium botulinum strains produce progenitor toxins designated as 12S, 16S, and 19S toxins. The 12S toxin consists of a neurotoxin (NTX, 7S) and a non-toxic non-hemagglutinin (NTNH). The 16S and 19S toxins are formed by conjugation of the 12S toxin with hemagglutinin (HA), and the 19S toxin is a dimer of the 16S toxin. Type A cultures produce all 3 of these progenitor toxins, while type E produces only the 12S toxin. The 7S toxin is cleaved into heavy (H) and light (L) chains by a protease(s) in some strains, and the H chain has 2 domains, the N-terminus (Hn) and C-terminus (Hc). It has been reported that type A toxins bind to the intestinal cells or cultured cells via either HA or Hc. In this study, we investigated the binding of type A and E toxins to Caco-2 cells using Western blot analysis. Both the type E 7S and 12S toxins bound to the cells, with the 7S toxin binding more strongly, whereas, in the type A strain, only the 16S/19S toxins showed obvious binding. Pre-incubation of the type E 7S toxin with IgG against recombinant type E Hc significantly inhibited the 7S toxin binding, indicating that He might be a main binding domain of the type E toxin.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC MICROBIOLOGY  

One of the unique features of Helicobacter pylori is its ability to assimilate free-cholesterol (FC) into its membranes. Via FC assimilation, H. pylori strengthens the membrane lipid barrier and/or evades the host immune system. No previous studies, however, have investigated the FC uptake mechanisms of the H. pylori cell. Phosphatidylethanolamine (PE) is the most prevalent lipid component of bacteria, including H. pylori, but the function of PE remains unclear. We were therefore interested in H. pylori PE (HpPE) and investigated the interaction of its PE with cholesterols. The PE isolated from H. pylori underwent a unique molecular interaction with FC, cholesterol ester (CE), and 2,6-di-O-methyl-beta-cyclodextrin (dM beta CD), a sterol solubilizer. HpPE interacted not only with the FC molecule, but also with the FC-dM beta CD inclusion complex. In contrast, Escherichia coli PE (EcPE), prepared as a reference PE, seemed to bind only FC, and only via a hydrophobic interaction, without binding dM beta CD. HpPE was clearly more potent than EcPE in binding FC. Intriguingly, HpPE had a negligible affinity for CE, while EcPE had a high affinity for CE, comparable to its affinity for FC. Further, HpPE interacted with 3 beta-OH steroids, pregnenolone and dehydroepiandrosterone, in the absence of dM beta CD. Gas chromatogram-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS) analyses revealed that the fatty acid compositions of HpPE were quite distinct from those of EcPE, and the C-14:0 fatty acid in the HpPE molecule was found to be significant in binding FC selectively. These results indicate that PE is a key candidate of nonesterified steroid-binding lipids in H. pylori.

DOI： 10.1128/JB.00105-12

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DOI： 10.4172/2161-703.S2-001

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Helicobacter pylori is a unique bacterial species that assimilates various steroids as membrane lipid components. Our group has recently found, however, that certain steroids may impair the viability of H. pylori. In this study, we go on to reveal that estradiol, androstenedione, and progesterone (PS) all have the potential to inhibit the growth of H. pylori. Of these three steroid hormones, progesterone demonstrated the most effective anti-H. pylori action. 17 alpha-hydroxyprogesterone caproate (17 alpha PSCE), a synthetic progesterone derivative, had a much stronger anti-H. pylori action than progesterone, whereas 17 alpha-hydroxyprogesterone, a natural progesterone derivative, completely failed to inhibit the growth of the organism. Progesterone and 17 alpha PSCE were both found to kill H. pylori through their bacteriolytic action. Among five bacterial species investigated, H. pylori was the only species susceptible to the bactericidal action of progesterone and 17 alpha PSCE. The other four species, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Staphylococcus epiderimidis, all resisted this action. Progesterone and free-cholesterol (FC) obstructed each other's effects against the H. pylori cell. Taken in sum, these results suggest that progesterone and FC may bind to the identical region on the H. pylori cell surface. We expect these findings to contribute to the development of a novel anti-H. pylori steroidal agent.

DOI： 10.1111/j.1574-6968.2011.02239.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER TOKYO  

We previously reported that eradication of Helicobacter pylori reduced the risk of developing gastric cancer in patients with peptic ulcer diseases. In the present study, we further followed up our patient group to investigate the occurrence and clinical features of gastric cancers that developed after cure of the infection.
Prospective post-eradication evaluations were conducted on 1674 consecutive patients who had received successful H. pylori eradication therapy. The patients had undergone endoscopic examination before eradication therapy to evaluate peptic ulcers, background gastric mucosal atrophy, and H. pylori infection. After confirmation of cure of the infection, follow-up endoscopy was performed yearly.
The patients were followed for up to 14.1 years (a mean of 5.6 years). During the follow-up, gastric cancer developed in 28 of the 1674 patients as long as 13.7 years after the cure of H. pylori infection. The risk of developing gastric cancer was 0.30% per year. Histologically, 16 of the gastric cancers were the intestinal type and 12 were the diffuse type; the risk of each cancer type was 0.17 and 0.13% per year, respectively. There was no significant inflammatory cell infiltration in the background gastric mucosa at the time the cancers were recognized.
There is a risk of developing gastric cancer of both the intestinal and diffuse types even after the cure of H. pylori infection and extinction of gastric inflammation. It is important to inform patients about the risk of gastric cancer after eradication therapy and offer them surveillance endoscopy.

DOI： 10.1007/s00535-010-0347-9

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Language：English   Publisher：HINDAWI PUBLISHING CORPORATION  

Adamantiades-Behcet's disease (ABD) is characterized by starting with oral aphthous ulceration and developing of the systemic involvements. The pathogenesis of ABD is closely correlated with the genetic factors and the triggering factors which acquire delayed-type hypersensitivity reaction against oral streptococci mediated by IL-12 cytokine family. HLA-B51 is associated in more than 60% of the patients and its restricted CD8+ T cell response is clearly correlated with the target tissues. Bes-1 gene encoded partial S. sanguinis genome which is highly homologous with retinal protein, and 65 kD heat shock protein (Hsp-65) released from streptococci is playing an important role with human Hsp-60 in the pathogenesis of ABD. Although Hsp-65/60 has homologies with the respective T cell epitope, it stimulates peripheral blood mononuclear cells (PBMCs) from ABD patients. On the other hand, some peptides of Hsp-65 were found to reduce IL-8 and IL-12 production from PBMCs of ABD patients in active stage.

DOI： 10.1155/2011/681956

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

In an attempt to prepare egg yolk immunoglobulin (IgY) to treat and prevent cholera, hens were immunized by a mixture of heat- or formalin-killed Vibrio cholerae O1 and O139 organisms, or by the recombinant cholera toxin B subunit (CTB). The IgYs were partially purified from egg yolk and orally administered to suckling mice before or after challenge with live O1 or O139 cells. The anti-O1 and O139 IgYs and the mixture of either IgY with anti-CTB IgY significantly protected the occurrence of cholera caused by both O1 and O139 infection. Since large amounts of IgY can be prepared very easily and at low cost, this seems to be a useful procedure for preventing and treating cholera.

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Language：Japanese   Publisher：(公社)日本薬学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

Helicobacter pylori assimilates various steroids as membrane lipid components, but it can also survive in the absence of steroids. It thus remains to be clarified as to why the organism relies on steroid physiologically. In this study, we have found that phosphatidylcholine carrying a linoleic acid molecule or arachidonic acid molecule has the potential to kill steroid-free H. pylori. The bactericidal action of phosphatidylcholines against H. pylori was due to the lytic activity of the phosphatidylcholines themselves and not due to the lytic activity of the unsaturated fatty acids or lyso-phosphatidylcholine resulting from the hydrolysis of the phosphatidylcholines. In contrast to the steroid-free H. pylori, the organism that absorbed and glucosylated free cholesterol was unaffected by the bactericidal action of the phosphatidylcholines. Similarly, H. pylori that absorbed estrone without glucosylating it also resisted the bactericidal action of the phosphatidylcholines. The steroids absorbed by H. pylori existed in both the outer and inner membranes, while the glucosyl-steroids produced via the steroid absorption were localized in the outer membrane rather than in the inner membrane. These results indicate that H. pylori absorbs the steroids to reinforce the membrane lipid barrier and thereby expresses resistance to the bacteriolytic action of hydrophobic compounds such as phosphatidylcholine.

DOI： 10.1111/j.1574-6968.2009.01807.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Background: Since the discovery of Helicobacter pylori, various enterohepatic Helicobacter spices have been detected in the guts of humans and animals. Some enterohepatic Helicobacters have been associated with inflammatory bowel disease or liver disease in mice. However the association of these bacteria with human diseases remains unknown. Materials and
Methods: We collected 126 bile samples from patients with cholelithiasis, cholecystitis, gallbladder polyp, and other nonbiliary diseases. Samples were screened for the presence of enterohepatic Helicobacter spp. using Cultures, nested PCR, or in situ hybridization. We tested for antibodies to H. pylori and H. hepaticus by Western blot analysis.
Results: Attempts at cultivation were unsuccessful. However, H. hepaticus was detected in bile samples with nested PCR whereas H. bilis was not. Helicobacter hepaticus in the bile was confirmed by in situ hybridization, but H. hepaticus from bile samples was coccoid in appearance. We detected immunoglobulin G antibodies to H. hepaticus in bile samples by Western blotting. Helicobacter hepaticus was detected in 40 (32%) of total 126 samples as H. hepaticus positive if at least one of the three methods with nested PCR, in situ, or Western blotting. Patients with cholelithiasis (41%) and cholecystitis with gastric cancer (36%) had significantly higher (p = .029) prevalence of H. hepaticus infection than samples from patients with other diseases.
Conclusion: Helicobacter hepaticus may closely associate with diseases of the liver and biliary tract in humans.

DOI： 10.1111/j.1523-5378.2009.00729.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SAGE PUBLICATIONS LTD  

Helicobacter pylori (H. pylori) is a predominant pathogen that causes not only gastroduodenal diseases but also extra-alimentary tract diseases. In this study, we demonstrated that H. pylori infection promoted atherogenesis in heterozygous apoe(+/-) ldlr(+/-) mice. The male mice were fed with high fat diet from the age of 6 weeks. At the age of 16 weeks, development of atherosclerotic lesions was observed in the H. pylori-infected mice, and it seemed to be associated with an elevation of Th1-immune response against H. pylori origin-heat shock protein 60 (Hp-HSP60) and an increment of transendothelial migration of T cells. Subcutaneous immunisation with Hp-HSP60 or H. pylori eradication with antibiotics significantly reduced the progression of atherosclerosis, accompanied by a decline of Th1 differentiation and reduction of their chemotaxis beyond the endothelium. Thus, oral infection with H. pylori accelerates atherosclerosis in mice and the active immunisation with Hp-HSP60 or the eradication of H. pylori with antibiotics can moderate/prevent cellular immunity, resulting in a reduction of atherosclerosis. Lupus (2009) 18, 1154-1168.

DOI： 10.1177/0961203309106600

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL PUBLISHING, INC  

In this study, we have demonstrated that Helicobacter pylori absorbs a steroid prehormone (pregnenolone) and two androgens (dehydroepiandrosterone and epiandrosterone), glucosylates these steroids, and utilizes glucosyl-steroid hormone compounds as the membrane lipid components. The only common structure among the steroid prehormone and the two androgens is a 3 beta-OH in the steroid framework. Our results indicate that the 3 beta-OH in the steroid hormones is a crucial conformation required for steroid glucosylation by H. pylori. In addition, we found that H. pylori absorbs and holds estrogens possessing 3-OH (estrone and estradiol) into the membrane. The effective absorption of estrogen into the membrane appeared to be controlled by the number of hydroxyl groups modifying the steroid framework. In contrast, H. pylori induced neither membrane absorption nor glucosylation of the other steroid hormones possessing 3=O (progesterone, androstenedione and testosterone) or 3 alpha-OH (androsterone). These results indicate that H. pylori selectively absorbs 3 beta-OH and 3-OH steroid hormones, and utilizes only 3 beta-OH steroid hormones as the materials for glucosylation.

DOI： 10.1111/j.1574-6968.2009.01685.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：HUMANA PRESS INC  

The immune response against heat shock protein 60 (HSP60) derived from pathogens causing chronic infections is thought to be an important pro-atherogenic mechanism because high serum levels of antibodies against HSP60 have been associated with atherosclerotic diseases, such as coronary artery diseases, or cerebro-vascular events. Furthermore, the presence of HSP60-specific T lymphocytes in circulation may increase the risk of atherosclerosis. Our recent in vitro and in vivo studies have also shown an association of Helicobacter pylori-HSP60 (Hp-HSP60) specific Th1 immune responses elicited by H. pylori infection with the progression of atherosclerosis in a hyperlipidemic mouse model. These Th1 dominant immune responses may cross-react with endogenous HSP60 expressed on stressed cells of the vascular endothelium, likely due to molecular mimicry. However, the exact mechanisms by which endothelial cells display their HSP60 molecule or present HSP60 antigenic epitopes on the surface are still unclear.

DOI： 10.1007/s12016-008-8097-7

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL PUBLISHING, INC  

Backgrounds and Aim: The effect on reflux esophagitis of eradicating Helicobacter pylori is variable and not fully defined. We previously reported that in patients who have reflux esophagitis associated with duodenal ulcer, a significant improvement in the preexisting reflux esophagitis occurred after H. pylori was eradicated. In the present study, we asked whether H. pylori eradication leads to de novo development of reflux esophagitis in peptic ulcer patients.
Methods: Prospective post-eradication evaluations were conducted in 1195 H. pylori-positive patients with peptic ulcer diseases who were confirmed not to have reflux esophagitis by endoscopic examination before eradication therapy. After eradication therapy, endoscopy and a urea breath test were performed yearly.
Results: A total of 1187 patients were followed for up to 10.0 years (a mean of 3.6 years). Reflux esophagitis developed in 279 of 1000 patients cured of infection and in 26 of 187 patients who had persistent infection (P < 0.0001, Fisher's exact test). The esophagitis was mild (Los Angeles grade A) in most patients, transient in approximately one-half, and rarely necessitated long-term medication for the condition. Cure of infection, alcohol consumption, younger age, and high body mass index were identified as significant factors for the risk of developing non-transient reflux esophagitis.
Conclusions: Cure of H. pylori infection may increase the risk of developing reflux esophagitis in patients with peptic ulcer, but the esophagitis is mostly mild and transient, and long-term medication is rarely required. Thus, H. pylori eradication therapy need not be withheld for fear of provoking reflux esophagitis.

DOI： 10.1111/j.1440-1746.2008.05606.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：HINDAWI PUBLISHING CORPORATION  

Helicobacter pylori (H. pylori) infection is a definite causative factor for gastric ulcers (GUs). In the present study we detected a specific antigen of gastric epithelial cells (HGC-27) using cell ELISA, which was recognized by the sera of GU patients (n = 20) but not in patients with chronic gastritis (CG; n = 20) or in healthy volunteers (HC; n = 10). This antigen was over-expressed by a stressful (heat-stressed) environment, and was identified as elongation factor 2 kinase (EF-2K) by western blotting. The GU patients' lymphocytes stimulated by H. pylori specifically disrupted heat-stressed HGC-27 cells in a cytotoxic assay. In flow cytometry, the effector cells (lymphocytes) from GU patients were significantly differentiated to T helper type 1 lymphocyte (Th1) and cytotoxic T lymphocyte (CTL) as opposed to those from CG patients. The target cells (HGC-27) expressed EF-2K and MHC-class I together with costimulatory molecules from heat stress. This antigen specific immune mechanism could have a prominent role in the pathogenesis of GU. Copyright (C) 2009 Kiyoshi Ayada et al.

DOI： 10.1155/2009/850623

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER GMBH, URBAN & FISCHER VERLAG  

Helicobacter pylori infection causes atrophic gastritis, peptic ulcer, and gastric cancer. The host immune response plays an important role in the pathogenesis of H. pylori-related diseases. Heat shock proteins are antigens involved in various diseases This study evaluated seropositivity for antibodies to H. pylori heat shock protein 60 in patients with gastric cancer.
Serum samples were obtained from 57 patients with gastric cancer (25 patients with diffuse-type gastric cancer and 32 with intestinal-type gastric cancer), 45 H. pylori-positive patients, and 49 H. pylori-negative patients without gastric cancer. Antibodies to heat shock protein 60 and H. pylori were assessed by enzyme-linked immunosorbent assay.
The positivity rate for antibodies to hsp60 was significantly higher in H pylori-positive patients than in H. pylori-negative patients (73.3% vs. 24.5%. p<0.001). In addition, the positivity rate for antibodies to hsp60 was higher in patients with gastric cancer than in H. pylori-positive patients without gastric cancer (87.7% vs. 73.3%, p = 0.06), and the positivity rate for antibodies to hsp60 was significantly higher in patients with diffuse-type gastric cancer than in M pylori-positive patients Without gastric cancer (96% vs. 73 3%, p<0.05).
H. pylori hsp60 might be associated with gastric carcinogenesis, especially in the case of diffuse cancer. (C) 2009 Elsevier GmbH. All rights reserved.

DOI： 10.1016/j.prp.2009.04.008

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Language：English   Publisher：JOHN LIBBEY EUROTEXT LTD  

Behcet's disease (BID) is still considered as a mysterious multisysternic disorder characterized by recurrent involvement of muco-cutaneous, ocular, intestinal, vascular and/or nervous system organs. In this review, we would like to highlight and discuss several important advances in our understanding of the pathogenesis of BD based on the intrinsic genetic factors including HLA-B51 and MICA expression and extrinsic triggering factors. As one of the extrinsic triggering factors, we focused on the hypersensitivity against oral streptococci which might be acquired through the innate immune mechanism. It was found that HLA-B51 restricted CD8 T cell response was clearly correlated with the target tissues expressing MICA*009 by stress in active BD patients with HLA-B51 as the intrinsic factors. Bes-l gene and HSP-65 derived from oral S. sanguinis, which is the uncommon serotype (KTH-1, strain BDl13-20), are supposed to play important roles as an extrinsic factor in BD pathogenesis. The peptides of the Bes-l gene are highly homologous with the retinal protein Brn3b and moreover, the Bes-l peptides were homologous with HSP-65 derived from microorganisms in association with the counterpart human HSP-60, which appeared reactively in the patients. HSP-65/60 also has high homologies with the respective T cell epitope of BD patients. Although HSP-65/60 and the peptides of Bes-l gene were found to stimulate PBMCs from BD patients in the production of pro-inflammatory Th1 type cytokines, some homologous peptides of HSP-65 with T cell epitopes were found to reduce IL-8, IL-12 and TNF-alpha produced from PBMCs of active BID patients. The findings might be correlated with the clinically therapeutic effects for BD patients with severe uveitis, who were led to immunotolerance by the peptide of human HSP-60 (336-351), as previously reported. Then, the pathogenesis of BD was discussed referring to intrinsic genetic factors and extrinsic triggering factors in aspects of streptococcal hypersensitivity, which might be acquired through the innate immune mechanisms. The BD symptoms were thought to be due to vascular reactions as immune responses in correlation with monocyte expressed streptococcal agents.

DOI： 10.1684/ejd.2008.0484

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Immune responses against heat shock protein 60 (HSP60) of pathogen-origin are thought to be defensive events which, due to molecular mimicry, misdirect to a human counterpart. Therefore, atherosclerosis may be serologically predicted by anti-HSP60 antibodies (Abs). In the present study, we analyzed the clinical prevalence of the serum IgG Abs against Helicobacter pylori (Hp)-derived HSP60 (Hp-HSP60) or its peptide fragments in patients with cardiovascular disease (CVD; n = 250), as compared to those in age- and gender-matched non-CVD patients (n = 293). Anti-Hp cell lysate Abs frequently appeared in Hp-infected patients who were not associated with CVD. In contrast, Abs against the particular amino acid sequence Hp-HSP60II3 (II3 region, Glu141-Leu160, in Hp-HSP60) predominantly appeared in CVD patients, as well as IgG anti-human HSP60 (Hu-HSP60w). Furthermore, neither titer of anti-Hp-HSP60II3 nor anti-Hu-HSP60w Abs was correlated with the levels of high sensitivity C-reactive protein (hsCRP). This data strongly suggested that IgG anti-Hp-HSP60II3 Abs cross-reacted with Hu-HSP60w were independent diagnostic markers relevant to CVD. Further, the 20 amino acid residues (Glu141-Leu160) might be predominant CVD-associated epitopes that induce anti-Hu-HSP60 auto-Abs, whose location was predicted in the tertiary structure of Hu-HSP60. © 2007 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.jaut.2007.05.004

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC MICROBIOLOGY  

The catabolic pathway for flavodoxin has yet to be clarified for any bacterial species. In this study, we found that the flavin mononucleotide in the flavodoxin of Helicobacter pylori is degraded to riboflavin via the phosphomonoesterase activity of class C acid phosphatase. The result is a conversion of holoflavodoxin to apoflavodoxin.

DOI： 10.1128/JB.00272-07

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Previous reports have indicated that Helicobacter pylori heat-shock protein 60 (H. pylori-HSP60), as an immunodominant antigen, induces interleukin (IL)-8 production in human monocytes. The exact mechanism by which H. pylori-HSP60 induces IL-8 production in monocytes has not been fully elucidated. In the present study, the downstream pathway by which H. pylori-HSP60 induces IL-8 secretion in human monocytic cell lines was investigated. Intact H. pylori, heat-killed H. pylori and H. pylori recombinant HSP60 (rHpHSP60) all induced the secretion of IL-8 and the activation of mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK) and p38, but not c-Jun N-terminal kinase (JNK), up to 24 In in NOMO1 cells. The specific inhibitors PD98059 and U0126 (for ERK1/2 signalling) and SB203580 (for p38 MAPK signalling) down-regulated IL-8 secretion from rHpHSP60-treated NOMO1 cells. An anti-Toll-like receptor (TLR)2 antibody or TLR2 small interfering RNA (siRNA) partialiy inhibited the secretion of IL-8, and anti-TLR2 antibody also suppressed activation of ERK and p38 MAPK in rHpHSP60-treated NOMO1 cells. These reactions were associated with nuclear factor-kappa B (NF-kappa B)-mediated transcriptional activation, since U01 26, SB203580 and the anti-TLR2 antibody decreased NF-kappa B activation. Taken together, the results suggest that ERK and p38 MAPK signalling linked to the TLR2 recognition receptor in human monocytes may be an important pathway in H. pylori-HSP60-induced IL-8 secretion.

DOI： 10.1099/jmm.0.46882-0

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Background. We previously reported that eradication of Helicobacter pylori could reduce the risk of developing gastric cancer in patients with peptic ulcer diseases. In the present study, we further followed up out-patient groups to identify factors associated with the development of gastric cancer. Methods. Prospective posteradication evaluations were conducted in 1342 consecutive patients (1191 men and 151 women; mean age, 50 years) with peptic ulcer disease who had received H. pylori eradication therapy. The patients had undergone endoscopic examination before eradication therapy to evaluate peptic ulcers, background gastric mucosa, and H. pylori infection. After confirmation of eradication, follow-up endoscopy was performed yearly. Results. A total of 1131 patients were followed for up to 9.5 years (mean, 3.9 years). Gastric cancer developed in 9 of 953 patients cured of infection and in 4 of 178 who had persistent infection (P = 0.04). The risk of developing gastric cancer after receiving H. pylori eradication therapy was increased according to the grade of baseline gastric mucosal atrophy (P = 0.01). In patients with peptic ulcer diseases, persistent infection of H. pylori (hazard ratio, 3.9; P = 0.03), the grade of baseline gastric mucosal atrophy (3.3, P = 0.01) and age (2.0, P = 0.04) were identified as significant risk factors for developing gastric cancer. Conclusions. The grade of gastric atrophy was closely related to the development of gastric cancer after receiving H. pylori eradication therapy. Thus, eradication of H. pylori before the significant expansion of atrophy is most beneficial to prevent gastric cancer.

DOI： 10.1007/s00535-006-1924-9

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Background/Aims: In Helicobacter pylori eradication therapy, using a proton pump inhibitor plus amoxicillin and clarithromycin (PPI/AC regimen), the impact of the clarithromycin dose and smoking on efficacy is conflicting. Here, we compared the efficacy of 400 and 800 mg of clarithromycin in the regimen in relation to smoking in patients with peptic ulcer disease. Methods: We studied 601H. pylori-positive patients with peptic ulcer disease who had received amoxicillin 750 mg and clarithromycin 200 or 400 mg together with lansoprazole 30 mg b. i. d. Results: 305 patients were treated with a regimen containing 400 mg of clarithromycin (C400 group), and 296 patients with a regimen containing 800 mg (C800 group). Overall cure rates between the two groups were not significantly different, but the cure rate in the C800 group was significantly better than that in the C400 group among patients infected with clarithromycin- sensitive strains (p = 0.03). This difference could be attributed to differences among smokers versus non-smokers: the cure rate among smokers in the C800 group (91.0%) was better than that in the C400 group (80.0%, p = 0.003). Conclusions: 800 mg of clarithromycin is recommended in the PPI/AC regimen for patients who smoke and are infected with clarithromycinsensitive H. pylori.

DOI： 10.1159/000102301

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Language：English   Publishing type：Research paper (international conference proceedings)   Publisher：Blackwell Publishing Inc.  

Immunoinflammatory processes due to chronic infection are thought to be one of the definitive atherogenetic processes. Especially, anti-heat shock protein antibodies have been related to the prevalence of disease such as coronary artery disease or cerebral infarction, etc., resulted from atherosclerosis. Furthermore, the presence of HSP60-specific T lymphocytes in circulation may increase the risk of atherosclerosis. We have recently demonstrated the evidences that Helicobacter pylori infection induced atherosclerosis in apoe+/-ldlr+/- mice and that Hp-anti-heat-shock protein specific Th1-dominant immune responses had a major involvement in the progression of atherosclerosis. These cellular immune responses caused autoimmunity against endogenous HSP60 (expressed on the stressed cells of vascular endothelium), due to the molecular mimicry. Therefore, an appropriate treatment with antibiotics or with anti-HSP60 antibodies, which regulates the Th1 induction, could sufficiently reduce the progression of atherosclerosis. © 2007 New York Academy of Sciences.

DOI： 10.1196/annals.1422.062

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Microbiology Society  

<italic>Clostridium botulinum</italic> type B strain produces two forms of progenitor toxin, 16S and 12S. The 12S toxin is formed by association of a neurotoxin (NTX) and a non-toxic non-haemagglutinin (NTNH), and the 16S toxin is formed by conjugation of the 12S toxin with a haemagglutinin (HA). HA consists of four subcomponents designated HA1, HA2, HA3a and HA3b. When mice were immunized with formalin-detoxified NTX, 12S or 16S, a significantly greater amount of anti-NTX antibody (Ab) was produced in the mice injected with 16S than in NTX- or 12S-injected mice. Immunization with NTX mixed with HA1 and/or HA3b also increased the anti-NTX Ab production, whereas NTX mixed with HA2 did not, indicating that HA1 and HA3b have adjuvant activity. This was further confirmed by immunizing mice with human albumin (Alb) alone or Alb mixed with either HA1 or HA3b. When mouse-spleen cells were stimulated with NTX, 16S or different HA subcomponents, 16S, HA1, HA3b and the mixture of HA1 and HA3 significantly increased interleukin 6 (IL6) production compared with NTX alone. Transcription of IL6 mRNA was low after stimulation with NTX alone, but increased to 16S-stimulation levels when NTX was mixed with HA1 or HA3b. In flow cytometry using labelled Abs against CD3 and CD19, the percentage of CD19 cells was higher following stimulation with 16S or NTX mixed with HA1 or HA3b compared with stimulation with NTX. The percentage of CD3 cells remained unchanged. These results suggest strongly that HA1 and HA3b demonstrate adjuvant activity via increasing IL6 production.

DOI： 10.1099/mic.0.28421-0

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Background &amp
Aims: Immune responses to Helicobacter pylori are important in the pathogenesis of gastric mucosa-associated lymphoid tissue (MALT) lymphoma. In this retrospective case study, we investigated whether certain alleles and haplotypes of major histocompatibility complex genes are associated with gastric MALT lymphoma and the efficacy of H pylori eradication therapy on the lymphoma. Methods: Blood samples were obtained from 18 patients with H pylori-positive gastric MALT lymphoma (5 men and 13 women
age range, 51-80 years), 30 patients with H pylori-positive non-ulcer dyspepsia (17 men and 13 women
age range, 37-77 years), and 30 patients with H pylori-negative non-ulcer dyspepsia (12 men and 18 women
age range, 37-77 years). HLA-DQA1 and DQB1 allele typing was performed by use of a polymerase chain reaction sequence-specific oligonucleotide procedure. All patients with MALT lymphoma were treated with H pylori eradication therapy and followed up by repeated endoscopy and biopsy. Results: We found a significant increase in alleles HLA-DQA1*0103 and HLA-DQB1*0601, and a haplotype DQA1*0103-DQB1*0601, in MALT lymphoma patients when compared with non-ulcer dyspepsia patients who were either H pylori-positive or not and with a healthy control population. After H pylori eradication, the lymphomas regressed completely in all 10 patients who possessed the DQA1*0103-DQB1*0601 haplotype but in only 4 of the 8 without this haplotype (P = .023). Conclusions: DQA1*0103-DQB1*0601 haplotype-positive gastric MALT lymphoma is likely to respond to therapy by eradication of H pylori. © 2005 by the American Gastroenterological Association.

DOI： 10.1016/S1542-3565(05)00185-0

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OBJECTIVES: Infection with Helicobacter pylori is a risk factor for the development of gastric cancer. However, it is not known whether eradication therapy can prevent the development of gastric cancer in persons in whom the cancer is not yet established. In the present study, we investigated whether the eradication of H. pylori in patients with peptic ulcer disease reduces the likelihood of their developing gastric cancer. METHODS: Prospective posteradication evaluations were conducted in 1,342 consecutive patients (1,191 men and 151 women
mean age: 50 yr) with peptic ulcer diseases who had received H. pylori eradication therapy. After confirmation of eradication, endoscopy and a urea breath test were performed yearly. RESULTS: A total of 1,120 patients completed more than 1-yr follow-up and were followed for up to 8.6 yr (a mean of 3.4 yr). Gastric cancer developed in 8 of 944 patients cured of infection and 4 of 176 who had persistent infection (p = 0.04
log-rank test). All the gastric cancer developed in patients with gastric ulcer, but none in patients with duodenal ulcer (p = 0.005
Fisher's exact test). In patients with gastric ulcer, persistent infection was identified as a significant factor for the risk of developing gastric cancer (hazard ratio: 3.35
95% confidence interval: 1.00-11.22
p = 0.04
Cox's proportional-hazards model). CONCLUSION: H. pylori eradication may reduce their risk of developing gastric cancer in patients with gastric ulcer. Large-scale studies in additional populations of this important international public-health issue are warranted. © 2005 by Am. Coll. of Gastroenterology Published by Blackwell Publishing.

DOI： 10.1111/j.1572-0241.2005.41384.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Immune reactions against microorganisms play an important pathogenic role in Adamantiades-Behcet's disease. We had previously obtained Streptococcus sanguinis (strain BD 113-20), isolated from the oral cavity of patients with Adamantiades-Behcet's syndrome. To investigate the pathogenesis of this isolate, we examined neutrophil reactions and levels of cytokine production by lymphocytes after stimulation with the strain. The reactions of neutrophils were examined by chemiluminescence assay using whole blood. The amounts of interferon gamma (IFN-gamma) and interleukin (IL)-4, IL-8, IL-10 and IL-12, produced by peripheral blood mononuclear cells, were measured by ELISA. Strain BD113-20 activated neutrophils from Adamantiades-Behcet's patients and healthy volunteers, and, in addition it increased the IFN-gamma production by lymphocytes. Lymphocytes from Adamantiades-Behcet's patients showed a dominant T helper-1 immune response. Results indicated that both bacterial stimulation and host hypersensitivity might be involved in the symptoms and pathogenesis of Adamantiades-Behcet's disease. (C) 2004 Federation of European Microbiological Societies. Published by Elsevier B.V. All rights reserved.

DOI： 10.1016/j.femsim.2004.07.007

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In this analysis of membrane lipid compositions in Helicobacter pylori, the membrane lipid profiles drastically changed during coccoid formation: cholesteryl-6-O-tetradecanoyl-α-D-glucopyranoside levels increased, cholesteryl-α-D-glucopyranoside and phosphatidyl ethanolamine decreased, and a coordinated increase in cardiolipin and decrease in phosphatidyl glycerol were observed. Cholesteryl-6-O-phosphatidyl-α-D-glucopyranoside was hardly detected in the spiral forms in the logarithmic phase, but subsequently increased throughout the coccoid conversion. These results suggest that environmental stresses induce the expression of certain regulatory systems for lipid metabolism in H. pylori, and that the resulting alterations in lipid composition play an important role in inducing the coccoid conversion. © 2004 Federation of European Microbiological Societies. Published by Elsevier B.V. All rights reserved.

DOI： 10.1016/j.femsle.2004.07.004

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Background & Aims: There has been significant controversy over the relationship between Helicobacter pylori infection and reflux esophagitis. We investigated the effects of eradicating H. pylori on the reflux esophagitis found in patients with peptic ulcers. Methods: Prospective posteradication evaluations were conducted yearly in 162 H. pylori-positive patients who had reflux esophagitis together with peptic ulcer disease (4 women and 158 men, mean age = 49.1 yr). The Los Angeles classification of the patients' esophagitis was: grade A, 90; grade B, 63; and grade C, 9. The follow-up evaluations began 1 to 2 months after completion of the eradication treatment (mean time of follow-up = 22 mo), and consisted of endoscopy and an interview focusing on heartburn. Results: Six patients were withdrawn from the study because of adverse drug reactions or a failure to regularly keep their appointments. After eradication therapy, we observed endoscopically that reflux esophagitis had improved in 87 (55.8%) of the 156 patients. The improvement rate was significantly higher in patients cured of infection (60.8%) than in those with persistent H. pylori infection (38.9%) (P = 0.04). Body mass index (odds ratio = 0.86, 95% confidence interval [CI] = 0.76-0.97), cure of infection (3.68, 95% CI = 1.56-8.69), the absence of a hiatal hernia (3.90, 95% CI = 1.83-8.28), and an ulcer located in the duodenum (2.75, 95% CI = 1.33-5.70) were identified as significant independent factors for the improvement of reflux esophagitis. Conclusions: In patients with reflux esophagitis associated with duodenal ulcer, a significant improvement in pre-existing reflux esophagitis was noted after H. pylori eradication.

DOI： 10.1053/S1542-3565(04)00165-X

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Background/Aims: Alterations of gastric mucin have been postulated as important pathogenic properties of Helicobacter pylori. In this study, we investigated gastric mucin synthesis in H. pylori-infected gastric mucosa by measuring UDP-galactosyltransferase activity, a key enzyme for the synthesis of mucin, and the amount of intracellular mucin in the gastric mucosa. Methodology: Gastric biopsy specimens were obtained from thirty-seven patients (20 H. pylori-positive and 17 H. pylori-negative). UDP-galactosyl-transferase activity of the biopsy specimens was measured by an assay system we had developed, using a peanut agglutinin lectin. The amount of intracellular mucin in the gastric epithelial cells was analyzed by measuring the cells' periodic acid-Schiff-alcian blue staining-positive substances. Results: UDP-galactosyltransferase activities in the antral mucosa, but not in the body mucosa, of H. pylori-positive patients were significantly lower than those of H. pylori-negative patients (p&lt
0.05). The amount of intracellular mucin in antral epithelial cells of H. pylori-positive patients was significantly lower than that of H. pylori-negative patients (p&lt
0.01). Conclusions: These findings suggest that H. pylori infection decreases gastric mucin synthesis via inhibition of UDP-galactosyltransferase. This effect may impair the gastric mucosal barrier and contribute to the mucosal injury induced by H. pylori infection.

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Background/Aims: At the assessment of eradication therapy of Helicobacter pylori, the results of 13C-urea breath test and other methods such as bacterial culture are occasionally inconsistent. In this study, we examined the outcomes of inconsistent results. Methodology: Four hundred and four patients with peptic ulcer who were H. pylori-positive and who had completed eradication therapy were studied. Bacterial culture, rapid urease tests and 13C-urea breath test were performed between one and three months after the end of the therapy. The cut-off value for the 13C-urea breath test used originally in this study was 2.5 per mil. We investigated the outcome of inconsistent results by following up the patients every 6 to 12 months. Results: At the initial assessment of eradication therapy, we observed inconsistent results with bacterial culture and 13C-urea breath test in 43 of 404 patients. Most of them (40 of 43) were culture-negative but urea breath test-positive, and the majority became negative for both tests. Based on the follow-up results, the optimum value for 13C-urea breath test at the assessment of eradication therapy was found to be 3.5 per mil. Conclusions: We found that outcomes of inconsistent results were variable, indicating the importance of the follow-up of patients after eradication therapy of H. pylori.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：KLUWER ACADEMIC/PLENUM PUBL  

DOI： 10.1007/0-306-48382-3_38

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier Inc.  

OBJECTIVES: Genetic polymorphism of interleukin (IL)-1β is associated with differences in gastric acid suppression in response to Helicobacter pylori (H. pylori) infection. Thus, the polymorphism might affect H. pylori eradication therapy, as antibiotics used in treatment regimens may be acid sensitive. In this study, we examined the impact of IL-1β genetic polymorphism on the cure rate of triple therapy for H. pylori in relation to cytochrome P (CYP) 2C19 genotype and antibiotic resistance. METHODS: A total 249 patients with peptic ulcer disease were randomized to receive one of the following regimens: amoxicillin and clarithromycin together with omeprazole, lansoprazole, or rabeprazole. CYP2C19 and IL-1β-511 genetic polymorphisms were analyzed by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: The intention-to-treat-based overall cure rate was 74.3% (95% CI = 68-79%). In the normal acid secretion IL-1β genotype group, the cure rate among CYP2C19 poor metabolizers (93.3%, 95% CI = 56-99%) was significantly higher than among subjects in the CYP2C19 homozygous (60.0%, 95% CI = 38-78%) and heterozygous (63.6%, 95% CI = 46-78%), i.e., extensive metabolizer, groups (p &lt
0.05). In the low acid secretion IL-1β genotype group, there was no difference in the cure rate among the CYP2C19 genotype groups. Multiple logistic regression analysis identified susceptibility to clarithromycin (p &lt
0.0001) and CYP2C19 genotype status (p = 0.03) as significant independent factors for treatment failure. CONCLUSION: IL-1β genetic polymorphism, although not an independent factor in treatment outcome, influences the impact of the CYP2C19 genotype on the cure rate of 1-wk triple therapy for H. pylori infection. © 2003 Am. Coll. of Gastroenterology.

DOI： 10.1016/S0002-9270(03)00713-5

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Mucosa-associated lymphoid tissue (MALT) lymphomata observed simultaneously in the stomach and colon are rare. We report concurrent gastric and colonic low-grade MALT lymphomata that originated from the same clone in a 58-year-old Japanese man without Helicobacter pylori infection. Endoscopy showed multiple erosive lesions in the gastric body and antrum, and a single flat elevation with an irregular margin in the sigmoid colon. Histopathological findings of both lesions suggested low-grade MALT lymphoma. Lymphoepithelial lesions were evident in the gastric lesions, but not in the colonic lesion. Southern blot analysis of lymphoma cells revealed the same immunoglobulin heavy-chain rearrangement pattern. The chromosomal translocation t(11
18)(q21
q21) was also observed. After six courses of cyclophosphamide, doxorubicin, vincristine and predonisolone, the gastric lesions disappeared endoscopically, while the colonic lesion persisted. A sigmoidectomy was consequently performed. The chromosomal translocation may be related to the pathogenesis of the present MALT lymphoma case without H. pylori infection. It is interesting that the gastric and colonic lesions differed in response to treatment and in their endoscopic and histologic features, despite having the same origin.

DOI： 10.1046/j.1443-1661.2003.00108.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Microbiology Society  

Of 11 monoclonal antibodies (MAbs) prepared against the non-toxic component of type C Clostridium botulinum 16S toxin to clarify the function of the non-toxic component, seven recognised HA1, three recognised HA3b and one recognised HA2. Results of epitope mapping indicated that three of the seven anti-HA1 MAbs recognised the region between amino acid residues 121 and 140 and four recognised the three-dimensional structure of HA1. Three anti-HA3b MAbs recognised different regions between (approximately) amino acids 405-430, 180-270 and 275-297. The ability of these MAbs to interfere with binding of 16S toxin or non-toxic component, HA1 or HA3b to erythrocytes and to intestine tissue sections of guinea-pig was observed. MAbs against HA3b and HA2 did not inhibit 16S toxin binding to either erythrocytes or epithelial cells, whereas some MAbs against HA1 did inhibit binding. The seven anti-HA1 MAbs can be classified into four groups based on their binding inhibition activities. The anti-HA1 MAbs that inhibited the binding of 16S toxin to the epithelial cells also neutralised or reduced the oral toxicity in mice, indicating that HA may play an important role in the absorption of the 16S toxin from the small intestine.

DOI： 10.1099/0022-1317-51-4-286

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC MICROBIOLOGY  

Infection with Helicobacter pylori induces humoral immune responses against various antigens of the bacterium. Heat shock proteins (hsps) are immunodominant antigens in various diseases including H. pylori infection. In the present study, we measured the anti-hsp antibody titers in 42 patients with H. pylori-infected peptic ulcers during a bacterial eradication study. The patients were treated with a proton pump inhibitor and antimicrobial agents to eradicate the organism. Their sera were obtained at pretreatment and at 1 month and 6 months after the eradication therapy. The titers of immunoglobulin G antibodies to the H. pylori hsp, whole-cell lysate, and urease (30-kDa subunit) antigens in serum were measured by a capture enzyme-linked immunosorbent assay. The levels of H. pylori hsp60 antibodies in sera collected 1 month after treatment had declined significantly, even when changes in the titers of antibodies to whole-cell and urease antigens were not apparent. These results suggest that measurement of antibodies to H. pylori hsp60 in serum is useful far the early monitoring of the effectiveness of eradication therapy.

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Helicobacter pylori is a major etiological agent in gastroduodenal disorders. The adhesion of H, pylori to gastric epithelial cells is the initial step of N, pylori infection. Inhibition of H, pylori adhesion is thus a therapeutic target in the prevention of H, pylori infection. me have reported that rebamipide and ecabet sodium, mucoprotective antiulcer agents, independently inhibit H. pylori adhesion. However, the antiadhesion activity of each antiulcer agent was incomplete. Experiments were performed to evaluate the combined effect of rebamipide and ecabet sodium on H, pylori adhesion to gastric epithelial cells, MKN-28 and MKN-45 cells, derived from human gastric carcinomas, were used as target cells, Twelve clinical isolates of H, pylori were used in this study. We evaluated the effects of rebamipide and ecabet sodium, individually and in combination, on H. pylori adhesion to target cells quantitatively using our previously established enzyme-linked immunosorbent assay. Rebamipide and ecabet sodium each partially inhibited H. pylori adhesion. In contrast, adhesion was almost completely inhibited by pretreating target cells and N, pylori with the combination of rebamipide and ecabet sodium, Our studies suggest that the synergistic antiadhesion activity of rebamipide and ecabet sodium is greater than that of each antiulcer agent alone.

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Language：English   Publisher：Okayama University Medical School  

DOI： 10.18926/AMO/31612

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Society for General Microbiology  

The 16S toxin and one subcomponent of haemagglutinin (HA), designated HA1, were purified from a type D culture of Clostridium botulinum by a newly established procedure, and their HA activities as well as that of purified type C 16S toxin were characterized. SDS-PAGE analysis indicated that the free HA1 forms a polymer with a molecular mass of approximately 200 kDa. Type C and D 16S toxins agglutinated human erythrocytes in the same manner. Their HA titres were dramatically reduced by employing erythrocytes that had been previously treated with neuraminidase, papain or proteinase K, and were inhibited by the addition of N-acetylneuraminic acid to the reaction mixtures. In a direct-binding test to glycolipids such as SPG (NeuAcα2-Galβ1-4GlcNAcβ1-3Galβ1-4Glcβ1-Cer) and GM3 (NeuAcα2-3Galβ1-4Glcβ1-Cer), and glycoproteins such as glycophorin A and/or B prepared from the erythrocytes, both toxins bound to sialylglycolipids and sialoglycoproteins, but bound to neither neutral glycolipids nor asialoglycoproteins. On the basis of these results, it was concluded that type C and D 16S toxins bind to erythrocytes through N-acetylneuraminic acid. HA1 showed no haemagglutination activity, although it did bind to sialylglycolipids. We therefore speculate that binding to glycoproteins rather than to glycolipids may be important in causing haemagglutination by type C and D 16S toxins.

DOI： 10.1099/00221287-145-9-2533

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

Helicobacter pylori (H. pylori) infection in the stomach is etiologically closely associated with chronic active gastritis, peptic ulcer, gastric cancer and gastric mucosa-associated lymphoid tissue lymphoma. In this study, we examined the antibody responses and cytokine profiles of three strains of mice (BALB/c, C3H/He, and C57BL/6) infected with H. pylori. Following this, correlations between host-immune reactions and intensity of inflammation were analyzed. H. pylori (ATCC43504) was intragastrically administered once a week to the mice from 4 weeks of age, and they were sacrificed at the ages of 4 and 7 months. In these mice, we examined the histology of the stomach, antibody titers against H. pylori, and serum levels of cytokines (IL-4, IL-10, TNF-alpha, IL-2 and Interferon-gamma). In BALB/c mice, inflammation of the stomach was minimal. Inflammation was observed in 63.6% of C57BL/6 mice and 33.3% of C3H/He mice. In C57BL/6 and C3H/He mice, all the cytokines tended to increase, In contrast, BALB/c mice were inactive in cytokine production except for IL-2, Two C3H/He mice developed severe inflammation with lymph follicles; one showed a response largely typical of Th-1, and the other showed a response largely typical of Th-2. Although a definite correlation was not shown between Th-1/Th-2 response evaluated by cytokine production and intensity of inflammation, it appears that in H. pylori-induced inflammation both cell-mediated (Th-1) and humoral (Th-2) immunity play a role in pathogenesis.

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Aims - To investigate the localisation of Helicobacter pylori antigens and the expression of human heat shock proteins (HSP) in stomachs affected by MALT lymphoma. Methods - Surgically resected stomachs from 24 patients with MALT lymphoma were immunostained with anti-H pylori rabbit antibodies (ORP-1 and ORP-2) and anti-human HSP60 mouse monoclonal antibodies (mAb) (LK-1 and LK-2). Results - Follicular dendritic cells of germinal centres in the stomachs affected by MALT lymphoma were immunostained with anti-H pylori polyclonal antibodies and with anti-human HSP60 mAb, as were the epithelial cells. None of the lymph node samples reacted. Conclusions - Human HSP60, which cross reacts with anti-H pylori polyclonal antibodies, is often expressed on follicular dendritic cells in gastric MALT lymphoma tissues and may be aetiologically relevant to lymphomagenesis of MALT lymphoma.

DOI： 10.1136/jcp.51.5.396

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Helicobacter pylori is a major etiological agent in gastroduodenal disorders. H. pylori adhesion to human gastric mucosa is the initial step of H. pylori colonization. Inhibition of H. pylori adhesion is thus a therapeutic target in preventing H. pylori infection. We have previously established a method using the enzyme-linked immunosorbent assay to analyze quantitatively H. pylori adhesion to gastric epithelial cells. This method is suitable for screening antiadhesion agents. Some mucoprotective agents are proved to have antiadhesion effects in vitro, and they may modify H. pylori adhesion. This evidence gives us a useful clue to analyze the molecular mechanism of H. pylori adhesion to mucosa. Furthermore, in clinical trials, these mucoprotective agents enhanced the eradication rate when administered with antibiotics. In conclusion, the antiadhesion agents may have potential as therapeutic regimens against H. pylori infection.

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The production of IgA protease in twelve strains of Streptococcus sanguis isolated from patients with Behcet's disease (BD) was examined, Protease activity was detected in 10 out of 12 strains, The protease was purified from one representative strain, S. sanguis 113-20, by employing Rotofor and DEAE-Sephacel chromatography, The molecular mass of the purified protease was approximately 100 kDa, and it cleaved the proline-threonine site of the IgA, Both IgG and IgA titers against the cells (113-20) and the purified IgA protease in the sera of BD patients and healthy controls, 36 each, were assayed, The IgG titers against the cells and protease were not significant in the BD patients or controls, but the IgA titers against the cells and protease in the BD patients were significantly higher than those of the controls, These data indicate that the BD patients are infected with IgA protease-producing S. sanguis strains, which cause an increase of IgA titer against these organisms and IgA protease antigen. Since the organisms can proliferate in BD patients for a long period of time (years), it seems that IgA antibodies cannot effectively eliminate the organisms.

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A rapid and simple method to quantitatively analyse Helicobacter pylori adhesion to human gastric epithelial cells was developed by using an enzyme- linked immunosorbent assay. This method made it possible to quantitatively evaluate the adhesion activities of many different H. pylori strains at a time. Our studies indicate that this method is well suited for the quantitative analysis of H. pylori adhesion to gastric epithelial cells.

DOI： 10.1111/j.1440-1746.1997.tb00445.x

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Language：Japanese   Publisher：一般社団法人 日本アレルギー学会  

DOI： 10.15036/arerugi.45.900_4

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The lipid and fatty acid profiles of eight Helicobacter spp. (H. nemestrinae, H. acinonyx, H. canis, Helicobacter sp. strain CLO-3, 'H. rappini' [Flexispira rappini], H. pametensis, Helicobacter sp. strain Bird- B, and Helicobacter sp. strain Bird-C) and the fatty acid profiles of five additional species (H. pylori, H. felis, H. muridarum, H. mustelae, and H. fennelliae) were analyzed and compared. A heterologous fatty acid profile was observed among the Helicobacter spp., and on that basis the species could be divided into two groups. Group A had 19-carbon cyclopropane fatty acid (19:0cyc) and tetradecanoic acid (14:0) as the major fatty acids, and group B characteristically lacked the 19:0cyc and had hexadecanoic acid (16:0) and octadecenoic (18:1) acids as the major fatty acids. The species of group A are primarily gastric colonizers, and those of group B are primarily intestinal colonizers. Seven of the eight species studied showed the unusual and characteristic presence of cholesteryl glucosides (CGs), and most of these seven showed a very large amount (9.7 to 27.4% of the weight of total extractable lipid). The types of CGs and their distribution in different species were as follows: cholesteryl-6-O-acyl-α-D-glucopyranoside (cholesteryl-6-O-tetradecanoyl-α-D-glucopyranoside in H. nemestrinae and mainly cholesteryl-6-O-dodecanoyl-α-D-glucopyranoside in 'H. rappini'), cholesteryl-α-D-glucopyranoside (H. nemestrinae, H. acinonyx, H. canis, Helicobacter sp. strain CLO-3, and 'H. rappini'), and cholesteryl-6-O- phosphatidyl-α-D-glucopyranoside (H. nemestrinae, H. acinonyx, H. canis, and Helicobacter sp. strain CLO-3). Besides this, we could also detect cholesteryl acyl glucoside in H. acinonyx, cholesteryl glucoside in Helicobacter sp. strains Bird-B and -C, and cholesteryl phosphatidyl glucoside in 'H. rappini' and Helicobacter sp. strain Bird-C. A selective accumulation of free cholesterol was observed in the neutral lipid fractions. On the basis of the detection of CGs in 11 of the 13 species studied so far, the presence of CGs appears to be a characteristic feature of the genus Helicobacter. In view of this and also because of a simple and rapid detection method described herein, the CGs can be used as a valuable chemotaxonomic marker.

DOI： 10.1128/jb.178.7.2065-2070.1996

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

Many of Helicobacter species have been found to have novel cholesteryl glucosides (CGs). To study the biosynthetic mechanism of CGs, the lipid profiles of H. pylori and H. mustelae grown in serum-supplemented and cholesterol-restricted serum-free media were investigated. In contrast to the serum-supplemented state, helicobacters had less CGs in the serum-free state; a trace amount of CGs and no CG was detected in H. pylori and H. mustelae, respectively. The proportion of total and individual phospholipid also showed significant alteration. Unknown lipids which did not contain phosphate and sugar were detected in the serum-free state, but not in the serum-supplemented state. The CGs were found to be distributed mainly in the membrane fractions, and one of the unknown lipids was found exclusively in the cytosol fraction. Based on these data,it is apparent that the CGs of helicobacters are synthesized by de novo uptake of cholesterol from the media. The unknown lipids detected in the serum-free state may be storage lipids, appearing in response to depletion of nutrients, especially cholesterol, or other factors in the media.

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Language：Japanese   Publisher：一般社団法人 日本アレルギー学会  

DOI： 10.15036/arerugi.44.412_3

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DOI： 10.15036/arerugi.44.414_4

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Society for Microbiology  

A chloroform-methanol-extracted lipid of Helicobacter pylori was studied. Three kinds of glycolipids, accounting for about 25% (wt/wt) of the total lipid, were detected and identified to be cholesteryl glucosides. The structures of two of them were determined to be cholesteryl-α-D- glucopyranoside and cholesteryl-6-O-tetradecanoyl-α-D-glucopyranoside, and the plausible structure of the third one was identified as cholesteryl-6-O- phosphatidyl-α-D-glucopyranoside. Cholesteryl glucosides are very rare in animals and bacteria. Furthermore, those in H. pylori had an α-glycosidic linkage, which is rather unusual for natural glycosides, and a phosphate- linked cholesteryl glycoside like the cholesteryl-6-O-phosphatidyl-α-D- glucopyranoside has not been reported previously. As the cholesterol glucosides were detected in strains obtained from diverse geographical locations, the presence of cholesteryl glucosides in H. pylori is a very unique and a characteristic feature of the species. These findings add a new facet to the physiology and biochemistry, especially the cholesterol and glucose metabolism, of H. pylori. Furthermore, the cholesteryl glucosides of H. pylori showed hemolytic activities.

DOI： 10.1128/jb.177.18.5327-5333.1995

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CENTER ACADEMIC PUBL JAPAN  

Helicobacter pylori was transurethrally inoculated into the mouse urinary tract. The organism established infection and induced inflammation in the urinary bladder and pelvis. During the infection, urinary pH was elevated, probably due to the production of NH3 by bacterial urease. H. pylori was recovered from the urinary bladder, kidney and urine of the infected mice. Histopathologically, severe neutrophil infiltration was observed in the mucosal layer of both organs. H. pylori was detected on the surface of the epithelial cells. These results indicate that low pH and bacterial flora were not essential factors in establishing the mucosal infection with H. pylori. This experimental system is useful to investigate the pathogenicity of H. pylori in mucosal organs.

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Language：English   Publisher：Center For Academic Publications Japan  

The cells of Helicobacter pylori were suspended in the medium containing ³⁵S-methionine. After a heat shock of the cells at 42C for 5, 10, and 30min, the production of proteins was analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography. Out of many proteins produced by the cells, only 66kDa protein production was dramatically increased by heat treatment. The N-terminal amino acid sequence of 66kDa protein was quite similar to that of 62kDa and 54kDa proteins previously suggested as heat shock protein (HSP) of H. pylori based on the reaction with polyclonal and monoclonal antibodies against HSP 60 family proteins produced by other bacteria. Therefore, it was concluded that H. pylori produces the 66kDa protein as its major heat shock protein which belongs to HSP 60 family.

DOI： 10.1111/j.1348-0421.1994.tb01799.x

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Language：Japanese   Publisher：一般社団法人 日本アレルギー学会  

DOI： 10.15036/arerugi.42.1398_2

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Helicobacter pylori is an emerging candidate agent for the genesis of chronic gastritis and peptic ulcer. There have been many challenges to establish an experimental infection with H. pylori in animals. In recent, several studies reported for animal infection with this organism. One of them was the study using urinary system. The study indicated the ability of H. pylori to induce inflammation without significant low pH condition. Experimental infection in Mongolian gerbils showed that H. pylori could colonize on the surface of the gastric mucosa in animals without human. The study of nude mice by Karita et al. showed several valuable facts concerning the relation between bacterial pathogenicity and potential of bacterial colonization in stomach. The study in which remaining of bacteria was extended showed that colonization of H. pylori was affected by bacterial flora in the stomach.

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In H. pylori, we examined the composition of total lipids. In thin-layer chromatography, three kinds of glycolipids were detected, which were named as G-1, G-2 and G-3. G-3 contained phosphates in addition to sugars. Total lipids consisted of 6.0% neutral lipids (weight %), 20.6% glycolipids (G-1, G-2) and 73.4% phospholipids (including G-3). Total glycolipids were approximately 25% of total lipids. After methanolysis, cholesterol was detected in the hexane extractable fraction and glucose was detected by GLC in the methanol fraction after trimethylsilylation, in all glycolipids. Therefore, these glycolipids are cholesteryl glycosides. Cholesteryl glycosides are found very rarely in bacteria, and have been detected only in a few species of mycoplasmas and spirochetes.

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DOI： 10.1016/s0248-8663(05)82442-7

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Language：English   Publisher：Center For Academic Publications Japan  

The serum antibody titers against oral streptococci were studied by enzyme-linked immunosorbent assay (ELISA) both in patients with Behçet's disease (BD) and control groups. The patients with BD showed significantly higher antibody titers to S. sanguis strains 113-20, 114-23, and 118-1 which were isolated from patients with BD, in comparison with control groups. Also, the reactions of high-titered sera to the crude cell wall and soluble (or membrane) fractions of the 113-20 strain were observed by western blot test. The sera of the patients with BD demonstrated strong bands of approximately 36kDa, 82kDa, and 87kDa in the crude cell wall fractions, and many bands of 80kDa to 150kDa in the membrane fractions, indicating that these proteins are the ones leading the high antibody titers to this bacterium in the sera of patients with BD.

DOI： 10.1111/j.1348-0421.1992.tb02083.x

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Helicobacter pylori was orally inoculated into Mongolian gerbils. The organisms were able to colonize in the gastro-mucosal layer of the gerbils, especially in those gerbils which had mucosal lesions caused by indomethacin treatment. The pathological changes developed by H. pylori infection were restricted to the stomachs, and only slightly inflammatory cells were observed. © 1991, Center For Academic Publications Japan. All rights reserved.

DOI： 10.1111/j.1348-0421.1991.tb01577.x

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DOI： 10.11150/kansenshogakuzasshi1970.64.597

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DOI： 10.12938/bifidus1982.9.1_27

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Zymosan-induced chemiluminescence was investigated in whole blood and in neutrophils: in both, the peak count was frequently elevated in Behçet's disease, and was significantly higher than in healthy controls
similarly the peak time was shorter. There were more uncommon serotypes of Streptococcus sanguis in the oral flora of patients with Behçet's disease. Common serotypes were present in the flora of healthy controls, but not in patients with the disease. The percentage of Strep. sanguis in the oral flora was significantly correlated with the level of chemiluminescence response. Thus infection with uncommon serotypes of Strep. sanguis may play a role in the aetiology of Behçet's disease. © 1990.

DOI： 10.1016/0003-9969(90)90113-O

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Language：Japanese   Publisher：日本歯科衛生学会  

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Language：Japanese   Publisher：(一社)日本ヘリコバクター学会  

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歯ブラシは使用の度に口腔内細菌が付着し、残存する。不潔な歯ブラシを使用することによって、齲蝕や口臭などの原因になることも報告されている。本研究は歯ブラシを清潔かつ衛生的に使用し、管理するという意識の向上に繋げることを目的とした。すなわち、1ヵ月間連続使用した歯ブラシに付着・残存する口腔内細菌数を調べて、同時に毛先の形態変化も確認した。さらに歯ブラシの使用条件や保管方法の違いによる歯ブラシに付着・残存した口腔内細菌数も比較した。1ヵ月間連続使用した歯ブラシには1.0×10^8CFUの口腔内細菌が付着・残存しており、毛先の広がりとともに歯ブラシへの付着・残存口腔内細菌の増加が認められた。また歯ブラシの使用条件による比較では、歯ブラシへの付着・残存していた口腔内細菌数にほとんど差はなく、保管方法ではケースに保管した場合に口腔内細菌が最も多く残存していた。今回の調査から1ヵ月間連続使用した歯ブラシの衛生状態は悪く、毛先の広がりや摩耗が口腔内細菌数の蓄積や残存の増加に影響していると考えられるため、定期的な交換が必要であろう。また湿潤状態が長く続く保管環境では、歯ブラシの付着・残存細菌数は増加していたので、歯ブラシの適切な保管方法が重要であると考える。(著者抄録)

DOI： 10.15053/2016.11.04

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：CLINICAL & EXPER RHEUMATOLOGY  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：CLINICAL & EXPER RHEUMATOLOGY  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：BLACKWELL PUBLISHING  

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Language：Japanese   Publisher：医歯薬出版  

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Other Link： http://search.jamas.or.jp/link/ui/2005286520

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Language：English   Publisher：SOC GENERAL MICROBIOLOGY  

Interleukin 8 (IL8) is usually produced in both epithelial and monocytic cells during bacterial infections, causing inflammation. Helicobacter pylori induces production of IL8 from gastric epithelial cells via its cag pathogenicity island (cag PAI) system, LPS and outer-membrane protein. In some bacteria, heat-shock protein 60 (HSP60) also elicits a strong pro-inflammatory response in cells of the innate immune system. Three recombinant H. pylori HSP60 (rHSP60) proteins of different sizes were produced and one of these was used to raise two monoclonal antibodies (2E7 and 7135). IL8 production was found to be induced in cultured monocytic cells treated with H. pylori cells or rHSP60 proteins, as measured by ELISA, and the amount of IL8 produced was dose-dependent. Pre-incubation of H. pylori cells or rHSP60 preparations with the antibody 2E7 significantly inhibited IL8 production from monocytic cells. These results indicated that HSP60 is closely associated with IL8 production in monocytic cells.

DOI： 10.1099/jmm.0.45871-0

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Language：Japanese   Publishing type：Book review, literature introduction, etc.  

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Language：English   Publisher：SOC GENERAL MICROBIOLOGY  

Contact between Helicobacter pylori and gastric epithelial cells results in activation of NF-kappaB followed by secretion of interleukin (IL)-8. However, host-cell receptor(s) and their ligands involved in H. pylori-related IL-8 production have yet to be fully defined. In this study, the interaction between Toll-like receptors (TLRs), which are host receptors for pathogens involved in the innate immune response, and heat-shock protein (HSP) 60, an immune-potent antigen of H. pylori, was examined during H. pylori-induced IL-8 secretion in vitro. Recombinant H. pylori HSP60 (rHpHSP60) was prepared and added to cultured KATO III human gastric epithelial cells with or without pre-incubation with mouse monoclonal anti-TLR2 or anti-TLR4 antibodies. IL-8 mRNA expression and IL-8 protein release were analysed by Northern blotting and immunoassay. Involvement of NF-kappaB activation was analysed immunocytochemically by anti-NF-kappaB p65 antibody and ammonium pyrrolidinedithiocarbamate (PDTC), an inhibitor of NF-kappaB-mediated transcriptional activation. rHpHSP60 induced IL-8 mRNA expression and IL-8 secretion in a dose-dependent manner in KATO III cells. Anti-TLR2 antibody inhibited rHpHSP60-induced IL-8 secretion by 75%, and anti-TLR4 antibody inhibited it by 30%. rHpHSP60 induced nuclear translocation of NF-kappaB p65, which was inhibited by pretreatment with anti-TLR2 antibody. Treatment with PDTC significantly decreased the secretion of IL-8 induced by rHpHSP60. These findings suggest that H. pylori HSP60 activates NF-kappaB and induces IL-8 production through TLR-triggered pathways in gastric epithelial cells. Thus, it is possible that H. pylori HSP60 and TLR interaction in host cells contributes to the development of gastric inflammation caused by H. pylori infection.

DOI： 10.1099/mic.0.27527-0

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：W B SAUNDERS CO  

DOI： 10.1111/j.1083-4389.2004.00225.x

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Language：English   Publisher：SOC GENERAL MICROBIOLOGY  

To date, two Helicobacter species, Helicobacter pylori and 'Helicobacter heilmanni' (formerly named 'Gastrospirillum hominis'), have been identified from the human stomach. In this study, we observed non-H. pylori-shaped bacteria in gastric tissue sections and successfully isolated them by cultivation. Elongated bacteria were isolated from a patient with gastric-mucosa-associated lymphoid-tissue lymphoma who had been diagnosed as H. pylori-negative by culture, rapid urease test and histopathology in another hospital. The bacteria were grown only on chocolate agar in a CO2 incubator, appeared more than 10 mum long in histological sections, formed small colonies and showed poor growth in a brain heart infusion broth; these characteristics apparently differed from common clinical isolates of H. pylori. However, the bacteria were identified as H. pyloriby PCR of the urease gene, 16S rDNA sequencing, protein profile and antigenicity examined by anti-H. pylori polyclonal antibody. These observations suggest that the H. pylori strain identified in this study may contribute to the development of gastroduodenal diseases in cases judged as H. pylori-negative by ordinary methods.

DOI： 10.1099/jmm.0.05281-0

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Language：Japanese   Publisher：日本細菌学会  

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Language：English   Publisher：SOC GENERAL MICROBIOLOGY  

We have reported previously that heat-shock protein 60 kDa (hsp60) of Helicobacter pylori is an important antigen in the pathogenesis of gastric mucosa-associated lymphoid tissue (MALT) lymphoma. In order to investigate associations with host immune reactions and hsp60 antigen, CD40 ligand (CD40L) expression and cytokine production were analysed following stimulation with hsp60. To provide a clear antigen-driven immune response, peripheral blood mononuclear cells (PBMC) from patients with low-grade MALT lymphoma and gastritis and those from healthy volunteers were stimulated with recombinant H. pylori hsp60 and H. pylori cell lysate in the presence of cytokines (IL4 and granulocyte-macrophage colony-stimulating factor). mRNA expression was also analysed by a cDNA microarray containing 1100 genes. Expression of CD40L on PBMCs of patients with MALT lymphoma was increased by cytokines or by combination with stimulation with hsp60 antigens. The production of IL4 in PBMC cultures was increased in patients with MALT lymphoma; however, production of IFN-gamma was at low levels. DNA microarray analysis indicated increased levels of HLA-DR and integrin mRNAs. In cases of low-grade MALT lymphoma, adaptive immune responses against hsp60 may be enhanced by host factors, such as antigen presentation and T-cell activation, resulting in B-cell proliferation, which can be demonstrated during chronic H. pylori infection.

DOI： 10.1099/jmm.0.05348-0

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：W B SAUNDERS CO  

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Language：English   Publisher：SOC GENERAL MICROBIOLOGY  

Clostridium botulinum types C and D produce a 16 S (500 kDa) toxin that is formed by conjugation of neurotoxin with a non-toxic component (nonTox). The amino acid sequences of type C and D nonTox components are almost identical. In a previous report it was proposed that nonTox is necessary for the effective absorption of the toxin from the small intestine. This suggested the hypothesis that mucosal immunity against nonTox in the small intestine might prevent the absorption of both C- and D-16 S toxins. The nonTox was purified from a mutant strain, (C)-N71, that does not produce neurotoxin. This nonTox or detoxified C-16 S toxin were mixed with adjuvant (a mutant form of heat-labile toxin of Escherichia coli), and inoculated into mice via the nasal or oral route, or both. The mice inoculated nasally four times with nonTox or toxoid produced high levels of antibodies (including IgA) against the immunogens, both in intestinal fluids and sera. When these nonTox-immunised mice were challenged orally with 2 and 20 oral minimum lethal doses (MLD) of C- or D-16 S toxins, the same results were obtained with both C and D; the mice survived after challenge with 2 MLD of either C or D but were killed by 20 MLD of either toxin although the time to death was significantly longer than in the control non-immunised mice. These results indicate that the local anti-nonTox antibodies reduce absorption of both C- and D-16 S toxins from the small intestine. The C-16 S toxoid-immunised mice showed similar behaviour with type D toxin challenge, probably due to the same mechanism, but were protected against 20 MLD of C-16 S toxin.

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Language：English   Publisher：BLACKWELL PUBLISHING ASIA  

Background and aims: Genetic polymorphism of cytochrome P450 (CYP) 2C19 influences the efficacy of Helicobacter pylori eradication therapy with a proton pump inhibitor (PPI) and amoxicillin. However, in triple therapy (PPI plus amoxicillin and clarithromycin), little is known about the impact of CYP2C19 polymorphism, or the use of rabeprazole, which is not well metabolized by CYP2C19. The efficacy of three PPI (omeprazole, lansoprazole, and rabeprazole) in a 1-week triple regimen were compared in relation to CYP2C19 polymorphism.
Method: One hundred and eighty-three patients were randomized to receive one of the following regimens: amoxicillin 500 mg t.i.d., clarithromycin 200 mg t.i.d., and PPI (omeprazole 20 mg, lansoprazole 30 mg, or rabeprazole 10 mg) b.i.d. CYP2C19 polymorphism was analyzed by PCR restriction fragment length polymorphism.
Results: Intention-to-treat-based overall cure rates for omeprazole, lansoprazole or rabeprazole regimens were 83.1% (95% confidence interval (CI): 69-89%), 86.7% (CI: 75-93%), and 76.6% (CI: 64-85%), respectively, without significant difference. The cure rate of the rabeprazole regimen (but not the lansoprazole or omeprazole regimens) tended to be correlated with CYP2C19 genotypes (P = 0.076). In patients with a homozygous extensive metabolizer genotype, the per protocol-based cure rate with rabeprazole (62.5%) was significantly lower than that with lansoprazole (90.0%; P = 0.038).
Conclusion: The overall cure rate of 1-week triple therapy for H. pylori eradication was not significantly different between regimens with omeprazole, lansoprazole or rabeprazole, but the impact of CYP2C19 genetic polymorphism on the cure rate appeared to differ between these PPI. (C) 2002 Blackwell Publishing Asia Pty Ltd.

DOI： 10.1046/j.1440-1746.2002.02790.x

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Language：English   Publisher：BLACKWELL PUBLISHING ASIA  

Background and Aim: In developed countries, reinfection of Helicobacter pylori (H. pylori) after eradication of the bacterium is unusual, while the reinfection rate in developing countries is variable. In this study, we determined the reinfection rate after successful H. pylori eradication in Japan, a country with a high prevalence of H. pylori infection.
Methods: After successful eradication, 377 patients were followed up by endoscopy and urea breath test annually. In reinfected patients, H. pylori strains isolated initially and after reinfection were compared by using random amplification of polymorphic DNA fingerprinting.
Results: H. pylori became positive in four of 337 patients (1.2%) 1 year after eradication and in two of 133 patients (1.5%) 2 years after eradication. One patient experienced an ulcer relapse 2 years after eradication therapy. Random amplification of polymorphic DNA fingerprinting of the isolated strains from four of the six patients showed two had identical strains (at 1 year) while the other two had different strains (one at 1 year and one at 2 years). When infection in the two patients reinfected with identical strains is considered a recrudescence, the true reinfection rate is &lt; 0.8% per patient year.
Conclusions: The reinfection rate after eradication of H. pylori is low in Japan despite the country's high prevalence of H. pylori infection. (C) 2002 Blackwell Science Asia Pty Ltd.

DOI： 10.1046/j.1440-1746.2002.02666.x

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Language：Japanese   Publisher：現代医療社  

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Other Link： http://search.jamas.or.jp/link/ui/2002188827

Language：English   Publisher：The Japanese Society for Lymphoreticular Tissue Research  

A molecular chaperonin in mammals, heat shock protein 60 (HSP60) is constitutively expressed in the mitochondria at a low level and is rapidly up-regulated under stress. However, the role of HSP60 in the lymphoid tissues has not been well clarified. In the present study, expression of HSP60 was examined by flow cytometry and immunohistochemistry in normal peripheral blood mononuclear cells, reactive lymphoid tissues, and malignant lymphomas. HSP60 was found to be present constitutively at low levels in a fraction of resting T cells and most monocytes. The blastic change upon mitogen stimulation induced HSP60 at much higher levels in more T, B and NK cells. In normal lymphoid tissues, HSP60 was expressed preferentially in the cytoplasm of large-sized lymphoid cells and macrophages in the germinal centers and the interfollicular area.<br>In non-Hodgkin lymphomas strong expression of HSP60 was detected in most cases of diffuse large B-cell lymphoma, follicular lymphoma, and grade 3 and NK/T cell lymphoma. No immunostaining was observed in low grade B-cell lymphomas, including follicular lymphoma, grade 1 and B-lymphoblastic lymphomas. HSP60 immunoreactivity was variable in T-cell lymphomas. Intense expression of HSP60 was observed in Reed-Sternberg cells in all cases of Hodgkin lymphoma.

DOI： 10.3960/jslrt.42.25

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Language：English   Publisher：AMER SOC MICROBIOLOGY  

Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is related to Helicobacter pylori infection. Specifically, it has been pointed out that pathogenesis of MALT lymphoma involves the 60-kDa heat shock protein (hsp60). To investigate humoral immune responses to the H. pylori hsp60 in patients with gastroduodenal diseases and patients with MALT lymphoma, the hsp60 of H. pylori was expressed with a glutathione S-transferase fusion protein and was purified (recombinant hsp60). Sera were obtained from H. pylori-positive patients with gastroduodenal diseases (MALT lymphoma, n = 13; gastric ulcer, n = 20; duodenal ulcer, n = 20; gastritis, n = 20) and from H. pylori-negative healthy volunteers (n = 9). Sera from patients with MALT lymphoma were also obtained at two times: before and after eradication therapy. Antibodies to hsp60 and H. pylori were assessed by enzyme-linked immunosorbent assay. The levels of immunoglobulin G (IgG) antibodies to the hsp60 of H. pylori-positive patients with gastroduodenal diseases were significantly elevated compared to those in the controls. The levels of IgG1 antibodies to hsp60 were elevated and correlated with the levels of anti-H. pylori antibodies in patients with MALT lymphoma. Humoral immunity against hsp60 may be important and relevant to gastroduodenal diseases induced by H. pylori infection.

DOI： 10.1128/CDLI.8.6.1056-1059.2001

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Language：English   Publisher：TAYLOR & FRANCIS LTD  

In order to clarify the presence and verotoxin (VT) inhibitory activity of globotriaosylceramide (Gb3) in bovine milk, we analyzed neutral glycosphingolipids (GSLs) from bovine milk and investigated the inhibitory effect of bovine milk Gb3 on the cytotoxicity of VT2. Five species of neutral GSLs, designated as N-1, N-2, N-3, N-4, and N-5, were separated on thin-layer chromatography (TLC). N-1, N-2, and N-3 showed the same mobility as glucosglceramide, lactosylceramide, and Gb3 on the TLC plate, respectively. N-4 and N-5 GSLs migrated below globoside on the TLC plate. N-3 GSL having the same TLC mobility as Gb3 from bovine milk was immunologically identified as Gb3 by monoclonal antibody against Gb3, anti-CD77 monoclonal antibody. Furthermore, the effect of bovine milk Gb3 on VT2-induced cytotoxicity mas investigated. We found that treatment of VT2 with bovine milk Gb3 can reduce the cytotoxic effect of VT2.

DOI： 10.1271/bbb.65.414

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Language：English   Publisher：AMER SOC MICROBIOLOGY  

The relationship between differential susceptibility to hemolytic-uremic syndrome (HUS) and levels of globotriaosylceramide (Gb3) in serum was studied in patients infected with verotoxin-producing Escherichia coli (VTEC). The serum Gb3 levels in patients with HUS were lower than these in diarrheal patients without subsequent HUS or in patients without clinical symptoms, indicating that individuals with a lower content of serum Gb3 show a higher incidence of HUS following VTEC infection.

DOI： 10.1128/JCM.39.2.798-800.2001

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Language：English   Publisher：Blackwell Publishing  

Background and Aim: The genetic polymorphism of cytochrome P450 (CYP) 2C19 has been shown to influence the efficacy of Helicobacter pylori eradication therapy with a proton pump inhibitor (PPI) and amoxicillin (so-called dual therapy). Omeprazole, a widely used PPI, and rabeprazole, a new PPI, are metabolized in different pathways in terms of CYP2C19 genetic polymorphisms. In this study, we compared the efficacy of omeprazole and rabeprazole in a 2-week dual therapy in relation to CYP2C19 polymorphism. Methods: One hundred and ninety-nine patients with peptic ulcer disease were randomly assigned to receive one of the following regimens: 500 mg t.i.d. amoxicillin together with either 20 mg b.i.d. omeprazole or 10 mg b.i.d rabeprazole. The eradication of H. pylori was evaluated by using a bacterial culture and a [13C]-urea breath test at 1-2 months after completion of treatment. Cytochrome P4502C19 polymorphism was analyzed by using polymerase chain reaction-restriction fragment length polymorphism. Results: Intention-to-treat-based cure rates for the omeprazole or rabeprazole regimens were 66.3% (95% CI, 56-75) and 62.4% (95% CI, 52-71), respectively, without significant difference. Cytochrome P4502C19 genetic polymorphism did not influence the cure rates in either of these regimens. We analyzed various factors associated with treatment failure (PPI, CYP2C19 genotype, and smoking habit) by using multiple logistic regression
smoking was the only significant independent factor for treatment failure. Conclusion: Omeprazole and rabeprazole were equally effective in combination with amoxicillin in eradicating H. pylori, irrespective of the PPI used (omeprazole or rabeprazole) and CYP2C19 genetic polymorphism. Smoking significantly decreased the cure rate of H. pylori infection in the dual therapy. © 2001 Blackwell Science Asia Pty Ltd.

DOI： 10.1046/j.1440-1746.2001.02526.x

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Language：Japanese   Publishing type：Book review, literature introduction, etc.  

H. pylori infection induces various humoral and cellular immunities in gastric mucosa. Some reports indicate predominant CD4+ cells infiltrate in H. pylori infected gastric mucosa, and these cells express the T helper 1 phenotype. Local humoral immunity is also induced. Gastric plasma cells produce anti-H. pylori antibodies, however, their protective immunity is not enough to eradicate bacteria in human. We found heat shock protein 60 kDa (hsp60) may be closely associated with pathogenesis in MALT lymphoma. IgG1 antibodies to hsp60 were significantly correlated with the antibodies to H. pylori whole cell in patients with MALT lymphoma. CD40-CD40L dependent B cell proliferation was induced by cytokine and/or hsp60 stimulations in those patients. Cytotoxicity of gastric epithelial cells which is associated with host immunity induced by H. pylori infection is still unclear. We found that lymphocytes from patients with peptic ulcer showed cytotoxicity to gastric cell line HGC-27 in vitro. Cytotoxicity was enhanced by cytokine stimulus to T-lymphocytes and by heat stress and/or patients' antibodies treatment of HGC-27 cells. The pathogenicity of H. pylori may involve not only bacterial virulence factor but also host immunity. Studies of mucosal local immunity will help explain the mechanisms of H. pylori induced gastrodoudenal diseases.

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Language：Japanese  

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Language：English   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

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Language：English   Publishing type：Book review, literature introduction, etc.   Publisher：NATL INST INFECTIOUS DISEASES  

Helicobacter pylori was first cultured in vitro in 1982. This bacterium is a spiral gram negative rod which grows under microaerophilic conditions. The ecological niche is the mucosa of the human stomach which had been thought to be aseptic before the discovery of this bacterium. This organism causes a long-lasting infection throughout a person's life if there is no medical intervention. Numerous persons are infected with the organism around the world, and the rate of infection in Japan is nearly 50% of the population. However, the route of infection remains unclear because the organism has not been isolated from any environment other than several animals. H. pylori is now recognized as a causative agent of gastritis and peptic ulcers. Though gastritis, and especially chronic active gastritis, is observed at least histologically in all persons with H. pylori, peptic ulcers develop in only some infected persons. Specific factors in the host and/or the bacteria are needed for the development of peptic ulcer disease. Furthermore, H. pylori is considered to be related to the development of gastric mucosa-associated lymphoid tissue (MALT) lymphoma, especially those of low grade. Also, H. pylori infection is a major determinant for initiating the sequence of events leading to gastric cancer. In some patients with low-grade gastric MALT lymphoma, the eradication of H. pylori led to a regression of lesion. Gastric cancer has been induced in Mongolian gerbils with long-term H. pylori infection. The combinations of drugs, which consist of an antisecretory agent (acid-supressing agent) and antimicrobial agents, are used for the eradication of the organism. Eradication therapy is recommended at least for patients with peptic ulcers.

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Language：English   Publisher：BRITISH MED JOURNAL PUBL GROUP  

Background-Development of gastric mucosa associated lymphoid tissue (MALT) lymphoma is thought to be closely associated with host immune reactions to Helicobacter pylori.
Aim-To investigate humoral immune responses in patients with MALT lymphoma to antigens shared by PI pylori and human gastric epithelial cells. IC
Methods-Sera were obtained from H pylori positive patients with MALT lymphoma (n = 11) or other gastroduodenal diseases (peptic ulcer, n = 40; nonulcer dyspepsia, n = 20) and from H pylori, negative healthy control subjects (n = 10). Antibodies to HGC-27 human gastric epithelial cells and human recombinant heat shock protein (Hsp) 60 were examined using an enzyme linked immunosorbent assay (ELISA) and immunoblotting.
Results-Antibody titres to HGC-27 cells were significantly elevated in H pylori positive patients with MALT lymphoma when compared with titres in patients with other gastroduodenal diseases and in healthy subjects. Immunoblotting of sera from patients with MALT lymphoma often detected a band with a molecular mass corresponding to Hsp60, and both ELISA and immunoblotting showed elevated antibody titres to the recombinant human Hsp60. Antigenic similarity between Hsp60 and H pylori HspB was documented by immunoblotting experiments.
Conclusions-Autoantibodies reactive with host gastric epithelial cells are often increased in MALT lymphoma, and Hsp60 is a major target antigen. Immune responses induced by immunological cross reactivity between H pylori HspB and human Hsp60 in gastric epithelium may be involved in the development of MALT lymphoma.

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Language：Japanese   Publisher：(株)最新医学社  

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Language：Japanese   Publisher：日本細菌学会  

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Language：Japanese   Publisher：日本細菌学会  

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Language：Japanese   Publisher：日本細菌学会  

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Language：English   Publisher：MARCEL DEKKER INC  

Clostridium botulinum strains produce seven immunologically distinct neurotoxins (NTX), type A to G. The NTXs associate with nontoxic components in cultures, and become large complexes with three forms (128, 16S, and 19S) designated progenitor toxins. The 12S toxin consists of a NTX and a nontoxic component having no hemagglutinin (HA) activity (described here as non-toxic non-HA, NTNH), and the 168 and 19S toxins are formed by conjugation of the 12S toxin with HA. Based on the genetic- and protein chemical-analyses of the progenitor toxins it became clear that 1) the HA consists of four subcomponents namely HA1 (Mr. 33 similar to 35 kDa), HA2 (15 similar to 17 kDa), HA3a (19 similar to 23 kDa), and HA3b (52 similar to 53 kDa), 2) the genes coding for NTX (ntx), NTNH (ntnh), and HA (ha) occur as a cluster; ha lies just upstream of ntnh, and ntx lies just downstream of ntnh, 3) ha is in the opposite orientation from that of ntnh and ntx, 4) ha consists of three ORFs (ha1, ha2, and ha3), 5) the gene product (70 kDa) of ha3 is split into HA3a and HA3b after translation, 6) HA3a is cleaved at several different sites of its N-terminal region to form proteins with slightly different Mrs, 7) the 19S toxin is a dimer of 16S toxin crosslinked by HA1, 8) The NTNHs of type A to D 12S toxins have a cleavage(s) on their N-terminal regions. It also became clear that the HA prays an important role when the 16S land 19S) toxin is absorbed from the small intestine.

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Language：English   Publisher：ACADEMIC PRESS LTD  

Eleven strains of Clostridium butyricum collected from different sources were analysed by both sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and pulsed-field gel electrophoresis (PFGE). The strains could be classified into four groups based on their banding profiles of the proteins extracted from the cells on SDS-PAGE. Group I consisted of seven strains, and these strains were further divided into five subgroups by PFGE. The strains belonging to groups II, III, and IV on SDS-PAGE were also classified into the same II to IV groups by PFGE. These data indicate that grouping of the strains of C. butyricum can be performed by employing both SDS-PAGE and PFGE. (C) 1998 Academic Press.

DOI： 10.1006/anae.1998.0163

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Language：English   Publisher：AMER SOC MICROBIOLOGY  

Helicobacter pylori is a major etiological agent in gastroduodenal disorders. The adhesion of H. pylori to human gastric epithelial cells is the initial step of H. pylori infection. Inhibition of H, pylori adhesion is thus a therapeutic target in the prevention of H, pylori infection. Experiments were performed to evaluate the effect of rebamipide, a novel antiulcer agent, on H. pylori adhesion to gastric epithelial cells. MKN-28 and MKN-45 cells, derived from human gastric carcinomas, were used as target cells. Ten H. pylori strains isolated from patients with chronic gastritis and gastric ulcer were used in the study. We evaluated the effect of rebamipide on H. pylori adhesion to MKN-28 and MKN-45 cells quantitatively using our previously established enzyme-linked immunosorbent assay. The adhesion of H. pylori to MKN-28 and MKN-45 cells was significantly inhibited by pretreatment of these cells with 100 mu g of rebamipide per mi. However, the adhesion was not affected by the pretreatment of H. pylori with rebamipide. On the other hand, the viabilities of H. pylori, MKN-28 cells, and MKN-45 cells were not affected by rebamipide, Our studies suggest that rebamipide inhibits the adhesion of H. pylori to gastric epithelial cells.

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Language：Japanese   Publisher：栄研化学(株)  

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Language：Japanese   Publisher：診断と治療社  

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Other Link： http://search.jamas.or.jp/link/ui/1998108533

Language：English   Publisher：SOC GENERAL MICROBIOLOGY  

Binding of the purified type C 7S (neurotoxin), 12S and 16S botulinum toxins to epithelial cells of ligated small intestine or colon of the guinea pig (in vivo test) and to pre-fixed gastrointestinal tissue sections (in vitro test) wasanalysed. The 165 toxin bound intensely to the microvilli of epithelial cells of the small intestine in both in vivo and in vitro tests, but did not bind to cells of the stomach or colon. The neurotoxin and 12S toxin did not bind to epithelial cells of the small intestine or to cells of the stomach or colon. Absorption of the toxins was assessed by determining the toxin titre in the sera of guinea pigs 6-8 h after the intra-intestinal administration of the toxins. When the 165 toxin [1 x 10(5) minimum lethal dose (MLD)] was injected, 200-660 MLD ml(-1) was detected in the sera, whereas when the 12S toxin (2 x 10(5) MLD) or 7S toxin (2 x 10(5) MLD) was injected, little toxin activity was detected in the sera. Therefore, the haemagglutinin of type C 16S toxin is apparently very important in the binding and absorption of botulinum toxin in the small intestine.

DOI： 10.1099/00221287-143-12-3841

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Language：Japanese   Publisher：共立出版  

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Other Link： http://search.jamas.or.jp/link/ui/1998021783

Language：Japanese  

DOI： 10.11477/mf.1542903244

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Language：Japanese   Publishing type：Book review, literature introduction, etc.  

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Language：Japanese   Publishing type：Book review, literature introduction, etc.   Publisher：PHARMACEUTICAL SOC JAPAN  

Helicobacter pylori is a gram negative spiral bacterium, which is colonized in human gastric mucosa. This organism was first reported in Australia, 1983. Now H. pylori has been recognized to cause chronic active gastritis, and is a major factor in the pathogenesis of duodenal ulcer and gastric ulcer. It was also reported that its infection is a risk factor for both MALT (mucosa associated lymphoid tissue) lymphoma and gastric adenocarcinoma.
H. pylori has many virulence factors. Urease is one of the most important colonization and virulence factors studied. Ammonia made by urease protects the organisms from gastric low pH, and is toxigenic to gastric epithelial cells. Vacuolating toxin and CagA proteins are thought to be pathogenic agents especially for causing gastric and duodenal ulcers. Neutrophil reactions against the bacteria, and the abnormal immunological reactions are also considered to cause the damage of gastric epithelial cells, although the detailed pathogenic mechanisms are still not clear.
In developing countries, infection by H. pylori is established in childhood, and the organisms can be identified in the mouth and feces, indicating its infection through water.
The infected organisms can be eradicated by administration with proton pump inhibitor and one or two antibiotics. This may provide an useful therapeutic means to the patients especially with recurrent ulceration and MALT lymphoma.

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Language：English   Publisher：WILEY-LISS  

Helicobacter pylori is a major etiologic agent in gastroduodenal disorders. In this study, immunoglobulin A (IgA) antibodies to H. pylori were estimated in serum and gastric juice specimens from patients with gastritis and peptic ulcers using antibody capture enzyme-linked immunosorbent assays (ACELISAs). The antibody titers of the ACELISAs are independent of the antibody concentration and reflect the ratio of H. pylori-specific IgA to total IgA. The ratio is stable, although the antibody concentration fluctuates in gastric juice. Using the ACELISAs it was possible to evaluate quantitatively not only serum IgA (SR-IgA) antibodies but also secretory IgA (SC-IgA) antibodies in gastric juice. There were significant differences between the patients and control group in the SR-IgA and SC-IgA ACELISAs. Furthermore, the ACELISAs made it possible to compare between SR-IgA antibodies in serum and SC-IgA antibodies in gastric juice. In all patients, the ratios of H. pylori-specific IgA were higher in gastric juice than in serum. These results suggest that H. pylori SC-IgA antibodies are mainly produced by the local immune response in the gastric mucosa. Our studies indicate that ACELISA is well suited for the analysis of local immune response in mucosa. (C) 1996 Wiley-Liss, Inc.

DOI： 10.1002/(SICI)1098-2825(1996)10:2<74::AID-JCLA3>3.0.CO;2-L

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Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

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Language：English   Publisher：Center For Academic Publications Japan  

Capture enzyme-linked immunosorbent assays (ELISAs) were developed to detect immunoglobulin G and M antibodies to group A streptococcal (GAS) antigens, streptolysin O, streptokinase, and group A carbohydrate. The sensitivities and the specificities of the IgM capture ELISAs to each GAS antigen were high enough to distinguish the patients with GAS infections (diagnosed as GAS pharyngitis or scarlet fever) from the control groups (healthy people and patients with pharyngitis from whom GAS could not be isolated). On the other hand, the specificities of the IgG capture ELISAs were not very effective in diagnosis of GAS infections. When the capture ELISA and an indirect ELISA detecting IgM antibodies to group A carbohydrate were compared, false-positive reactions due to rheumatoid factor occurred in the indirect ELISA, but did not occur in the capture ELISA. These results indicate that the capture ELISA works better than the indirect ELISA in detecting the IgM antibody, and that the IgM capture ELISA to GAS antigen provides a rapid and highly reliable serodiagnosis for GAS infections employing only a single serum.

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The genetic control of Streptococcus sanguis antigen response was studied. Mice sensitized with inactivated S. sanguis organisms antigen-injected at the base of the tail developed footpad swelling. Those with an I-Ak,q,r region of H-2 showed a strong footpad response, whereas those with an I-Ab,d,s region showed a weak response to S. sanguis cell wall antigen. Footpad response was mediated by CD4+, 8- T cells by using in vitro monoclonal antibody treatment. Similar evidence of genetic control was obtained with an in vitro T cell proliferation assay. However, quantitation of antibodies against S. sanguis showed that antibody production was not controlled by H-2. These results indicated that both in vivo footpad swelling and in vitro T cell proliferation responses were functions of helper (CD3+, 4+, 8-) T cells and controlled by the I-A region of H-2. © 1993.

DOI： 10.1016/0923-1811(93)90765-H

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Language：English   Publisher：W B SAUNDERS CO  

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Language：English   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Uncommon serotypes were tested for their ability to induce aggregation in platelet-rich plasma. Both uncommon and common serotypes induced platelet aggregation in rabbit platelet-rich plasma, but serotonin release was higher with the uncommon serotypes. Aggregation at ATP release varied between uncommon and common serotypes. With human platelet-rich plasma, only uncommon serotypes showed aggregation. Differences in serotype selectivity and the rate of aggregation were noted among platelet donors. About half of the patients with Behcet's disease and 30% of health controls showed platelet aggregation. Plasma from non-responder patients with Behcet's disease inhibited aggregation of healthy responder platelets within 20 min. Thus selective binding of uncommon serotypes of Strep. sanguis to plateletes might cause the vasculitis in Behcet's disease.

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Language：English   Publisher：Informa Healthcare  

Various strains of Streptococcus sanguis adhered to the buccal epithelial cells from both healthy controls and patients with Behçet's disease (BD). Almost all of them strongly adhered to the epithelial cells from patients with BD, whereas smaller numbers of the bacteria were observed on the cells from healthy controls. This phenomenon was especially clear when uncommon serotypes (clinical isolates) were used. Two or more peaks were observed in the distribution of the epithelial cells from patients with BD in the adherence test. In contrast, a single peak was observed in the distribution of the epithelial cells from healthy controls. Cytological differences of the epithelial cells between both groups were not observed in the microscopic image analysis. All the strains of S.sanguis showed agglutination of rabbit erythrocytes, but not agglutination of sheep, horse, swine and duck erythrocytes. Line cell adherence of S.sanguis uncommon serotypes was greater than that of common ones. All strains of S.sanguis showed a reactivity with aggregated human β2-microglobulin, but not with the monomer. The different level of reactivity to aggregated β2-microglobulin was recognised between uncommon and common serotypes. The reaction between aggregated β2-microglobulin and S.sanguis is one of human-bacterium interaction which should be considered in studies of BD. ©1990 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted.

DOI： 10.3109/08910609009140254

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