How antibiotic resistances could change Helicobacter pylori treatment:A matter of geography?

Therapeutic management of Helicobacter pylori(H.pylori)remains an unsolved issue.Indeed,no therapeutic regimen is able to cure the infection in all treated patients,and in many the infection persists despite the administration of several consecutive standard therapies.Although antibiotic resistance reports describe alarming results,the outcome of therapeutic regimens does not seem to parallel this scenario in most cases,since a successful performance is often reached in more than 80%of cases.However,the phenomenon of increasing antibiotic resistance is being closely studied,and the results show controversial aspects even in the same geographic area.For the continents of Europe,America,Asia,Africa,and Oceania,minimal and maximal values of resistance to the main antibiotics(clarithromycin,amoxicillin,metronidazole,and levofloxacin)feature wide ranges in different countries.The real enigma is therefore linked to the several different therapeutic regimens,which show results that often do not parallel the in vitro findings even in the same areas.A first aspect to be emphasized is that some regimens are limited by their use in very small geographic districts.Moreover,not all therapeutic trials have considered bacterial and host factors affecting the therapeutic outcome.The additional use of probiotics may help to reduce adverse events,but their therapeutic impact is doubtful.In conclusion,the"ideal therapy",paradoxically,appears to be a"utopia",despite the unprecedented volume of studies in the field and the real breakthrough in medical practice made by the discovery and treatment of H.pylori.The ample discrepancies observed in the different areas do not encourage the development of therapeutic guidelines that could be valid worldwide.On these bases,one of the main challenges for the future might be identifying a successful solution to overcome antibiotic resistances.In this context,geography must be considered a relevant matter.

New fecal test for non-invasive Helicobacter pylori detection:A diagnostic accuracy study

AIM To assess the diagnostic accuracy of a new fecal test for detecting Helicobacter pylori(H. pylori), using ^(13)Curea breath test as the reference standard, and explore bacterial antibiotic resistance. METHODS We conducted a prospective two-center diagnostic test accuracy study. We enrolled consecutive people≥ 18 years without previous diagnosis of H. pylori infection, referred for dyspepsia between February and October 2017. At enrollment, all participants underwent 13 C-urea breath test. Participants aged over 50 years were scheduled to undergo upper endoscopy with histology. Participants collected stool samples 1-3 d after enrollment for a new fecal investigation(THD fecal test). The detection of bacterial 23 S rRNA subunit gene indicated H. pylori infection. We also used the index diagnostic test to examine mutations conferring resistance to clarithromycin and levofloxacin. Independent investigators analyzed index test and reference test standard results blinded to the other test findings. We estimated sensitivity, specificity, positive(PPV) and negative(NPV) predictive value, diagnostic accuracy, positive and negative likelihood ratio(LR), together with 95% confidence intervals(CI).RESULTS We enrolled 294 consecutive participants(age: Median 37.0 years, IQR: 29.0-46.0 years; men: 39.8%). Ninetyfive(32.3%) participants had a positive ^(13)C-urea breath test. Twenty-three(7.8%) participants underwent upper endoscopy with histology, with a full concordance between ^(13)C-urea breath test and histology in detecting H. pylori infection. Four(1.4%) out of the 294 participants withdrew from the study after the enrollment visit and did not undergo THD fecal testing. In the 290 participants who completed the study, the THD fecal test sensitivity was 90.2%(CI: 84.2%-96.3%), specificity 98.5%(CI:96.8%-100%), PPV 96.5%(CI: 92.6%-100%), NPV 95.6%(CI: 92.8%-98.4%), accuracy 95.9%(CI: 93.6%-98.2%), positive LR 59.5(CI: 19.3-183.4), negative LR 0.10(CI: 0.05-0.18). Out of 83 infected participants identified with the THD fecal test, 34(41.0%) had bacterial genotypic changes consistent with antibiotic-resistant H. pylori infection. Of these, 27(32.5%) had bacterial strains resistant to clarithromycin, 3(3.6%) to levofloxacin, and 4(4.8%) to both antibiotics. CONCLUSION The THD fecal test has high performance for the non-invasive diagnosis of H. pylori infection while additionally enabling the assessment of bacterial antibiotic resistances.

Mechanisms of Helicobacter pylori antibiotic resistance:An updated appraisal

Helicobacter pylori(H. pylori) antibiotic resistance is the main factor affecting the efficacy of the current eradicating therapies. The aim of this editorial is to report on the recent information about the mechanisms accounting for the resistance to the different antibiotics currently utilized in H. pylori eradicating treatments. Different mechanisms of resistance to clarithromycin,metronidazole,quinolones,amoxicillin and tetracycline are accurately detailed(point mutations,redox intracellular potential,pump efflux systems,membrane permeability) on the basis of the most recent data available from the literature. The next hope for the future is that by improving the knowledge of resistance mechanisms,the elaboration of rational and efficacious associations for the treatment of the infection will be possible. Another auspicious progress might be the possibility of a cheap,feasible and reliable laboratory test to predict the outcome of a therapeutic scheme.

主要 clarithromycin 抵抗到 Helicobacter pylori : 这是为三倍的治疗失败的主要原因？

Conventional triple therapies for Helicobacter pylori (H. pylori ) eradication have recently shown a disappointing reduction in effectiveness in many countries. The main reason for failure was found to be bacterial resistance to one of the most commonly used antibiotics, clarithromycin. An additional problem for conventional triple therapy is the high rate of resistance to metronidazole found in Europe, America and Asia. In Italy, in the last 15 years a 2-fold increase in resistance has occurred. A recent study of the whole of Italy included about 20 patients from each region at the first endoscopic diagnosis of H. pylori infection. The most surprising result was the patchy distribution of resistance, which was almost absent in two regions (one northern and one southern), although the highest prevalence was found in some regions of the South. In the paediatricpopulation we found a 25% prevalence of resistance in a sample of H. pylori positive children observed between 2002 and 2007, mirroring data obtained in southern European countries. Clarithromycin resistance assessment is currently based on phenotypic detection performed after culture the agar dilution method or E-test, and genotypic methods based on polymerase chain reaction (PCR). In a recent comparative study we found a 71.2% agreement between the two methods. Culture-free techniques are highly accurate in finding even minimal traces of genotypically resistant strains. Moreover, PCR-based tools are accurate in detecting a heteroresistant status, defined as the co-existence of some strains that are susceptible and some resistant to the same antibiotic in an individual patient. Three point mutations, namely A2143G , A2142G and A2142C , are responsible for 90% of cases of primary clarithromycin resistance in H. pylori strains isolated in Western countries, although we previously demonstrated that the presence of the A2143G mutation, but not A2142G or A2142C , significantly lowered the H. pylori eradication rate. Treatment failure has considerable cost/benefit implications because of 'waste' of National Health System and patient resources, in terms of drugs, further diagnostic tests and medical examination expenses. Therefore, in future it would be very useful to be able to test for clarithromycin resistance before starting conventional triple therapy. Hopefully, fast, effective noninvasive tests may soon be devised to determine this condition.

Noninvasive molecular analysis of Helicobacter pylori : Is it time for tailored first-line therapy?

The main problem of Helicobacter pylori(H. pylori) infection management is linked to antibiotic resistances. This phenomenon has grown in the last decade, inducing a dramatic decline in conventional regimen effectiveness. The causes of resistance are point mutations in bacterial DNA, which interfere with antibiotic mechanism of action, especially clarithromycin and levofloxacin. Therefore, international guidelines have recently discouraged their use in areas with a relevant resistance percentage, suggesting first-line schedules with expected high eradication rates, i.e., bismuth containing or non-bismuth quadruple therapies. These regimens require the daily assumption of a large number of tablets. Consequently, a complete adherence is expected only in subjects who may be motivated by the presence of major disorders. However, an incomplete adherence to antibiotic therapies may lead to resistance onset, since sub-inhibitory concentrations could stimulate the selection of resistant mutants. Of note, a recent meta-analysis suggests that susceptibility tests may be more useful for the choice of first than second-line or rescue treatment. Additionally, susceptibility guided therapy has been demonstrated to be highly effective and superior to empiric treatments by both meta-analyses and recent clinical studies. Conventional susceptibility test is represented by culture and antibiogram. However, the method is not available everywhere mainly for methodology-related factors and fails to detect hetero-resistances. Polymerase chain reaction(PCR)-based, culture-free techniques on gastric biopsy samples are accurate in finding even minimal traces of genotypic resistant strains and hetero-resistant status by the identification of specific point mutations. The need for an invasive endoscopic procedure has been the most important limit to their spread. A further step has, moreover, been the detection of point mutations in bacterial DNA fecal samples. Few studies on clarithromycin susceptibility have shown an overall high sensitivity and specificity when compared with culture or PCR on gastric biopsies. On these bases, two commercial tests are now available although they have shown some controversial findings. A novel PCR method showed a full concordance between tissue and stool results in a preliminary experience. In conclusion, despite poor validation, there is increasing evidence of a potential availability of noninvasive investigations able to detect H. pylori resistances to antibiotics. These kinds of analysis are currently at a very early phase of development and caution should be paid about their clinical application. Only further studies aimed to evaluate their sensitivity and specificity will afford novel data for solid considerations. Nevertheless, noninvasive molecular tests may improve patient compliance, time/cost of infection management and therapeutic outcome. Moreover, the potential risk of a future increase of resistance to quadruple regimens as a consequence of their use on large scale and incomplete patient adherence could be avoided.

Evolution of nonspecific duodenal lymphocytosis over 2 years of follow-up

AIM: To assess the evolution of duodenal lymphocytosis(DL), a condition characterized by increased intraepithelial lymphocytes(IELs), over 2 years of follow-up.METHODS: Consecutive patients undergoing upper endoscopy/histology for abdominal pain, diarrhea, weight loss, weakness or other extraintestinal features compatible with celiac disease(CD) were included. Evaluation of IELs infiltrate in duodenal biopsy sampleswas carried out by CD3-immunohistochemistry and expressed as number of positive cells/100 enterocytes. Diagnostic agreement on the IELs count was tested by calculating the weighted k coefficient. All patients underwent serological detection of autoantibodies associated with CD: Ig G and Ig A anti-tissue transglutaminase and endomysium. Each patient underwent further investigations to clarify the origin of DL at baseline and/or in the course of 2 years of follow-up every six months. Autoimmune thyroiditis, intestinal infections, parasitic diseases, bacterial intestinal overgrowth, hypolactasia and wheat allergy were detected. Colonoscopy and enteric magnetic resonance i m a g i n g w e r e p e r f o r m e d w h e n n e c e s s a r y. R i s k factors affecting the final diagnosis were detected by multinomial logistic regression and expressed as OR.RESULTS: Eighty-five patients(16 males, 69 females, aged 34.1 ± 12.5 years) were followed up for a mean period of 21.7 ± 11.7 mo. At baseline, endoscopy/duodenal biopsy, CD3 immunohistochemistry revealed: > 25 IELs/100 enterocytes in 22 subjects, 15-25 IELs in 37 and < 15 IELs in 26. They all had negative serum anti-transglutaminase and anti-endomysium, whilst 5 showed Ig G anti-gliadin positivity. In the course of follow-up, 23 developed CD seropositivity and gluten sensitivity(GS) was identified in 19. Other diagnoses were: 5 Helicobacter pylori infections, 4 jejunal Crohn's disease, 1 lymphocytic colitis and 1 systemic sclerosis. The disease in the remaining 32 patients was classified as irritable bowel syndrome because of the lack of diagnostic evidence. At multivariate analysis, the evolution towards CD was associated with an IELs infiltrate > 25(OR = 1640.4) or 15-25(OR = 16.95), human leukocyte antigen(HLA) DQ2/8(OR = 140.85) or DQA1*0501(OR = 15.36), diarrhea(OR = 5.56) and weakness(OR = 11.57). GS was associated with IELs 15-25(OR = 28.59), autoimmune thyroiditis(OR = 87.63), folate deficiency(OR = 48.53) and diarrhea(OR = 54.87).CONCLUSION: DL may have a multifactorial origin but the IELs infiltrate and HLA are strong predictive factors for CD development and a clinical diagnosis of GS.

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 reexpression, 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 nonspecific 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.

在煽动性的肠疾病的 Fibrogenesis 和纤维变性: 一样的硬币的好、坏的方面？

Fibrogenesis in inflammatory bowel diseases is a complex phenomenon aimed at mucosal repair. However, it may provoke intestinal fibrosis with the development of strictures which require surgery. Therefore, fibrogenesis may be considered as a 'two-faced' process when related to chronic intestinal inflammation. Many types of cells may be converted into the fibrogenic phenotype at different levels of the intestinal wall. A complex interaction of cytokines, adhesion molecules and growth factors is involved in the process. We report an overview of recent advances in molecular mechanisms of stricturizing Crohn’s disease(CD) including the potential role of trasforming growth factor beta, protein kinase C and Ras, Raf and ERK proteins. Fibrotic growth factors such as vascular endothelial growth factor and platelet-derived growth factor, as well as the Endothelial-to-Mesenchymal Transition induced by transforming growth factor-β, are considered. Finally, our experience, focused on tumor necrosis factor α(the main cytokine of inflammatory bowel diseases) and the link between syndecan 1(a heparan sulphate adhesion molecule) and basic fibroblast growth factor(a strong stimulator of collagen synthesis) is described. We hypothesize a possible molecular pattern for mucosal healing as well as how its deregulation could be involved in fibrotic complications of CD. A final clinical point is the importance of performing an accurate evaluation of the presence of fibrotic strictures before starting anti-tumor necrosis α treatment, which could worsen the lesions.

Altered molecular pattern of mucosal healing in Crohn's disease fibrotic stenosis

AIM: To investigate tumor necrosis factor-α (TNF-α), syndecan 1 and basic fibroblast growth factor (bFGF) balance in Crohn's disease (CD) strictures. METHODS: Our study was performed on 24 surgical specimens of CD fibrotic stenosis. Ten histological normal surgical samples were retrieved for both the large and small bowel from patients with benign conditions and healthy tissue represented control collection. Sex and age in controls did not differ from CD group. Three endoscopic biopsy specimens taken after informed consent in subjects with normal colon were also used as negative controls. TNF-α, syndecan 1 and bFGF were detected by both reverse transcriptase reverse transcriptase polymerase chain reaction after mRNA extraction (results expressed as fold-change) and immunohistochemistry.RESULTS: TNF-α did not show any significant difference between CD and control specimens (1.54 ± 1.19; P > 0.05). Very high levels of bFGF were observed in CD (11.76 ± 4.65; P < 0.001) unlike syndecan 1 which showed a moderate increase (5.53 ± 2.18; P < 0.005). analysis of variance (ANOVA) plus Student-NeumannKeuls showed: bFGF > syndecan 1 > TNF-α = control. Immunoreactivity for bFGF was observed in epithelial, stromal, endothelial cells and even in the muscular layer, whilst in normal tissue it was almost unexpressed. Syndecan 1 and TNF-α staining was confined to mucosal epithelial and stromal cells, while in controls syndecan 1 was found in its normal site, i.e. , basolateral area of the crypts and TNF-α very poorly expressed. CONCLUSION: Fibrotic stenosis of CD may be the final result of an irreversible transformation of different cells into fibrogenic phenotype no longer inhibited by posttranscriptional regulation.

Role of concomitant therapy for Helicobacter pylori eradication: A technical note

We read with interest the recent meta-analysis by Lin et al who evaluated the effectiveness of concomitant regimen for Helicobacter pylori(H. pylori) in Chinese regions. They found that 7-d concomitant regimen is undoubtedly superior to 7-d triple therapy(91.2% vs 77.9%, P < 0.0001). However, it is a common belief that a triple therapy lasting 7 d should be definitively removed from the clinical practice for its ineffectiveness. Only its prolongation to 14 d may give satisfactory success rate. Thus, the assessment of an old and outdated treatment versus a more recent and successful one does not seem to bring novel and useful information. Moreover, a 7-d duration has not been ascertained for concomitant regimen, as main guidelines recommend a 10-d schedule for this scheme. Therefore, only studies comparing 10-d concomitant versus 14-d triple seem to be appropriate according to current Guidelines and would clarify which regimen is the most suitable worldwide. Additionally, in this metaanalysis concomitant and sequential therapy showed similar performances, despite it is common opinion that sequential is more prone than concomitant therapy to fail when metronidazole resistance occurs, and China is characterized by high rate of resistance to this antibiotic. None of the included studies evaluated a priori antibiotic resistances, and the lack of this detail hampers the unveiling of this apparent contradiction. In conclusion, the lack of the evaluation of the quality of included trials as well as their high heterogeneity constitute a burdensome limit to draw solid conclusions in this meta-analysis. On the bases of these considerations and the low number of examined trials, we believe that further studies and the knowledge of antibiotic resistances will support with high quality evidence which is the best regimen and its optimal duration.

May the assessment of baseline mucosal molecular pattern predict the development of gluten related disorders among microscopic enteritis?

AIM To evaluate mucosal baseline m RNA expression of tissue transglutaminase 2(t TG2), interferon gamma(IFNγ), toll-like receptor 2(TLR2) and Myeloid Differentiation factor 88(MyD 88) in patients with microscopic enteritis(ME).METHODS We retrospectively enrolled 89 patients with ME of different etiology, which was defined within a 2-year mean period of follow-up. Baseline histological examination was performed on Hematoxylin-Eosin stained sections and CD3 lymphocyte immunohistochemistry was used for intraepithelial lymphocyte count(IELs). ME was defined according to the criteria of Bucharest Consensus Conference. For each patient, formalin embedded biopsy samples of the duodenum referred to the period of ME diagnosis were retrieved. Real-time polymerase chain reaction(RT-PCR) was used to detect the amount of mR NA coding for tT G2, IFNγ, TLR2 and My D88, and the quantity was expressed as fold change compared to controls. Control group was represented by duodenal normal specimens from 15 healthy subjects undergoing endoscopy for functional symptoms. Comparisons among continuous variables were performed by One way analysis of variance(ANOVA) and Bonferroni’s test. The χ~2 test was used for categorical variables. Pearson’s test was used to evaluate correlations. Receiver operating curves were drawn for all four markers to estimate sensitivity and specificity in discriminating the development of CD and GS.RESULTS After a period of follow up of 21.7 ± 11.7 mo, the following diagnoses were achieved: gluten related disorders in 48 subjects(31 CD; 17 GS) and non-gluten related ones in 41(29 Irritable Bowel Syndrome- IBS; 12 Others). CD patients had the highest tT G2 levels(8.3 ± 4.5). The ANOVA plus Bonferroni analysis showed that CD > Other ME > GS = IBS > negative controls. A cut off value of 2.258 was able to discriminate between CD and GS with a sensitivity of 52.94% and a specificity of 87.1%. Additionally, CD patients had the highest IFNγ levels(8.5 ± 4.1). ANOVA plus Bonferroni demonstrated CD > Other ME > GS = IBS > negative controls. A cut off of 1.853 was able to differentiate CD and GS with a sensitivity of 47.06% and a specificity of 96.77%. Patients with non gluten-related causes of ME exhibited the highest TLR2 levels(6.1 ± 1.9) as follows: Other ME > CD = GS = IBS > negative controls. TLR2 was unable to discriminate CD from GS. Patients with CD overexpressed MyD 88 levels similarly to non gluten-related causes of DL(7.8 ± 4.9 and 6.7 ± 2.9), thus CD = Other ME > GS = IBS > negative controls. A cut off of 3.722 was able to differentiate CD from GS with a sensitivity of 52.94% and a specificity of 74.19%. IELs count(15-25 and more than 25/100 enterocytes) strongly correlated with mR NA levels of all tested molecules(P < 0.0001).CONCLUSION Our results confirm that a single marker is unable to predict a discrimination among ME underlying conditions as well as between CD and GS. Mucosal high levels of t TG and IFNγ m RNA may predict the development of CD more than GS with high specificity, despite an expected low sensitivity. TLR2 does not discriminate the development of CD from GS. My D88 levels indicate that intestinal permeability is more increased when a severe intestinal damage underlies ME in both gluten related and unrelated conditions. Therefore, the results of the present paper do not seem to show a clear translational value.

Silymarin,boswellic acid and curcumin enriched dietetic formulation reduces the growth of inherited intestinal polyps in an animal model

BACKGROUND Some substances of plant origin have been reported to exert an effect in reducing intestinal neoplasm development,especially in animal models.Adenomatous polyposis coli multiple intestinal neoplasia-ApcMin/+is the most studied murine model of genetic intestinal carcinogenesis.AIM To assess whether an enriched nutritional formulation(silymarin,boswellic acid and curcumin)with proven“in vitro”and“in vivo”anti-carcinogenetic properties may prevent inherited intestinal cancer in animal model.METHODS Forty adenomatous polyposis coli multiple intestinal neoplasia-ApcMin/+mice were used for the study of cancer prevention.They were divided into two groups:20 assumed standard and 20 enriched diet.At the 110th d animals were sacrificed.In each group,four subgroups received intraperitoneal bromodeoxyuridine injection at different times(24,48,72 and 96 h before the sacrifice)in order to assess epithelial turnover.Moreover,we evaluated the following parameters:Intestinal polypoid lesion number and size on autoptic tissue,dysplasia and neoplasia areas by histological examination of the whole small intestine,inflammation by histology and cytokine mRNA expression by real-time polymerase chain reaction,bromodeoxyuridine and TUNEL immunofluorescence for epithelial turnover and apoptosis,respectively.Additionally,we performed western blotting analysis for the expression of estrogen alpha and beta receptors,cyclin D1 and cleaved caspase 3 in normal and polypoid tissues.RESULTS Compared to standard,enriched diet reduced the total number(203 vs 416)and the mean±SD/animal(12.6±5.0 vs 26.0±8.8;P<0.001)of polypoid lesions.In enriched diet group a reduction in polyp size was observed(P<0.001).Histological inflammation and pro-inflammatory cytokine expression were similar in both groups.Areas of low-grade dysplasia(P<0.001)and intestinal carcinoma(IC;P<0.001)were significantly decreased in enriched diet group.IC was observed in 100%in standard and 85%in enriched formulation assuming animals.Enriched diet showed a faster epithelial migration and an increased apoptosis in normal mucosa and low-grade dysplasia areas(P<0.001).At western blotting,estrogen receptor beta protein was well expressed in normal mucosa of enriched and standard groups,with a more marked trend associated to the first one.Estrogen receptor alpha was similarly expressed in normal and polypoid mucosa of standard and enriched diet group.Cleaved caspase 3 showed in normal mucosa a stronger signal in enriched than in standard diet.Cyclin D1 was more expressed in standard than enriched diet group of both normal and polypoid tissue.CONCLUSION Our results are suggestive of a chemo-preventive synergic effect of the components(silymarin,boswellic acid and curcumin)of an enriched formulation in inherited IC.This effect may be mediated by the reduction of epithelial proliferation,the increase of apoptosis and the acceleration of villous cell renewal due to dietary formulation intake.

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.

Quinolone-based first, second and third-line therapies for Helicobacter pylori

Helicobacter pylori(H. pylori) is a very common bacterium that infects about 50% of the world population in urban areas and over 90% of people living in rural and developing countries. Fluoroquinolones, a class of antimicrobials, have been extensively used in eradication regimens for H. pylori. Levofloxacin is the most commonly used, and in second-line regimens, is one of the most effective options. However, an increasing resistance rate of H. pylori to fluoroquinolones is being observed, that will likely affect their effectiveness in the near future. Other novel fluoroquinolone molecules, such as moxifloxacin, sitafloxacin, gatifloxacin and gemifloxacin, have been proposed and showed encouraging results in vitro, although data on their clinical use are still limited. Further studies in large sample trials are needed to confirm their safety and efficacy profile in clinical practice.

Reversal of IgM deficiency following a gluten-free diet in seronegative celiac disease

Selective Ig M deficiency(s IGMD)is very rare;it may be associated with celiac disease(CD).We present the case of an 18-year-old man with s IGMD masking seronegative CD.Symptoms included abdominal pain,diarrhea and weight loss.Laboratory tests showed reduced Ig M,DQ2-HLA and negative anti-transglutaminase.Villous atrophy and diffuse immature lymphocytes were observed at histology.Tissue transglutaminase m RNA mucosal levels showed a 6-fold increase.The patient was treated with a gluten-free diet(GFD)and six months later the symptoms had disappeared,the villous architecture was restored and mucosal tissue transglutaminase m RNA was comparable to that of healthy subjects.After 1 year of GFD,a complete restoration of normal Ig M values was observed and duodenal biopsy showed a reduction of immature lymphocytes and normal appearance of mature immune cells.