Vaccine development against infection with Helicobacter pylori

Infection with Helicobacter pylori, is one of the most prevalent infections world-wide, where approximately 50% of adults in the developed world and over 90% of inhabitants in the developing world are infected. Chronic infection with H. pylori is the cause of gastritis, peptic ulcer disease and is a risk factor for gastric adenocarcinoma. Recent studies have demonstrated the suitability of an immunization strategy in the prevention and treatment of H. pylori infection, and the potential for management of disease. Mucosal administration of purified recombinant sub-unit proteins of H. pylori, together with a mucosal adjuvant, has identified urease to be highly efficacious in prophylactic and therapeutic animal model studies, and show partial therapeutic activity in humans. Several other antigens are also effective, and the recent sequencing of the H. pylori genome has led to an intensive effort in antigen discovery. Other research has centered on the identification of novel approaches for delivery, and the immunological mechanisms underlying protective immunity. In this review, preclinical data and the results of early-stage clinical trials and directions for future research on Helicobacter vaccines are described.     

Gastric diffusion of antibiotics used against Helicobacter pylori

Only a few pharmacological studies have been carried out on men and guinea pigs to determine the gastric diffusion of antibiotics, which are active against Helicobacter pylori. The results of these studies have been analysed in considering the physicochemical nature, the mode of administration, the way of gastric diffusion (topic and/or systemic) and the pharmacological interactions. The correlation of these pharmacokinetic results with those obtained in clinical trials is difficult because of the heterogeneity of the pharmacological and pharmacodynamic data. The absence of a convenient and suitable animal or in vitro study model renders further standardized pharmacokinetic studies in infected man and at steady state necessary.     

Direct activity of recombinant human lactoferrin against Helicobacter pylori

We report the activity of recombinant human lactoferrin against Helicobacter pylori. Lactoferrin exerted a time- and dose-dependent action against 8 of the 13 clinical isolates of H. pylori tested in vitro. These results highlight a potential therapeutic use for lactoferrin against H.pylori infection.     

Relevance of Helicobacter pylori infection in the development of gastric tumors

The efficacy of a 6-week rehabilitation program was evaluated in 100 consecutive patients, age 15-42 years, with acute anterior cruciate ligament (ACL) injury. Arthroscopy revealed associated lesions in 82% of the patients. Except for resections on menisci with large and unstable lesions, no surgery was performed. The patients were randomly assigned to supervised training or self-monitored training after instruction. RESULTS: At the 6-week follow-up there was no difference between the groups with regard to pain at rest, pain during walking, or experience of giving-way episodes, Tegner activity level of Lysholm knee score. Only 2 of the 100 patients were observed without joint mobility restriction. The only significant difference between the groups was the improvement of muscle function in men in the supervised training group. Conclusion: Six weeks' rehabilitation is too short a time period from original injury to obtain normal mobility and restored knee function.     

Production of a monoclonal antibody against the 128 kDa (CagA) protein of Helicobacter pylori

We report a case of herpes simplex encephalitis in which the patient was repeatedly examined by magnetic resonance imaging (MRI) and single photon emission computed tomography (SPECT). The patient was a 36 year-old woman who had been transferred to our institution 6 days after the onset of symptoms with mild consciousness disturbance, nuchal rigidity, and high fever. Cerebrospinal fluid examination revealed an elevated mononuclear cell count with normal sugar concentration. Intravenous aciclovir was started 7 days after the onset of symptoms. The initial plain computed tomography (CT) scans did not reveal any abnormal findings, but contrast enhanced CT the next day showed a slight enhancement effect around the affected middle cerebral artery. Serial MRI showed the initial high intensity lesion starting on the medial cortex of the temporal lobe, then spreading to throughout the entire temporal lobe. During this period SPECT showed a marked, broad hot spot in the temporal lobe. The medial temporal lobe was high density on the CT 15 days after the onset. As the encephalitic lesion spread more laterally, the hot spot on SPECT moved laterally and then decreased in activity. Eleven weeks after the onset, the MRI showed intracerebral vacuolization of the lesion and it appeared as a wide cold spot on SPECT. The cause of the hot spot seen in the acute period was thought to be vasoparalysis of the affected area rather than breakdown of the blood-brain barrier, or impaired washout of the isotope, because the SPECT images after acetazolamide administration showed the cold spot even in the subacute phase.     

Helicobacter pylori: challenges for the paediatrician

During the last 15 years, a great body of knowledge about Helicobacter pylori has been accumulated. Much, however, remains to be studied, particularly in relation to children. The vast majority of infections occur in childhood. It is towards children that any widespread screening, prevention or treatment strategies would need to be aimed. In this annotation, we discuss the epidemiology, symptomatology, diagnosis and treatment of H. pylori in children.     

Novel bismuth compounds have in vitro activity against Helicobacter pylori

We examined the in vivo effects of ONO-5046xNa, a specific neutrophil elastase (NE) inhibitor, on the growth of 2 non-small cell lung cancer cell lines, EBC-1 and PC-3, transplanted into severe combined immunodeficiency (scid) mice. The daily intraperitoneal injection of ONO-5046xNa (50 mg/kg/day) completely suppressed the tumor growth in EBC-1, a human squamous carcinoma cell line which produces immunoreactive NE. By contrast, in PC-3, a human adenocarcinoma cell line which is unable to produce immunoreactive NE, the ONO-5046xNa treatment caused delayed growth of the tumor. These findings suggest that ONO-5046xNa may have a clinical role in preventing the growth of human non-small cell lung cancer.     

Systemic immunization with urease protects mice against Helicobacter pylori infection

The ability of systemic immunization to induce protection against Helicobacter pylori infection has been evaluated in a mouse model. It was observed that if appropriate formulations and adjuvants were used such immunization elicited in outbred Swiss mice levels of protection similar or better than those induced by the oral route in the presence of cholera toxin or Escherichia coli heat labile toxin. Recombinant urease mixed with adjuvants, which induced strong Th1 and Th2 responses elicited better protection than urease mixed with adjuvants which induced a predominant Th2 type response only. These experiments demonstrate the feasibility of parenteral immunization against H. pylori and suggest that an appropriate balance between Th1 and Th2 type responses is required to achieve complete protection.     

Suggestion against an oral-oral route of transmission for Helicobacter pylori infection: a seroepidemiological study in a rural area

In this study the seroepidemiology of H. pylori and Epstein-Barr virus was compared in the same setting. A sample of 705 subjects completed a structured questionnaire. A serum sample was drawn from each subject and assayed for H. pylori IgG. Antibodies to Epstein-Barr virus were determined in a subgroup of 466 subjects. Cross-tabulation of data showed that 274 (58.8%) subjects were seropositive and 20 (4.3%) were seronegative for both infections, 17 (3.6%) were seropositive for H. pylori, and 155 (33.3%) were seropositive for Epstein-Barr virus (odds ratio=2.08, 95% confidence interval: 1.008-4.3). Nevertheless, the agreement between H. pylori and Epstein-Barr virus seropositivity was no better than chance (kappa=0.067) and the age-related seroprevalence curve of Epstein-Barr virus was similar in H. pylori seropositive and seronegative subjects. Furthermore, multiple logistic regression analysis did not show any risk factor shared by both infections. The findings of this study do not support the hypothesis that H. pylori and Epstein-Barr virus share a common mode of transmission. It can be speculated that the oral cavity may not be an important reservoir for H. pylori.     

Absence of a post-antibiotic effect (PAE) of beta-lactams against Helicobacter pylori NCTC 11637

PURPOSE: The study contained herein was undertaken to demonstrate that mesenteric desmoid tumors can cause significant symptoms other than by a mass effect and that surgery can be effective in treating these symptoms. METHODS: The medical records of patients with intra-abdominal desmoid disease in the David G. Jagelman Inherited Colorectal Cancer Registry were reviewed. Four cases are described in which intramesenteric desmoid tumors adjacent to the bowel caused mucosal ischemia in patients with familial adenomatous polyposis. RESULTS: In one patient with an ileorectal anastomosis, this was manifest by multiple small-bowel strictures and treated by multiple strictureplasties. The other three patients had ileal pouches and presented with bleeding and pain from mucosal ulceration. All pouches needed to be removed. CONCLUSION: Intra-abdominal desmoid tumors may cause problems other than by mass effect. Patients with familial adenomatous polyposis and symptoms suggestive of desmoid disease but with no detectable mass should not be denied surgery.     

Characterization of a Helicobacter pylori neutrophil-activating protein

Antibody-blocking studies have demonstrated the role of CD6 in thymocyte-thymic epithelial (TE) cell adhesion. Here we report that CD6 expressed by COS cells mediates adhesion to TE cells and that this interaction is specifically blocked with an anti-CD6 monoclonal antibody (mAb) or with a mAb (J4-81) that recognized a TE cell antigen. We isolated and expressed a cDNA clone encoding this antigen and show that COS cells transfected with this cDNA bind a CD6 immunoglobulin fusion protein (CD6-Rg). This antigen, which we named ALCAM (activated leukocyte-cell adhesion molecule) because of its expression on activated leukocytes, appears to be the human homologue of the chicken neural adhesion molecule BEN/SC-1/DM-GRASP. The gene was mapped to human chromosome 3q13.1-q13.2 by fluorescence in situ hybridization of cDNA probes to metaphase chromosomes. We prepared an ALCAM-Rg fusion protein and showed that it binds to COS cell transfectants expressing CD6, demonstrating that ALCAM is a CD6 ligand. The observations that ALCAM is also expressed by activated leukocytes and that both ALCAM and CD6 are expressed in the brain suggest that ALCAM-CD6 interactions may play a role in the binding of T and B cells to activated leukocytes, as well as in interactions between cells of the nervous system.     

Possible role of Helicobacter pylori infection in early gastric cancer development

BACKGROUND: Gastric cancer is the most frequently diagnosed malignancy in Japan. The possible relationship between Helicobacter pylori infection and gastric cancer in Japan was evaluated. METHODS: H. pylori infection was identified by the presence of anti-H. pylori IgG. The frequency of H. pylori infection was compared in 213 patients with gastric cancer and the same number of asymptomatic control subjects matched for age and sex. RESULTS: The presence of IgG antibody to H. pylori was significantly more prevalent (P < 0.001) in those with gastric cancer compared with asymptomatic control subjects (88.2% versus 74.6%). H. pylori positive rates were significantly greater in patients with the intestinal type (90.4%, P < 0.001) and diffuse type (86.4%, P < 0.05) of gastric cancer than in control subjects. Ninety-three percent of the patients with early gastric cancer tested positive for H. pylori (P < 0.001 compared with control subjects), whereas no significant difference was observed between those with advanced gastric cancer and control subjects. The intestinal type of early gastric cancer showed only the significantly increased frequency of high titer (optical density > 1.50) of H. pylori IgG antibody (P < 0.001) compared with control subjects without cancer. CONCLUSIONS: These results suggest that H. pylori infection may be associated with the development of early gastric cancer in Japan.     

HpSS: a new silver staining method for Helicobacter pylori

Fifty-seven patients with clinically localized prostate cancer were treated by radical prostatectomy or external radiation therapy following pelvic lymphadenectomy. Comparing the outcome of radiotherapy with that of prostatectomy in 42 T2 patients without lymph node metastasis, the 5-year cause-specific survival did not differ between the radical prostatectomy group (n = 31) and radiotherapy group (n = 11). The 5-year disease-free survival of the prostatectomy group, however, was superior to that of radiotherapy group (p = 0.01). To cure patients with T2 prostate cancer, therefore, it is supposed that radical prostatectomy should be performed. To improve the treatment outcome after radiotherapy, stereotactic radiosurgery for prostate cancer has been attempted in our institution. Phantom experiments using a linear accelerator demonstrated a round dose distribution, and high reproducibility of prostate positioning was confirmed by CT when a thermoplastic immobilization device was used to fix the pelvis. In one patient with localized prostate cancer treated by radiosurgery, acute complication has not been recognized during the 5 week follow-up. Radiosurgery may be available to treat clinically localized prostate cancer.     

Helicobacter pylori: a eubacterium lacking the stringent response

Accumulation of 16S rRNA and production of guanosine polyphosphates (pppGpp and ppGpp) were studied during amino acid starvation in three wild-type strains of Helicobacter pylori. All strains exhibit a relaxed phenotype with respect to accumulation of 16S rRNA. This constitutes the first example of a wild-type eubacterium showing a relaxed phenotype. The guanosine polyphosphate levels do not rise as a result of amino acid starvation, as expected for relaxed organisms. However, in both growing and starved cells, basal levels of the two polyphosphates appeared to be present, demonstrating that the enzymatic machinery for guanosine polyphosphate production is present in this organism. These findings are discussed within the framework of the hypothesis that stringent control is a physiological control mechanism more important for the fitness of prokaryotes growing in the general environment than for those that inhabit protected niches.     

Evidence for a conjugation-like mechanism of DNA transfer in Helicobacter pylori

Many strains of Helicobacter pylori are naturally competent for transformation in vitro. Since there is a high degree of genetic variation among H. pylori strains, we sought to determine whether mechanisms of DNA exchange other than transformation exist in these organisms. Studies were done with H. pylori cells that each were resistant to two different antibiotics; the procedure used involved mating of cells on plates or in broth, in the absence or presence of DNase. In each experiment, such matings produced progeny with the markers of both parents. Examination of the full resistance profile and random arbitrarily primed DNA PCR (RAPD-PCR) profiles of the progeny indicated that DNA transfer was bidirectional. DNase treatment reduced but did not eliminate transfer; only the presence of both DNase and a membrane separating the cells did so. For progeny derived from matings in the presence of DNase, antibiotic resistance and RAPD profiles indicated that transfer was unidirectional. DNase-treated cell-free supernatants also did not transform, ruling out transduction. These experiments indicate that both a DNase-sensitive mechanism (transformation) and a DNase-resistant conjugation-like mechanism involving cell-to-cell contact may contribute to DNA transfer between H. pylori cells.     

Evaluation of a new ultrashort triple therapy for Helicobacter pylori disease

BACKGROUND: 1-week proton pump inhibitor-based triple therapies are considered the most effective and convenient drug combinations for curing Helicobacter pylori infection. Short therapies, lasting less than 1 week have been investigated rarely. AIM: To assess the efficacy and tolerability of a 3-day lansoprazole triple therapy after 1 day of lansoprazole pre-treatment. METHODS: Seventy H. pylori-positive (rapid urease test and histology) patients received LAzT3 regimen (lanzoprazole 30 mg b.d. and azithromycin 500 mg o.m. for 3 days; tinidazole 2000 mg o.m. on day 1 and 1000 mg o.m. on days 2-3) after 1 day of lansoprazole pretreatment. Patients with active ulcer received lansoprazole 30 mg o.m. for an additional 4 weeks. Follow-up gastroscopy was carried out 4-6 weeks after completion of therapy. Eradication was defined as negative histology and rapid urease test. RESULTS: Four patients failed to attend the follow-up endoscopy. One patient complained of minor side-effects. H. pylori was eradicated in 57 of 66 patients suitable for evaluation, with a per-protocol cure rate of 86.3% (95%CI: 76-94%), and an intention-to-treat cure rate of 81.4% (95%CI: 70-90%). CONCLUSIONS: This new ultrashort triple therapy including lansoprazole, azithromycin and tinidazole seems to be effective in eradicating H. pylori. It is safe and well-tolerated, and may be taken into consideration as a valid alternative to the better known and widely used 1-week proton pump inhibitor-based triple therapies.