Primary clarithromycin resistance in Helicobacter pylori: the Multicentric Italian Clarithromycin Resistance Observational (MICRO) study.

BACKGROUND: Primary clarithromycin resistance markedly reduces Helicobacter pylori eradication rate following standard therapies. Prevalence of primary clarithromycin resistance in H. pylori is increasing, and three point mutations are mainly involved. AIM. To assess both the prevalence of primary clarithromycin resistance in Italy, and the distribution of the involved point mutations. METHODS: Primary clarithromycin resistance was assessed by TaqMan real-time polymerase chain reaction on antral biopsies of 253 consecutive, H. pylori infected patients enrolled in 13 Italian centres between January and September 2010. RESULTS: Primary clarithromycin resistance was detected in 25 (9.9%) patients, with prevalence values widely ranging from 0 to 25%. Clarithromycin resistance rate was higher in female as compared to male patients (13.4% vs. 5.3%, p=0.03), and it tended to be higher in non-ulcer dyspepsia than in peptic ulcer patients (10.6% vs. 6.9%, p=0.5), female patients with non-ulcer dyspepsia showing the highest value (15.4%). The A2143G point mutation was detected in 13 (52.0%) patients, the A2142G in 9 (34.6%), whilst a double point mutation (A2143G plus A2142G) in 3 (11.6%) cases. CONCLUSIONS: Primary clarithromycin resistance is highly variable in different Italian geographic areas. High resistance rates were observed in female and in dyspeptic patients. Among the three point mutations of clarithromycin resistance, the A2143G remains the most frequently observed.

Infliximab therapy downregulation of basic fibroblast growth factor/syndecan 1 link: a possible molecular pathway of mucosal healing in ulcerative colitis.

BACKGROUND: It is known that syndecan 1 in inflammatory bowel diseases is able to migrate from epithelial basolateral site to the stromal area and apical surface of epithelium with a consequent activation and modulation of basic fibroblast growth factor (bFGF), and this process sustains mucosal healing of ulcers. On the other hand, tumour necrosis factor (TNF) α mucosal levels are directly related to the entity of the damage in these disorders. Aim of the study A 'post-hoc' retrospective study was performed to estimate mucosal TNF α in rectal biopsies of subjects with ulcerative colitis (UC) before and after effective infliximab therapy and its relationship with syndecan 1, bFGF and endoscopic mucosal healing. MATERIAL AND METHODS: Paraffin-embedded rectal samples from 12 patients with UC responders to infliximab were analysed for TNF α, syndecan 1 and bFGF before and 6 months after therapy using a real-time reverse transcriptase polymersase chain reaction. Additionally, syndecan 1 location was evaluated by immunohistochemistry. Samples from 12 subjects with irritable bowel symptoms without endoscopic/histological abnormalities represented the control group. Mucosal healing induced by the treatment was defined by an endoscopic Mayo subscore changing from 2-3 to 0. ANOVA plus Student-Newman-Keuls was used for statistical analysis. RESULTS: The authors found that in the active disease, an increase in TNF α (p<0.001) is accompanied by raised levels of both syndecan 1 (p<0.005) and bFGF (p<0.005) compared with the control group. Infliximab-induced TNF α decrease to levels similar to controls is associated with both endoscopic mucosal healing and adhesion molecule/growth factor significant reduction. Additionally, syndecan 1 location, which is predominant in the stromal cells and apical epithelium in the active disorder, is quite exclusively located at the basolateral epithelial area in both healed mucosa and controls. CONCLUSIONS: Balanced interaction among TNF α inhibition by infliximab, syndecan 1 migration, bFGF repair modulation and final adhesion molecule reversal to its normal location might represent a suitable molecular pathway of endoscopic mucosal healing in UC.

From chronic liver disorders to hepatocellular carcinoma: Molecular and genetic pathways.

Hepatocarcinogenesis is a process attributed to progressive genomic changes that alter the hepatocellular phenotype producing cellular intermediates that evolve into hepatocellular carcinoma (HCC). During the preneoplastic phase, the liver is often the site of chronic hepatitis and/or cirrhosis, and these conditions induce liver regeneration with accelerated hepatocyte cycling in an organ that is otherwise proliferatively at rest. Hepatocyte regeneration is accelerated by upregulation of mitogenic pathways involving molecular and genetic mechanisms. Hepatic growth factors, inhibitors and triggers may also play a role. This process leads to the production of monoclonal populations of aberrant and dysplastic hepatocytes that have telomerase re-expression, microsatellite instability, and occasionally structural aberrations in genes and chromosomes. Development of dysplastic hepatocytes in foci and nodules and the emergence of HCC are associated with the accumulation of irreversible structural alterations in genes and chromosomes even if the genomic basis of the malignant phenotype is largely heterogeneous. Therefore, a malignant hepatocyte phenotype may be produced by changes in genes acting through different regulatory pathways, thus producing several molecular variants of HCC. On these bases, a key point for future research will be to determine whether the deletions are specific, due to particular loci in the minimally deleted regions of affected chromosome arms, or whether they are non-specific with loss of large portions of chromosomes or entire chromosome arms leading to passive deletion of loci. The final aim is the possibility of identifying a step where carcinogenetic processes could be terminated.

Metabolic syndrome and gastro-esophageal reflux: A link towards a growing interest in developed countries.

The aim of this Editorial is to describe the growing possibility of a link between gastro-esophageal reflux disease (GERD) and metabolic syndrome on the light of recent epidemiological and pathophysiological evidence. The state of the art of GERD is described, based on recent definitions, pathophysiological evidence, epidemiology in developed countries, clinical subtypes together with a diagnostic approach specifically focussed on the appropriateness of endoscopy. Metabolic syndrome is accurately defined and the pivotal role of insulin resistance is emphasized. The strong relationship between GERD and metabolic syndrome has been pathophysiologically analyzed, taking into account the role of obesity, mechanical factors and metabolic changes. Data collected by our group regarding eating habits and GERD are briefly summarized at the end of a pathophysiological analysis. The literature on the subject strongly supports the possibility that lifestyle and eating habits may be involved in both GERD and metabolic syndrome in developed countries.

Helicobacter pylori vacA arrangement and related diseases: a retrospective study over a period of 15 years.

Peptic ulcer disease incidence is decreasing. Both s1m1 and s1m2 vacA gene combinations of Helicobacter pylori have been associated with the development of major gastroduodenal diseases. This study assessed whether H. pylori vacA gene arrangement changed over 15 years in a Southern Italy area. H. pylori-positive patients observed in January-June 1989 and January-June 2005 were selected. Histological specimens were retrieved to extract DNA for vacA arrangement characterization (mid-m and peptide signal-s regions) by using the polymerase chain reaction. Fifty-nine patients in the first period and 56 matched patients in the second period were evaluated. A correlation between s1 presence and intestinal metaplasia at histology was found. Overall, the s1m1 combination increased (P < 0.01) and s2m2 decreased (P < 0.001) during the study period. In detail, s1m1 (P < 0.05) and s1m2 (P < 0.01) increased, and s2m2 decreased (P < 0.001) in dyspeptic patients, while only s1m1 increased (P < 0.01) in peptic ulcer patients. Finally, few cases of s2m1 combination in both series were found. Our results show some unexpected aspects that require confirmation. In detail, the increased prevalence of potential more virulent H. pylori strains contrasts with peptic ulcer incidence reduction.

Prevalence of primary clarithromycin resistance in Helicobacter pylori strains over a 15 year period in Italy.

OBJECTIVES: The frequency of primary clarithromycin resistance in Helicobacter pylori strains is increasing worldwide, and its presence significantly reduces the treatment efficacy of infection. This study aimed to evaluate whether the progression of the prevalence of clarithromycin resistance over a 15 year period has increased and whether a possible change in the distribution of the three most frequent point mutations, which account for the large majority of clarithromycin resistance cases, has taken place. METHODS: Antral biopsies of consecutive H. pylori-positive patients observed between January 1989 and December 1990 and between January 2004 and December 2005 were retrieved. A TaqMan real-time PCR was performed in all cases to assess point mutations involved. RESULTS: Primary clarithromycin resistance was assessed for 147 patients observed in the first period 1989-90 and 178 cases observed in the second period 2004-05. The overall frequency of clarithromycin resistance increased from 10.2% (15 patients) to 21.3% (38 patients) during the study period (P = 0.01). The increase was more evident in females [4 out of 55 patients (7.2%) versus 24 out of 103 patients (23.3%); P = 0.01] and in non-ulcer dyspepsia patients [13 out of 106 patients (12.2%) versus 37 out of 140 (26.4%) patients; P = 0.009]. A2143G was the most frequent point mutation observed in both study periods, and its prevalence rate remained unchanged [11 out of 15 (73.3%) patients versus 27 out of 38 (71%) patients; P = 1]. CONCLUSIONS: A 2-fold increase in primary clarithromycin resistance in H. pylori strains occurred during the last 15 years in Italy. A2143G remains the most prevalent point mutation involved, thus suggesting that new therapeutic strategies are needed.