Secondary analysis of effectivness of tinidazole-containing-quadruple eradication therapy in asymptomatic H. pylori infected children in El Paso

Helicobacter pylori infection is frequently acquired during childhood. This microorganism is known to cause gastritis, and duodenal ulcer in pediatric patients, however most children remain completely asymptomatic to the infection. Currently there is no consensus in favor of treatment of H. pylori infection in asymptomatic children. The firstline of treatment for this population is triple medication therapy including two antibacterial agents and one proton pump inhibitor for a 2 week duration course. Decreased eradication rate of less than 75% has been documented with the use of this first-line therapy but novel tinidazole-containing quadruple sequential therapies seem worth investigating. None of the previous studies on such therapy has been done in the United States of America. As part of an iron deficiency anemia study in asymptomatic H. pylori infected children of El Paso, Texas, we conducted a secondary data analysis of study data collected in this trial to assess the effectiveness of this tinidazole-containing sequential quadruple therapy compared to placebo on clearing the infection. Subjects were selected from a group of asymptomatic children identified through household visits to 11,365 randomly selected dwelling units. After obtaining parental consent and child assent a total of 1,821 children 3-10 years of age were screened and 235 were positive to a novel urine immunoglobulin class G antibodies test for H. pylori infection and confirmed as infected using a 13C urea breath test, using a hydrolysis urea rate >10 μg/min as cut-off value. Out of those, 119 study subjects had a complete physical exam and baseline blood work and were randomly allocated to four groups, two of which received active H. pylori eradication medication alone or in combination with iron, while the other two received iron only or placebo only. Follow up visits to their houses were done to assess compliance and occurrence of adverse events and at 45+ days post-treatment, a second urea breath test was performed to assess their infection status. The effectiveness was primarily assessed on intent to treat basis (i.e., according to their treatment allocation), and the proportion of those who cleared their infection using a cut-off value >10 μg/min of for urea hydrolysis rate, was the primary outcome. Also we conducted analysis on a per-protocol basis and according to the cytotoxin associated gene A product of the H. pylori infection status. Also we compared the rate of adverse events across the two arms. On intent-to-treat and per-protocol analyses, 44.3% and 52.9%, respectively, of the children receiving the novel quadruple sequential eradication cleared their infection compared to 12.2% and 15.4% in the arms receiving iron or placebo only, respectively. Such differences were statistically significant (p<0.001). The study medications were well accepted and safe. In conclusion, we found in this study population, of mostly asymptomatically H. pylori infected children, living in the US along the border with Mexico, that the quadruple sequential eradication therapy cleared the infection in only half of the children receiving this treatment. Research is needed to assess the antimicrobial susceptibility of the strains of H. pylori infecting this population to formulate more effective therapies. ^

Is H. pylori infection associated with diarrhea in a cohort of 3- to 8-year-old Colombian children?

The Estudio Comunitario sobre la Salud del Niño cohort study followed 326 3- to 8-year-old Colombian children for 4 years to observe the natural history of Helicobacter pylori infection and identify risk factors for acquisition, recurrence and persistence. Acute H. pylori infection during childhood may predispose to other enteric infections and therefore increase the risk of diarrheal disease. This dissertation aimed to estimate the effect of H. pylori infection on the occurrence of diarrhea and parasitic co-infections. The analysis used Generalized Estimating Equations to obtain odds ratios to estimate relative risks for diarrhea and the Zhang-Yu algorithm to estimate relative risks for on parasitic infections. Andersen-Gill models were used to estimate rate ratios for the effect of H. pylori status on the recurrence of parasitic infections. H. pylori status was classified for the entire follow-up duration in 1 of 3 categories: persistently positive, intermittently positive, and persistently negative. Multivariable models included child’s sex, age, symptoms, medication use, and socio-environmental factors. H. pylori infection was weakly and imprecisely associated with diarrheal disease, which occurred at an unexpectedly low frequency in this study. Persistently H. pylori-positive children had a somewhat higher incidence of reported diarrhea than intermittently positive or persistently negative children. Stratified analysis revealed that the presence of specific helminthes modified the effect of persistent H. pylori infection on diarrhea. The incidence of any parasitic infections was higher in children with persistent H. pylori infection relative to those with intermittent or persistently negative status, but this association did not hold when adjusted for the full set of selected covariates. The effects of H. pylori persistent status were similar for the occurrence or recurrence of Giardia duodenalis, Entamoeba histolytica, and Ascaris lumbricoides. These results show that H. pylori frequently co-exists with other parasites in Andean children and suggest that intermittently H. pylori–positive children might be at a lower risk of parasitic infections than persistently positive children. The relationship of H. pylori infection, helminthic infection and diarrheal disease should be further explored in studies that devote more intensive resources to accurate ascertainment of diarrhea.^

Habitat e genoma: possibili adattamenti di H. pylori allo stomaco umano

Helicobacter pylori è un batterio patogeno che infetta e abita lo stomaco umano. La sua diffusione è ubiquitaria nel mondo ed esso è responsabile di varie patologie, sia gastriche che extra-gastriche. Vista l’estrema ostilità del suo habitat, H. pylori necessita di specifici adattamenti che lo rendono unico nella sua capacità di tollerare l’estrema acidità dello stomaco umano, oltre ad evitare la risposta immunitaria dell’ospite. In questa tesi verranno adottati degli approcci bioinformatici per cercare di individuare quali possano essere gli adattamenti e le caratteristiche del genoma di questo batterio correlati con la sopravvivenza nell’ambiente gastrico e l’adattamento all’ospite umano.

H. Pylori y su relación con tumores del colon: un estudio casos y controles 2007

El Helicobacter Pylori ha sido asociado en la carcinogénesis del cáncer gástrico. Algunos estudios lo han asociado también al desarrollo de pólipos o cáncer colorectal, pero otros estudios no han encontrado dicha asociación. La mayoría de trabajos que muestran una asociación a favor provienen de países industrializados donde la prevalencia de tumores colorectales es alta en comparación con países en vías de desarrollo como el nuestro. Por otro lado, nosotros tenemos una mayor prevalencia de infección por H. Pylori. Es un estudio de casos y controles retrospectivo basados en registros informatizados provenientes de una sola institución; se seleccionaron 73 casos que fueron pareados con 149 controles por edad, sexo y año de realización de la colonoscopia. El diagnóstico de infección por H. Pylori fue determinado en su mayoría por el test rápido de urcasa pero también se recurrió a la serología, y patología en ambos grupos. El diagnóstico de cáncer colorecta y pólipos colorectales fue hecho con video colonoscopia. No se encontró diferencia entre la prevalencia de infección por H. Pylori en el grupo casos (70 por ciento) y en el grupo control (69 por ciento). El "Odds Ratio" fue de 1.03 (95 IC, 0.56-1.90). Por regresión logística bivariada se analizaron las variables nivel social y lugar residencial (urbana y rural) sin encontrar modificación alguna de la asociación

Drugs and the gastrointestinal tract

16.1. Agents to control acidity 16.1.1 Antacids 16.1.2 Proton pump inhibitors and antibiotics for Helicobacter pylori 16.1.3 Histamine H2 receptor antagonists 16.1.4 Misoprostol 16.1.5 Sucralfate 16.2. Prokinetics and emetics 16.2.1 Introduction to prokinetics 16.2.2 Prokinetic agents 16.2.3 Emesis with cytotoxic drugs and drugs for 16.2.4 Motion sickness and drugs for 16.2.5 Drugs for post-operative emesis 16.3. Agents used for diarrhea, constipation, irritable bowel syndrome 16.3.1 Treatment for diarrhea 16.3.2 Treatment for constipation 16.3.3 Treatment for opioid-induced constipation 16.4. Drugs for inflammatory bowel disease 16.4.1 Mesalazine 16.4.2 Glucocorticoids 16.4.3 Infliximab

Genomic and functional profiling of gastric cancer

Helicobacter pylori infection is a risk factor for gastric cancer, which is a major health issue worldwide. Gastric cancer has a poor prognosis due to the unnoticeable progression of the disease and surgery is the only available treatment in gastric cancer. Therefore, gastric cancer patients would greatly benefit from identifying biomarker genes that would improve diagnostic and prognostic prediction and provide targets for molecular therapies. DNA copy number amplifications are the hallmarks of cancers in various anatomical locations. Mechanisms of amplification predict that DNA double-strand breaks occur at the margins of the amplified region. The first objective of this thesis was to identify the genes that were differentially expressed in H. pylori infection as well as the transcription factors and signal transduction pathways that were associated with the gene expression changes. The second objective was to identify putative biomarker genes in gastric cancer with correlated expression and copy number, and the last objective was to characterize cancers based on DNA copy number amplifications. DNA microarrays, an in vitro model and real-time polymerase chain reaction were used to measure gene expression changes in H. pylori infected AGS cells. In order to identify the transcription factors and signal transduction pathways that were activated after H. pylori infection, gene expression profiling data from the H. pylori experiments and a bioinformatics approach accompanied by experimental validation were used. Genome-wide expression and copy number microarray analysis of clinical gastric cancer samples and immunohistochemistry on tissue microarray were used to identify putative gastric cancer genes. Data mining and machine learning techniques were applied to study amplifications in a cross-section of cancers. FOS and various stress response genes were regulated by H. pylori infection. H. pylori regulated genes were enriched in the chromosomal regions that are frequently changed in gastric cancer, suggesting that molecular pathways of gastric cancer and premalignant H. pylori infection that induces gastritis are interconnected. 16 transcription factors were identified as being associated with H. pylori infection induced changes in gene expression. NF-κB transcription factor and p50 and p65 subunits were verified using elecrophoretic mobility shift assays. ERBB2 and other genes located in 17q12- q21 were found to be up-regulated in association with copy number amplification in gastric cancer. Cancers with similar cell type and origin clustered together based on the genomic localization of the amplifications. Cancer genes and large genes were co-localized with amplified regions and fragile sites, telomeres, centromeres and light chromosome bands were enriched at the amplification boundaries. H. pylori activated transcription factors and signal transduction pathways function in cellular mechanisms that might be capable of promoting carcinogenesis of the stomach. Intestinal and diffuse type gastric cancers showed distinct molecular genetic profiles. Integration of gene expression and copy number microarray data allowed the identification of genes that might be involved in gastric carcinogenesis and have clinical relevance. Gene amplifications were demonstrated to be non-random genomic instabilities. Cell lineage, properties of precursor stem cells, tissue microenvironment and genomic map localization of specific oncogenes define the site specificity of DNA amplifications, whereas labile genomic features define the structures of amplicons. These conclusions suggest that the definition of genomic changes in cancer is based on the interplay between the cancer cell and the tumor microenvironment.

Gastrointestinal complications after kidney transplantation

The aim of the study was to evaluate gastrointestinal (GI) complications after kidney transplantation in the Finnish population. The adult patients included underwent kidney transplantation at Helsinki University Central Hospital in 1990-2000. Data on GI complications were collected from the Finnish Kidney Transplantation Registry, patient records and from questionnaires sent to patients. Helicobacter pylori IgG and IgA antibodies were measured from 500 patients before kidney transplantation and after a median 6.8-year follow up. Oesophagogastroduodenoscopy with biopsies was performed on 46 kidney transplantation patients suffering from gastroduodenal symptoms and 43 dyspeptic controls for studies of gastroduodenal cytomegalovirus (CMV) infection. Gallbladder ultrasound was performed on 304 patients after a median of 7.4 years post transplantation. Data from these 304 patients were also collected on serum lipids, body mass index and the use of statin medication. Severe GI complications occurred in 147 (10%) of 1515 kidney transplantations, 6% of them fatal after a median of 0.93 years. 51% of the complications occurred during the first post transplantation year, with highest incidence in gastroduodenal ulcers and complications of the colon. Patients with GI complications were older and had more delayed graft function and patients with polycystic kidney disease had more GI complications than the other patients. H.pylori seropositivity rate was 31% and this had no influence on graft or patient survival. 29% of the H.pylori seropositive patients seroreverted without eradication therapy. 74% of kidney transplantation patients had CMV specific matrix protein pp65 or delayed early protein p52 positive findings in the gastroduodenal mucosa, and 53% of the pp65 or p52 positive patients had gastroduodenal erosions without H.pylori findings. After the transplantation 165 (11%) patients developed gallstones. A biliary complication including 1 fatal cholecystitis developed in 15% of the patients with gallstones. 13 (0.9%) patients had pancreatitis. Colon perforations, 31% of them fatal, occurred in 16 (1%) patients. 13 (0.9%) developed a GI malignancy during the follow up. 2 H.pylori seropositive patients developed gastroduodenal malignancies during the follow up. In conclusion, severe GI complications usually occur early after kidney transplantation. Colon perforations are especially serious in kidney transplantation patients and colon diverticulosis and gallstones should be screened and treated before transplantation. When found, H.pylori infection should also be treated in these patients.

Helikobakteeri ja sylki

Helicobacter pylori -infektio on yksi tavallisimpia infektiotauteja maailmassa. Bakteeri aiheuttaa aina tulehduksen mahalaukun limakalvolla, joka voi johtaa peptiseen haavatautiin ja jopa mahasyöpään. Helikobakteerin diagnostiikassa käytetään usein hyväksi bakteerin ureaasiaktiivisuutta. Bioteknologiayritys Biohitin ureaasipikatesteillä voidaan määrittää mahalaukun helikobakteeri-infektio biopsianäytteen avulla. Tämän tutkimuksen tavoitteena oli selvittää, voisiko Biohitin kehittämiä pikatestejä käyttää helikobakteerin toteamiseen myös sylkinäytteistä. Ureaasipikatestien lisäksi bakteerin läsnäolo syljessä tarkistettiin PCR-menetelmän avulla. Ureaasipikatestien perusteella 40 sylkinäytteestä saatiin 31 positiivista ja 9 negatiivista tulosta. PCR-menetelmän avulla helikobakteeri pystyttiin toteamaan yhdestä sylkinäytteestä. Tutkimus osoitti, ettei ureaasipikatestiä voi käyttää helikobakteerin luotettavaan toteamiseen sylkinäytteestä.

Differential modulation of intracellular survival of cytosolic and vacuolar pathogens by curcumin

Curcumin, a principal component of turmeric, acts as an immunomodulator regulating the host defenses in response to a diseased condition. The role of curcumin in controlling certain infectious diseases is highly controversial. It is known to alleviate symptoms of Helicobacter pylori infection and exacerbate that of Leishmania infection. We have evaluated the role of curcumin in modulating the fate of various intracellular bacterial pathogens. We show that pretreatment of macrophages with curcumin attenuates the infections caused by Shigella flexneri (clinical isolates) and Listeria monocytogenes and aggravates those caused by Salmonella enterica serovar Typhi CT18 (a clinical isolate), Salmonella enterica serovar Typhimurium, Staphylococcus aureus, and Yersinia enterocolitica. Thus, the antimicrobial nature of curcumin is not a general phenomenon. It modulated the intracellular survival of cytosolic (S. flexneri and L. monocytogenes) and vacuolar (Salmonella spp., Y. enterocolitica, and S. aureus) bacteria in distinct ways. Through colocalization experiments, we demonstrated that curcumin prevented the active phagosomal escape of cytosolic pathogens and enhanced the active inhibition of lysosomal fusion by vacuolar pathogens. A chloroquine resistance assay confirmed that curcumin retarded the escape of the cytosolic pathogens, thus reducing their inter- and intracellular spread. We have demonstrated that the membrane-stabilizing activity of curcumin is crucial for its differential effect on the virulence of the bacteria.

Prognostic Role of Host Cyclooxygenase and Cytokine Genotypes in a Caucasian Cohort of Patients with Gastric Adenocarcinoma

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Genome-wide analysis of restriction-modification system in unicellular and filamentous cyanobacteria

Cyanobacteria are an ancient group of gram-negative bacteria with strong genome size variation ranging from 1.6 to 9.1 Mb. Here, we first retrieved all the putative restriction-modification (RM) genes in the draft genome of Spirulina and then performed a range of comparative and bioinformatic analyses on RM genes from unicellular and filamentous cyanobacterial genomes. We have identified 6 gene clusters containing putative Type I RMs and 11 putative Type II RMs or the solitary methyltransferases (MTases). RT-PCR analysis reveals that 6 of 18 MTases are not expressed in Spirulina, whereas one hsdM gene, with a mutated cognate hsdS, was detected to be expressed. Our results indicate that the number of RM genes in filamentous cyanobacteria is significantly higher than in unicellular species, and this expansion of RM systems in filamentous cyanobacteria may be related to their wide range of ecological tolerance. Furthermore, a coevolutionary pattern is found between hsdM and hsdR, with a large number of site pairs positively or negatively correlated, indicating the functional importance of these pairing interactions between their tertiary structures. No evidence for positive selection is found for the majority of RMs, e. g., hsdM, hsdS, hsdR, and Type II restriction endonuclease gene families, while a group of MTases exhibit a remarkable signature of adaptive evolution. Sites and genes identified here to have been under positive selection would provide targets for further research on their structural and functional evaluations.

Evolução na abordagem Fármaco-terapêutica da úlcera péptica

Projeto de Pós-Graduação/Dissertação apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Mestre em Ciências Farmacêuticas

Úlcera péptica

Projeto de Pós-Graduação/Dissertação apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Mestre em Ciências Farmacêuticas

The breath test--a call for more regional use

Although the 13C-urea breath test is commonly used for detection of Helicobacter pylori infection and eradication, access to commercial testing centres for analysis may at times limit its use. We have addressed this issue by establishing a regional-based means of analysis as a Hospital-University collaboration.

Gastroretentive Extended-Release Floating Granules Prepared Using a Novel Fluidized Hot Melt Granulation (FHMG) Technique

The objective of this work was to investigate the feasibility of using a novel granulation technique, namely, fluidized hot melt granulation (FHMG), to prepare gastroretentive extended-release floating granules. In this study we have utilized FHMG, a solvent free process in which granulation is achieved with the aid of low melting point materials, using Compritol 888 ATO and Gelucire 50/13 as meltable binders, in place of conventional liquid binders. The physicochemical properties, morphology, floating properties, and drug release of the manufactured granules were investigated. Granules prepared by this method were spherical in shape and showed good flowability. The floating granules exhibited sustained release exceeding 10 h. Granule buoyancy (floating time and strength) and drug release properties were significantly influenced by formulation variables such as excipient type and concentration, and the physical characteristics (particle size, hydrophilicity) of the excipients. Drug release rate was increased by increasing the concentration of hydroxypropyl cellulose (HPC) and Gelucire 50/13, or by decreasing the particle size of HPC. Floating strength was improved through the incorporation of sodium bicarbonate and citric acid. Furthermore, floating strength was influenced by the concentration of HPC within the formulation. Granules prepared in this way show good physical characteristics, floating ability, and drug release properties when placed in simulated gastric fluid. Moreover, the drug release and floating properties can be controlled by modification of the ratio or physical characteristics of the excipients used in the formulation.