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Copyright of HNO is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of HNO is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background The clinical management of Helicobacter pylori infected patients who failed standard eradication therapies remains a challenge. Aim To investigate the efficacy of rifabutin-based triple therapy and high-dose dual therapy for rescue treatment of H. pylori, and the correlation between cytochrome P450 2C19 (CYP2C19) polymorphisms and treatment outcome. Methods Patients infected with H. pylori resistant to both metronidazole and clarithromycin ( n = 145) were randomized to either esomeprazole 20 mg, rifabutin 150 mg and amoxicillin 1 g, each given b.d. for 7 days (ERA), or to omeprazole 40 mg and amoxicillin 1000 mg, each given t.d.s. for 14 days (OA). Crossover therapy was offered in cases of persistent infection. CYP2C19 polymorphisms were determined by polymerase chain reaction restriction fragment length polymorphism. Results Intention-to-treat and per-protocol eradication rates were: ERA 74% (62.4–83.6) and 78% (66.7–87.3); high-dose OA 70% (57.5–79.7) and 75% (62.5–84.5). Crossover therapy was successful in seven of 10 patients with ERA and in eight of 10 patients with OA. Premature discontinuation of treatment occurred in 2% and 5% of patients, respectively. There was only a non-significant trend to lower eradication rates in homozygous extensive metabolizers. Conclusions Triple therapy with esomeprazole, rifabutin and amoxicillin and high-dose omeprazole/amoxicillin are comparable and effective and safe for rescue therapy of H. pylori regardless of the patient's CYP2C19 genotype. [ABSTRACT FROM AUTHOR]

Acidic noncaspase proteases-like cathepsins have been introduced as novel mediators of apoptosis. A clear role for these proteases and the acidic endolysosomal compartment in apoptotic signalling is not yet defined. To understand the role and significance of noncaspases in promoting and mediating cell death, it is important to determine whether an intersection of these proteases and the caspase pathway exists. We recently identified the endolysosomal aspartate protease cathepsin D (CTSD) as a target for the proapoptotic lipid ceramide. Here, we show that tumor necrosis factor (TNF)-induced CTSD activation depends on functional acid sphingomyelinase (A-SMase) expression. Ectopic expression of CTSD in CTSD-deficient fibroblasts results in an enhanced TNF-mediated apoptotic response. Intracellular colocalization of CTSD with the proapoptotic bcl-2 protein family member Bid in HeLa cells, and the ability of CTSD to cleave directly Bid in vitro as well as the lack of Bid activation in cathepsin-deficient fibroblasts indicate that Bid represents a direct downstream target of CTSD. Costaining of CTSD and Bid with Rab5 suggests that the endosomal compartments are the common ‘meeting point’. Caspase-9 and -3 activation also was in part dependent on A-SMase and CTSD expression as revealed in the respective deficiency models. Our results link as novel endosomal intermediates the A-SMase and the acid aspartate protease CTSD to the mitochondrial apoptotic TNF pathway.Cell Death and Differentiation (2004) 11, 550-563. doi:10.1038/sj.cdd.4401382 Published online 23 January 2004 [ABSTRACT FROM AUTHOR]

: This study aimed to investigate the effectiveness of a one-week triple therapy with esomeprazole, clarithromycin and metronidazole for eradication of Helicobacter pylori infection in the absence of antimicrobial resistance. : Patients testing positive for H. pylori susceptible to metronidazole and clarithromycin ( E-test) were randomized to receive a one-week regimen with either esomeprazole 2 × 20 mg or omeprazole 2 × 20 mg in combination with clarithromycin 2 × 250 mg and metronidazole 2 × 400 mg. Follow-up endoscopy with histology and culture and/or rapid urease test was performed 4–8 weeks after the end of treatment. : Eighty patients were randomized. Helicobacter pylori infection was cured in 38/39 patients of the esomeprazole group and 31/33 patients of the omeprazole group (per protocol 97.4% (95% confidence interval [CI], 86.2–99.9), 93.7% (95% CI, 79.2–99.2), P = 0.59); intention-to-treat 90.4% (95% CI: 77.4–97.3), 81.6% (95% CI: 65.7–92.3), respectively. No major side effects occurred. Minor side effects occurred in eight (20%) and six (23%) patients during esomeprazole and omeprazole therapy, respectively. Post-treatment susceptibility testing revealed resistance to both metronidazole and clarithromycin in two of the three patients who failed. : We conclude that esomeprazole, clarithromycin and metronidazole as one-week triple therapy is effective for eradication of H. pylori in the absence of antimicrobial resistance. [ABSTRACT FROM AUTHOR]

Background & Aim: Esomeprazole-based triple therapy with clarithromycin and amoxicillin has recently been shown to be effective for H. pylori eradication. The aim of this study was to determine the efficacy of a 7-day triple therapy with esomeprazole, clarithromycin and metronidazole for eradication of H. pylori in the absence of antimicrobial resistance. Patients & Methods: Patients infected with H. pylori sensitive to metronidazole and clarithromycin (E-Test) were randomized to one-week triple therapy with either esomeprazole 2 × 20 mg, clarithromycin 2 × 250 mg and metronidazole 2 × 400 mg, (ECM), or omeprazole 2 × 20 mg, clarithromycin 2 × 250 mg and metronidazole 2 × 400 mg (OCM). Control endoscopy with histology and culture and/or rapid urease test was performed 4 to 8 weeks after the end of treatment. Results: 76 patients were randomized. So far, 63 patients returned to control examinations and were analyzed (23 females, 27 peptic ulcer disease, median age 43 years). All 63 patients completed their therapy as scheduled. There were no major side effects leading to discontinuation of treatment. Minor side effects occurred in 8 (23.5%) and 4 (13.8%) patients during ECM and OCM therapy, respectively. So far, 33 of 34 patients of the ECM group (97%) and 27 of 29 patients of the OCM group (93%) were cured of H. pylori infection. Post-treatment antimicrobial susceptibility testing showed resistance to both metronidazole and clarithroymcin in 2 of 3 patients. Conclusion: Our preliminary data suggest a high efficacy of esomeprazole-based triple therapy with clarithromycin and metronidazole for eradication of H. pylori in the absence of antimicrobial resistance. [ABSTRACT FROM AUTHOR]

Background & Aim: Failure of primary Helicobacter pylori therapy may lead to a high rate of post-treatment resistance to both metronidazole (MET) and clarithromycin (CLA). Due to the lack of acceptance of quadruple therapy in Germany the search for alternative salvage therapies is warranted. The aim of this study was to compare the efficacy and tolerability of a rifabutin-containing triple therapy with that of a high-dose dual therapy in eradicating H. pylori resistant to both MET and CLA. Patients & Methods: Patients with at least one previous treatment of H. pylori therapy and documented resistance to both MET & CLA (ETest) were randomized to receive either esomeprazole 2 × 20 mg, rifabutin 2 × 150 mg, and amoxicillin 2 × 1 g for 7 days (ERA), or omeprazole 3 × 40 mg and amoxicillin 3 × 1 g for 14 days (HD-OA). Control examinations were conducted 4 to 6 weeks after end of therapy. In case of persistent H. pylori infection, a cross-over therapy with the alternative regimen was performed. Results: So far, 76 patients were randomized, of those 66 have so far completed. 29 of 35 patients became H. pylori-negative after ERA therapy (82.9%), and 23 of 31 after HD-OA therapy (74.2%). Both regimens were well tolerated. Only one patient of the HD-OA group discontinued treatment prematurley due to side effects. 4 of 5 patients who failed HD-OA therapy received cross-over ERA therapy, all 4 became H. pylori-negative. 5 of 6 patients who failed ERA therapy received cross-over HD-OA therapy, 2 of them returned to the second control examination, one became H. pylori-negative. Conclusion: Our data suggest a comparable high efficacy of a 7-day triple therapy containing esomeprazole, rifabutin and amoxicillin and of the high-dose omeprazole/amoxicillin dual therapy in eradicating H. pylori resistant to both metronidazole and clarithromycin. [ABSTRACT FROM AUTHOR]

Helicobacter cystein-rich protein A (HcpA) was recently shown by us to be capable of inducing high levels of interferon-γ (IFN-γ) from naive murine splenocytes. IFN-γ is the signature cytokine of the Th1 subset of helper T cells which are commonly held responsible for inflammatory response in Helicobacter pylori infected patients. We could demonstrate that IFN-γ secretion induced by H. pylori or HcpA is dependent on IL-12 secretion by antigen-presenting cells (APCs). Inhibition of IL-12 by application of anti-IL-12 antibodies leads to a decrease in total levels of IFN-γ produced by murine splenocytes. This suggests a common pathway for inducing a Th1 directed immune response for H. priori and HcpA by activating APCs as the main source of IL-12. These results could be confirmed by depletion experiments where in absence of APCs dramatically reduced IFN-γ levels were obtained. The same was also true for splenocytes depleted of NK cells indicating that they are the main producer of IFN-γ in response to H. pylori or HcpA. In silico molecular analysis of HcpA showed a pattern of cysteins and predicted helices strongly resembling HcpB, which is known to have a modular structure of four motifs of two adjacent helices linked together by disulphide bonds. We studied the importance of these motifs in HcpA and found that the carboxyterrninal part is associated with IFN-γ-secretion. A predicted coiled-coil segment at the carboxyterminus could be further shown to be relevant for the ability of HcpA to induce high levels of IFN-γ. Our recent work confirmed the immunostimulatory effects of HcpA and extents our knowledge of its molecular mechanism of action by the identification of distinct regions of HcpA to be responsible for its IFN-γ-inducing capacity. [ABSTRACT FROM AUTHOR]

Objective: The cag PAI is considered to be one of the major virulence determining factors of H. pylori. Although the cagA gene is conventionally used as a surrogate marker for the presence of the PAI, several studies have limited the use of cagA PCR as a suitable marker. In order to determine the presence of the whole PAI we developed a PCR-based system to analyse the PAl in different clinical H. pylori strains. Methods: Based on the published sequence of H. pylori 26695 a PCRbased amplification system was developed to cover the whole PAl with overlapping amplicons of 1000-1200 bp in size. 14 clinical Hp isolates that were all shown to induce IL-8 in AGS cells were chosen to evaluate this assay system. The obtained PCR-product were visualised by gel electrophoresis. Results: Using 31 primer pairs we could successfully amplify the whole PAI in 12 of 14 strains. In two strains there were no amplicons obtained at the N- and C-terminus of HP0547, but the rest of the PAI was completely amplified. Comparison of the PCR products revealed that the PAl was highly conserved because nearly all amplicons were of equal size. When PCR products were absent with a given primer it was possible to amplify the missed region with upstream and downstream primers. This was tree for HP0527 and HP0544 that could only be amplified by long-distance PCR because of multiple gene rearrangements or sequence variations, respectively. Conclusions: Although there were differences detectable with respect to sequence variations (primer mismatch) and amplicon size in some regions the genetic variability seems to be limited. Work is in progress to determine now the sequence of the whole PAI of all 14 H. pylori strains to compare the open reading frames in more detail. [ABSTRACT FROM AUTHOR]

Objective: Helicobacter pylori CagA protein has been shown to be translocated into gastric epithelial cells and after phosphorylation to be essential for the induction of the so-called "hummingbird" phenotype. Phosphorylafion has been demonstrated to occur at tyrosine residue 972 (Y-972). Several phosphorylation motifs have been identified so fan In order to correlate these motifs with the induction of the hummingbird phenotype in AGS cells we determined the cagA Y-972 motifs in different Helicobacter pylori isolates. Methods: The complete cagA gene was amplified by PCR and sequenced from 60 H. pylori strains obtained from different clinical entities (duodenal ulcer, gastric ulcer, gastric carcinoma, and MALToma) and the Y-972 motifs were determined. AGS cells were then infected with H. pylori strains representing each motif and analysed for the induction of the hummingbird phenotype. Results: The most frequent motif found was a single SVSPEPIY in 18 strains, a single sequence repeat in 9 isolates, and one strain with 5 repeats, followed by 16 strains with a single SASPEPIY, 6 with a single repeats, and one with 3 repeats. Two strains showed a single SANHEPIY, and one 4 repeats. The motifs SASSEPIY, and SASPEEPIY were only found in one strain, respectively. 4 strains had no Y-972 motif. From each motif one strain was randomly chosen to determine the hummingbird phenotype and only the strain Ly27a harbouring 4 repeats of the motif SANHEPIY was found positive. Conclusions: The mere PCR-based determination of Y-972 does not necessarily correlate with the sequence-predicted hummingbird phenotype and supports the view that additional bacterial factors may contribute to the full virulence phenotype. Work is in progress to test all isolates for the hummingbird phenotype and, in addition, for IL-8 induction and to correlate PAI function with genotype of theY-972 motif and CagA function. [ABSTRACT FROM AUTHOR]

Presents a correction to the omission of Paul Saftig and Christoph Peters as co-authors of a paper "Cathepsin D targeted by acid sphingomyelinase-derived ceramide" published in the previous issue of the "EMBO Journal".