Dimitrios Chatzopoulos

Apoptosis in hepatitis C

Summary. The apoptotic process appears to be a host defence mechanism against viral infections and tumourigenesis. However, many viral genomes encode proteins, which repress apoptosis so as to escape from immune attack by the host. Therefore, virus–host interactions may determine viral persistence, extent and severity of liver inflammation and possibly viral hepatocarcinogenesis. Apoptosis of liver cells may play a significant role in the pathogenesis of hepatitis C. Pathomorphologic features of increased apoptosis include shrinkage and fragmentation of nuclei/cytoplasm in piecemeal necrosis areas, acidophilic bodies, and focal cell dropout in the liver lobule. The hepatitis C virus (HCV) core protein exhibits both proapoptotic or antiapoptotic actions. Modulation of apoptosis may involve binding of HCV core protein to the intracellular signal transducing portion of death receptors and displacement of signalling molecules. Apoptosis may occur in the absence of significant transaminase elevation, thereby explaining the lack of correlation between biochemical activity and liver cell histological injury. Monitoring caspase activation might provide a reliable tool to estimate the efficacy of HCV therapy, and might open challenging therapeutic strategies in HCV infection. The antiviral effect of interferon may be mediated through induction of apoptosis. Lastly, administration of the antiapoptotic ursodeoxycholic acid in HCV infection is compatible with the notion that apoptosis may represent a mechanism for viral shedding rather than for viral elimination, thereby raising the concept that inhibition of apoptosis could ameliorate hepatitis C.

Relationship between Helicobacter pylori infection and glaucoma

OBJECTIVE To determine the frequency of Helicobacter pylori (H. pylori) infection in glaucoma patients and in anemic control participants. DESIGN Prospective, nonrandomized, comparative study. PARTICIPANTS The authors investigated 32 patients with chronic open-angle glaucoma (COAG), 9 patients with pseudoexfoliation glaucoma (PEG), and 30 age-matched anemic control participants. METHODS Upper gastrointestinal endoscopy was performed to evaluate macroscopic abnormalities, and gastric mucosal biopsy specimens were obtained for the presence of H. pylori infection tested by rapid urease slide test (CLO test) and by Cresyl fast violet staining, Giemsa staining, or both. The presence of gastritis was classified in accordance with the Sydney system by using hematoxylin and eosin stain. In addition, intestinal metaplasia was evaluated with Alcian blue stain. Saliva samples were also tested by CLO. Serum was analyzed for the presence of H. pylori-specific IgG antibodies by enzyme-linked immunosorbent assay. MAIN OUTCOME MEASURE Histologic examination for the presence of H. pylori. RESULTS In 87.5% of the COAG patients, 88.9% of the PEG patients, and 46.7% of the anemic control participants, H. pylori infection was histologically confirmed (odds ratio, 8.00; chi-square, 11.81; P = 0.0006 and 9.14; chi-square, 5.01; P = 0.02, respectively). H. pylori was detected by urease test: (1) in the gastric mucosa in 71.9% of the COAG patients, in 77.8% of the PEG patients, and in 46.7% of the anemic control participants (P = 0.03 and P > 0.05, respectively); and (2) in the saliva in 37.5% of the COAG patients, in 55.6% of the PEG patients, and in 30% of the anemic control participants (P > 0.05). Sixty-eight percent of glaucoma patients and 30% of anemic control participants were seropositive for H. pylori (P = 0.002). When compared with anemic control participants, glaucoma patients exhibited less often endoscopic normal appearance of gastric mucosa (P = 0.01), and more often antral gastritis (P = 0.0004) or peptic ulcer disease (P = 0.01). Histologic grade 3 gastritis was observed only in the glaucoma patients (P = 0.03). CONCLUSIONS H. pylori infection seems more frequent in glaucoma patients. If confirmed, this may indicate either a common factor that causes susceptibilities to both glaucoma and H. pylori infection or that H. pylori may be a causal factor for developing glaucoma.

A concept on the role of Helicobacter pylori infection in autoimmune pancreatitis.

Autoimmune pancreatitis, an inflammatory process of the pancreas due to an autoimmune mechanism establishing etiology of chronic pancreatitis, is characterized by the presence of autoantibodies, hypergammaglobulinemia, pancreatic enlargement, pancreatic duct strictures, and pathologic features of fibrotic changes with intense, mainly lymphocytic infiltrations, which may contribute to tissue destruction probably by apoptosis. In almost 60% of the cases, this type of pancreatitis coexists with other autoimmune diseases such as Sjögrens syndrome, sclerosing extrahepatic cholangitis, primary biliary cirrhosis, autoimmune hepatitis, or other extrapancreatic disorders, and recently with gastric peptic ulceration. The diversity of extrapancreatic lesions with similar histopathologic findings suggests general involvement of the digestive system in this disease, although the presence of such involvement has not been fully elucidated. Similarly, Helicobacter pylori (H. pylori) infection, a well known cause of gastric ulcer, has been associated, via molecular mimicry of host structures by its constituents with the same autoimmune conditions, also characterized by fibrotic changes and/or lymphoplasmacytic inflammations, accompanied by aberrations of T cell apoptosis that contribute to hepatobiliary‐ or extrahepatic‐tissue destruction. Considering that H. pylori is involved in the pathogenesis and pathophysiology of these autoimmune disorders, we propose that this organism might trigger autoimmune pancreatitis through induction of autoimmunity and apoptosis.

Association between Helicobacter pylori infection and acute inflammatory demyelinating polyradiculoneuropathy.

The aim of this study was to investigate a possible association between Helicobacter pylori infection and acute inflammatory demyelinating polyradiculoneuropathy (AIDP). Of 17 consecutive patients with Guillain–Barré syndrome (GBS), 13 patients (six females; mean age 50 ± 24 years) with AIDP were investigated. Clinical status was evaluated according to Hughes’ score, and electrophysiological tests were performed within 2 weeks from disease onset. Helicobacter pylori infection was detected histologically and serum H. pylori‐specific IgG antibodies were analysed by ELISA. Twenty asymptomatic patients (12 females; mean age 63 ± 8 years), undergoing upper gastrointestinal endoscopy for investigation of mild iron deficiency anaemia, served as controls. Helicobacter pylori was found in 12 of 13 AIDP patients (92%), and in 10 of 20 controls (50%), (P = 0.02). Electrophysiological studies showed demyelination in all AIDP patients. High levels of anti‐H. pylori IgG antibodies correlated with advanced clinical status. Five of seven AIDP patients with high levels of anti‐H. pylori IgG antibodies had delayed F‐wave latencies, indicating affection of proximal segments of peripheral nerves. Helicobacter pylori infection seems to be more frequent in AIDP patients. Anti‐H. pylori titre might reflect advanced clinical status. Anti‐H. pylori IgG antibodies are also associated with involvement of the proximal parts of peripheral nerves in AIDP.

Association between Helicobacter pylori infection and mild cognitive impairment

The association of Helicobacter pylori infection and Alzheimers disease (AD) has recently been addressed, but no relative data exist regarding mild cognitive impairment (MCI), a prodromal phase of AD. The aim of this prospective study was to evaluate H. pylori infection, by histology in a Greek MCI cohort. Sixty‐three consecutive patients with amnestic MCI and 35 normal controls underwent upper gastrointestinal endoscopy, histologic and serological examinations. The prevalence of H. pylori infection was 88.9% (56/63) in MCI patients and 48.6% (17/35) in anaemic controls, as confirmed by biopsy (P < 0.001, odds ratio: 8.47, 95% CI: 3.03–23.67). Mean serum anti‐H. pylori IgG concentration and plasma total homocysteine (Hcy) titre were higher in MCI patients than controls (74.86 ± 57.22 vs. 17.37 ± 9.30 U/ml; and 16.03 ± 4.28 vs. 13.5 ± 1.20 μmol/l; P < 0.001 and P = 0.015, respectively). When compared with the anaemic participants, MCI patients exhibited more often multifocal (body and antral) gastritis (92.1% vs. 68.6%; P = 0.03); in H. pylori positive MCI patients cognitive state correlated with serum anti‐H. pylori IgG concentration. In conclusion, H. pylori prevalence was significantly higher in MCI patients than controls. This infection might contribute, at least in part, to the pathophysiology of MCI, possibly through induction of chronic atrophic gastritis and elevated Hcy consequences.

Increased Cerebrospinal Fluid Helicobacter Pylori Antibody in Alzheimer’s Disease

Background: Helicobacter pylori (H. pylori) infection may play a role in Alzheimers disease (AD). Aim: A prospective, nonrandomized, comparative study was car- ried out to examine the levels of anti-H. pylori-specific IgG antibodies in the cerebrospinal fluid (CSF) and serum of AD patients, compared with those of age-matched cognitively normal controls. Patients: CSF was aspirated from 27 AD patients and 27 age-matched cognitively normal patients with prostate hyperplasia or long-bone fractures necessitating surgery after epidural anesthesia. Serum samples were obtained from AD patients and the day before surgery from controls. Methods: CSF and serum anti-H. pylori IgG concentrations were measured by means of an enzyme-linked immunosorbent assay. Results: The mean concentration of anti-H. pylori-specific IgG was significantly greater in (a) the CSF of AD patients (10.53 ± 12.54 U/mL) than in controls (8.63 ± 8.01 U/mL, p = 0.047), and (b) the serum of AD patients (30.44 ± 33.94 U/mL) than in controls (16.24 ± 5.77 U/mL, p = 0.041). CSF anti-H. pylori IgG antibodies correlated with the degree of severity of the disease. Conclusion: H. pylori-specific IgG antibody levels are significantly increased in CSF and serum of AD; its titer in CSF might reflect the AD severity, thereby supporting a role for this common infection in the pathobiology of the disease.

Immunomodulatory benefits of cyclosporine A in inflammatory bowel disease

Etiopathogenesis of mucosal inflammation in inflammatory bowel disease remains a complex and enigmatic field; various factors (genetic, environmental and microbial) trigger an event that activates intestinal immune and nonimmune systems cluminating in inflammation and tissue injury. Specifically, both innate and adaptive immune systems seem to play important roles in the pathophysiology of this disease. Cyclosporine A represents a macrolide immune modulator with primary inhibitory effects on T helper lymphocyte production of interleukin‐2, and other cytokines leading to altered T‐lymphocyte and B‐lymphocyte function. The diversity of its therapeutic outcome reported in inflammatory bowel disease may be due to the intricate immuno‐pathogenic profile of the disease and the variety of the applied dose‐dependent courses of therapy. Cyclosporine A exerts additional actions on other components of the inflammatory infiltrate, including neutrophils and mast cells, thereby appearing to be a multi‐dynamic therapeutic approach, although with potential drawbacks, that may be applied alone or combined with other immunomodulatory agents in inflammatory bowel disease patients. Because cyclosporine A induces apoptosis of T‐lymphocytes responsible for perpetuation of the chronic inflammatory process in the disease with potential tumorigenic effect, it may exert a further inhibitory effects on cancer development in inflammatory bowel disease patients, and can be combined with other relative agents, such as rapamycin, which also promotes T‐lymphocyte apoptosis. Therefore, recently established multifactorial action of cyclosporine A in relation to the pathogenesis of the disease can open new horizons for prospective, controlled trials in large cohorts, aiming to emphasize cyclosporine As potential.

Physical education and moral development: An intervention programme to promote moral reasoning through physical education in high school students:

Moral development is one of the goals of physical education (PE). However, few programmes have been implemented to investigate how moral development is promoted in PE settings. This study was designed in order to explore the effective ness of a six-week specially designed moral development intervention in the PE domain in high school students, and to examine whether moral reasoning differs between males and females. The interventions design was based on the creation of a task-orientated motivation climate and on reciprocal teaching style. The sample (n= 157) was assigned to control (n= 80) and experimental (n= 77) groups. At the beginning and end of the intervention the Moral Judgment Test was applied. The results revealed that the experimental group exhibited statistically greater moral reasoning after the intervention compared to the control group; however, no significant gender differences were found. These findings indicate that an appropriate design of PE could support moral development.

Apoptosis, inflammatory bowel disease and carcinogenesis: Overview of international and Greek experiences

Apoptosis is critical for organ development, tissue homeostasis, the elimination of abnormal cells and the maintenance of immune homeostasis by variable regulatory mechanisms. The death of T lymphocytes following their activation involves a series of proteases (caspases), which comprise the central executioners of apoptosis. Abnormal regulation of apoptosis results in disease. T-cell resistance against apoptosis contributes to inappropriate T-cell accumulation and the perpetuation of the chronic inflammatory process in inflammatory bowel disease with potential tumourigenic effect. The use of antitumour necrosis factor-alpha, anti-interleukin-6R and anti-interleukin-12 antibodies suppresses colitis activity by induction of T-cell apoptosis, thereby having important implications for the design of effective therapeutic strategies in inflammatory bowel diseases. Contrary to international data, the incidence of cancer in Greek patients with inflammatory bowel disease appears to be low. A balance between cell proliferation (Ki-67 overexpression) and apoptosis (Bax protein overexpression) may partly explain the low incidence of cancer development in Greek inflammatory bowel disease patients.

Helicobacter pylori Infection Might Contribute to Esophageal Adenocarcinoma Progress in Subpopulations With Gastroesophageal Reflux Disease and Barrett's Esophagus

To the Editor, Fischbach et al. [1] concluded that estimates for the effect of Helicobacter pylori (H. pylori) on Barrett’s esophagus (BE) were heterogenous across studies; although overall H. pylori, and particularly cagA cytotoxin, tended to be protective for BE in most studies, H. pylori effect on BE varied by geographic location. Barrett’s esophagus is a complication of long-standing gastroesophageal reflux disease (GERD) and wellrecognized premalignant condition playing a pivotal role in the development of esophageal adenocarcinoma (EA), the most common esophageal malignancy in Western countries with increasing faster incidence than any other cancer [2]; GERD plays a crucial role in the pathophysiology and the clinical identification of BE [2]. In this regard, our data show that H. pylori infection (H. pylori-I) is frequent in Greek patients with GERD and even with nonendoscopical reflux disease [2], and H. pylori eradication leads to better control of GERD symptoms and improves esophagitis [2,3]. Moreover, consistent associations with the Greek data were shown by others [3] also reporting improvement in reflux symptoms following H. pylori treatment. It is important to note that some other authors, usually prior supporters of the theory that H. pylori “protects” against GERD, relented their initial findings, claiming that H. pylori eradication does not cause or protect against GERD and, moreover, recommending H. pylori eradication in GERD [4]. Additionally, although epidemiologic studies do not suggest causality with H. pylori, however, such studies support our and others’ findings; for instance, a large study (~21,000 cases) showed that the decrease in H. pylori-I parallels the decrease in peptic ulcer prevalence, and the increase in GERD and reappearance of GERD after H. pylori eradication is rare. Moreover, contrary to expectation, patients hospitalized with duodenal ulcers (61,548 cases), obviously attributed to H. pylori-I, had a significant 70% excess risk of EA. Much evidence further potentiates the concern that H. pylori is not “protective” against GERD [5] and its complications including BE and EA. The interplay between H. pylori and host factors plays an important role in the pathogenesis of GERD. Specifically, H. pylori may contribute to GERD pathogenesis by several mechanisms including release of several mediators, cytokines, and nitric oxide, which may adversely affect the lower esophageal sphincter (LES); direct damage of the esophageal mucosa by bacterial products; increased production of prostaglandins that sensitize afferent nerves and reduce LES pressure; and augmented acidity (by gastrin release) that exacerbate GERD [3]. The authors considered some putative pathways involving H. pylori and a decreased risk of BE [1]. However, these pathways might represent the one BE pathogenic “coin’s” side. Regarding the other alternative side, gastrin, induced by H. pylori-I, is an oncogenic growth factor contributing to esophageal, gastric, and colon carcinogenesis and, in particular, playing a potential causal effect on neoplastic progression in BE; gastrin stimulates proliferation via JAK2and Akt-dependent NF-kappaB (NF-jB) activation in Barrett’s EA cells, shows antiapoptotic activity through upregulation of Bcl-2 and survivin, and upregulates cyclooxygenase (COX)-2 expression [2]. In this regard, H. pylori-I activates NF-jB, an oxidantsensitive transcription regulator of inducible expression of inflammatory genes such as COX-2, which regulates gastrointestinal cancer cell growth and proliferation. In particular, H. pylori-I induced NF-jB and COX-2 expression in esophageal epithelial cells, playing a role in inflammation associated with BE and tumorigenesis in the esophagus [2]; upon colonizing esophagus, H. pylori increases the severity of esophageal inflammation and the incidence of BE and EA [6]. Moreover, recent evidence indicates that 1, H. pylori-I prevalence is high in BE; 2, neither H. pylori-I nor H. pylori-I by CagA+ strains reduce the risk of BE in certain populations with high prevalence of H. pylori-I; 3, the expected incidence of EA with persistent H. pylori-I is higher than that of EA after eradication of infection [5]; H. pylori-I may affect specific molecular alterations (genetic instability, E-cadherin methylation, and monoclonal antibody Das-1) associated with the pathogenesis of BE; and 4, H. pylori induces