Quadruple therapy with furazolidone for retreatment in patients with peptic ulcer disease

AIM: To establish the efficacy and safety of a 7-d therapeutic regimen using omeprazole, bismuth suticitrate, furazolidone and amoxicillin in patients with peptic ulcer disease who had been previously treated with other therapeutic regimens without success. METHODS: Open cohort study which included patients with peptic ulcer who had previously been treated unsuccessfully with one or more eradication regimens. The therapeutic regimen consisted of 20 mg omeprazole, 240 mg colloidal bismuth subcitrate, 1000 mg amoxicillin, and 200 mg furazolidone, taken twice a day for 7 d. Patients were considered as eradicated when samples taken from the gastric antrum and corpus 12 wk after the end of treatment were negative for Helicobacter pylori (H pylori) (rapid urease test and histology). Safety was determined by the presence of adverse effects. RESULTS: Fifty-one patients were enrolled. The eradication rate was 68.8% (31/45). Adverse effects were reported by 31.4% of the patients, and these were usually considered to be slight or moderate in the majority of the cases. Three patients had to withdraw from the treatment due to the presence of severe adverse effects. CONCLUSION: The association of bismuth, furazolidone, amoxicillin and a proton-pump inhibitor is a valuable alternative for patients who failed to respond to other eradication regimens. It is an effective, cheap and safe option for salvage therapy of positive patients. (C) 2008 The WJG Press. All rights reserved.

Ultra-Deep Sequencing Reveals the microRNA Expression Pattern of the Human Stomach

Background: While microRNAs (miRNAs) play important roles in tissue differentiation and in maintaining basal physiology, little is known about the miRNA expression levels in stomach tissue. Alterations in the miRNA profile can lead to cell deregulation, which can induce neoplasia. Methodology/Principal Findings: A small RNA library of stomach tissue was sequenced using high-throughput SOLiD sequencing technology. We obtained 261,274 quality reads with perfect matches to the human miRnome, and 42% of known miRNAs were identified. Digital Gene Expression profiling (DGE) was performed based on read abundance and showed that fifteen miRNAs were highly expressed in gastric tissue. Subsequently, the expression of these miRNAs was validated in 10 healthy individuals by RT-PCR showed a significant correlation of 83.97% (P<0.05). Six miRNAs showed a low variable pattern of expression (miR-29b, miR-29c, miR-19b, miR-31, miR-148a, miR-451) and could be considered part of the expression pattern of the healthy gastric tissue. Conclusions/Significance: This study aimed to validate normal miRNA profiles of human gastric tissue to establish a reference profile for healthy individuals. Determining the regulatory processes acting in the stomach will be important in the fight against gastric cancer, which is the second-leading cause of cancer mortality worldwide.

Trends in socioeconomic inequalities in cancer mortality in Barcelona: 1992-2003

Background: The objective of this study was to assess trends in cancer mortality by educational level in Barcelona from 1992 to 2003. Methods: The study population comprised Barcelona inhabitants aged 20 years or older. Data on cancer deaths were supplied by the system of information on mortality. Educational level was obtained from the municipal census. Age-standardized rates by educational level were calculated. We also fitted Poisson regression models to estimate the relative index of inequality (RII) and the Slope Index of Inequalities (SII). All were calculated for each sex and period (1992-1994, 1995-1997, 1998-2000, and 2001-2003). Results: Cancer mortality was higher in men and women with lower educational level throughout the study period. Less-schooled men had higher mortality by stomach, mouth and pharynx, oesophagus, larynx and lung cancer. In women, there were educational inequalities for cervix uteri, liver and colon cancer. Inequalities of overall and specific types of cancer mortality remained stable in Barcelona; although a slight reduction was observed for some cancers. Conclusion: This study has identified those cancer types presenting the greatest inequalities between men and women in recent years and shown that in Barcelona there is a stable trend in inequalities in the burden of cancer.

Gastroduodenal opportunistic infections and dyspepsia in HIV-infected patients in the era of Highly Active Antiretroviral Therapy

Background and Aim: Dyspeptic symptoms are frequently reported by human immuno-defficiency virus (HIV)-infected patients under highly active antiretroviral therapy. Whether opportunistic infections are a cause of dyspepsia is still unknown. In this study we prospectively compare the prevalence of gastrointestinal opportunistic infections in dyspeptic versus non-dyspeptic HIV-infected patients with advanced immunodeficiency. Patients and Methods: Six hundred and ninety HIV-infected patients under highly active antiretroviral therapy underwent esophagogastroduodenoscopy with mucosal biopsies from the stomach and duodenum. Group 1: 500 patients (161 women, 339 men; mean age 38.8 years; mean CD4 count 154.3 cells/mm(3) with dyspeptic symptoms such as epigastric pain, nausea, vomiting and fullness. Group 2: 190 patients (169 men, 21 women; mean age 40.7 years; mean CD4 count 171.6 cell/mm(3)) with no dyspeptic symptoms. Results: Group 1: Gastrointestinal opportunistic infections were observed in eight (1.6%), and non-opportunistic parasites in two (0.4%), patients. They were: Cytomegalovirus (four patients), Cryptosporidium sp. (two patients), Schistosoma mansoni sp. (one patient), Strongyloides stercoralis (one patient) and Giardia sp. (two patients). In five patients esophagogastroduodenoscopy showed no mucosal lesions. Group 2: Giardia sp. was detected in two patients (1.1%: P = 0.07947). Conclusion: Gastrointestinal opportunistic infections were shown in a small number of HIV-infected patients under highly active antiretroviral therapy with advanced immunodeficiency. Although gastrointestinal opportunistic infections were detected exclusively in the dyspeptic patient group, they could not be related to these symptoms, since the number of infected patients was not statistically significant. To correctly diagnose opportunistic infections, multiple biopsy specimens may be necessary even from normal-appearing mucosa.

Rebound acid hypersecretion after withdrawal of gastric acid suppressing drugs: new evidence of similitude

Background: Homeopathy is based on the principle of similitude (similia similibus curentur) using medicines that cause effects similar to the symptoms of disease in order to stimulate the reaction of the organism. Such vital, homeostatic or paradoxical reaction of the organism is closely related to rebound effect of drugs. Method: Review of the literature concerning the rebound effects of drugs used to suppress gastric acidity, particularly proton pump inhibitors (PPIs). Results: The mechanism of action of these effects is discussed. Rebound in terms of clinical symptoms and physiological effects occur in about 40% of people taking PPIs, their timing depends on the half-life of the drug and the adaptation period of the physiological mechanisms involved. The wide use of PPIs may be linked to the rising incidence of carcinoid tumours. Conclusions: These findings support Hahnemann`s concept of secondary action of drugs. We are developing a homeopathic materia medica and repertory of modern drugs on the basis of reported rebound effects. Homeopathy (2011) 100, 148-156.

Two Atypical Enteropathogenic Escherichia coli Strains Induce the Production of Secreted and Membrane-Bound Mucins To Benefit Their Own Growth at the Apical Surface of Human Mucin-Secreting Intestinal HT29-MTX Cells

In rabbit ligated ileal loops, two atypical enteropathogenic Escherichia coli (aEPEC) strains, 3991-1 and 0421-1, intimately associated with the cell membrane, forming the characteristic EPEC attachment and effacement lesion of the brush border, induced a mucous hypersecretion, whereas typical EPEC (tEPEC) strain E2348/69 did not. Using cultured human mucin-secreting intestinal HT29-MTX cells, we demonstrate that apically aEPEC infection is followed by increased production of secreted MUC2 and MUC5AC mucins and membrane-bound MUC3 and MUC4 mucins. The transcription of the MUC5AC and MUC4 genes was transiently upregulated after aEPEC infection. We provide evidence that the apically adhering aEPEC cells exploit the mucins` increased production since they grew in the presence of membrane-bound mucins, whereas tEPEC did not. The data described herein report a putative new virulence phenomenon in aEPEC.

Altered mucin expression in the gastrointestinal tract: a review

Early studies of changes in mucin expression in disorders of the gastrointestinal tract focused on alterations in the carbohydrate chain. This review briefly considers the various mechanisms by which such alterations may come about: (a) normal variation, (b) sialic acid alterations, (c) defective assembly of carbohydrate side-chains, (d) changed expression of core proteins and (e) epithelial metaplasia. The availability of monoclonal antibodies to mucin core proteins adds a new dimension to mucin histochemistry. It is now possible to offer explanations for traditional mucin histochemical findings on the basis of lineage-specific patterns of mucin core protein expression. Changes in core protein expression are described in inflammatory, metaplastic and neoplastic disorders of the gastrointestinal tract. The possibility that mucin change could be important in the aetiology of some diseases such as ulcerative colitis and H. pylori gastritis is considered. It is more probable, however, that changes in mucin expression are secondary to reprogramming of cellular differentiation and altered cell turnover. As such they may serve as markers to explain pathogenesis and provide novel diagnostic and prognostic information.

Timely topic: Premalignant lesions associated with adenocarcinoma of the upper gastrointestinal tract

The changing incidence of adenocarcinomas, particularly in the oesophagus and gastric cardia, has led to the rapid expansion of screening programmes aimed at detecting the precursor lesion of dysplasia before adenocarcinoma develops. The pathologist now has an important role in first diagnosing patients at risk for developing dysplasia, and then correctly classifying dysplasia when it occurs. Barrett's oesophagus has had different diagnostic criteria in previous years but is currently diagnosed by the presence of intestinal metaplasia of any length in the true oesophagus. Intestinal metaplasia confined only to the gastro-oesophageal junction or cardia is of uncertain significance but is probably common, with less risk of progressing to dysplasia or malignancy. In the stomach, patients with autoimmune atrophic gastritis and Helicobacter-associated multifocal atrophic gastritis have an increased risk of adenocarcinoma, but screening protocols are not well-developed compared with those used for Barrett's oesophagus. Dysplasia of glandular epithelium can be classified using well-described criteria. Low grade dysplasia is the most common type and regresses or remains stable in the majority of patients. High grade dysplasia is more ominous clinically, with a propensity to coexist with or progress to adenocarcinoma.

Receptor-mediated endocytosis of Neisseria gonorrhoeae into primary human urethral epithelial cells: the role of the asialoglycoprotein receptor

Urethral epithelial cells are invaded by Neisseria gonorrhoeae during gonococcal infection in men. To understand further the mechanisms of gonococcal entry into host cells, we used the primary human urethral epithelial cells (PHUECs) tissue culture system recently developed by our laboratory. These studies showed that human asialoglycoprotein receptor (ASGP-R) and the terminal lactosamine of lacto-N-neotetraose-expressing gonococcal lipooligosaccharide (LOS) play an important role in invasion of PHUECs. Microscopy studies showed that ASGP-R traffics to the cell surface after gonococcal challenge. Co-localization of ASGP-R with gonococci was observed. As ASGP-R-mediated endocytosis is clathrin dependent, clathrin localization in PHUECs was examined after infection. Infected PHUECs showed increased clathrin recruitment and co-localization of clathrin and gonococci. Preincubating PHUECs in 0.3 M sucrose or monodansylcadaverine (MDC), which both inhibit clathrin-coated pit formation, resulted in decreased invasion. N. gonorrhoeae strain 1291 produces a single LOS glycoform that terminates with Gal(beta1-4)Glc-Nac(beta1-3)Gal(beta1-4)Glc (lacto-N-neotetraose). Invasion assays showed that strain 1291 invades significantly more than four isogenic mutants expressing truncated LOS. Sialylation of strain 1291 LOS inhibited invasion significantly. Preincubation of PHUECs in asialofetuin (ASF), an ASGP-R ligand, significantly reduced invasion. A dose-response reduction in invasion was observed in PHUECs preincubated with increasing concentrations of NaOH-deacylated 1291 LOS. These studies indicated that an interaction between lacto-N-neotetraose-terminal LOS and ASGP-R allows gonococcal entry into PHUECs.

The genetics of glycosylation in Gram-negative bacteria

In recent years there has been a dramatic increase in reports of glycosylation of proteins in various Gram-negative systems including Neisseria meningitidis, Neisseria gonorrhoeae, Campylobacter jejuni, Pseudomonas aeruginosa, Escherichia coli, Caulobacter crescentus, Aeromonas caviae and Helicobacter pylori. Although this growing list contains many important pathogens (reviewed by Benz and Schmidt [Mol. Microbiol. 45 (2002) 267-276]) and the glycosylations are found on proteins important in pathogenesis such as pili, adhesins and flagella the precise role(s) of the glycosylation of these proteins remains to be determined. Furthermore, the details of the glycosylation biosynthetic process have not been determined in any of these systems. The definition of the precise role of glycosylation and the mechanism of biosynthesis will be facilitated by a detailed understanding of the genes involved. (C) 2002 Federation of European Microbiological Societies. Published by Elsevier Science B.V. All rights reserved.

A import��ncia da 'baixa' tecnologia na inova����o em biomedicina ou o caminho 'modesto' para o Pr��mio Nobel

Em Julho de 2005, o Pr��mio Nobel da Medicina ou Fisiologia foi atribu��do a dois australianos, o patologista Robin Warren e o m��dico Barry Marshall, pelo seu trabalho sobre a bact��ria Helicobacter pylori e a sua rela����o com patologias comuns da regi��o g��strica. Para alguns, a distin����o n��o era sen��o o reconhecimento, h�� muito merecido, de uma contribui����o de grande relev��ncia para a medicina. Para outros, ela significou o triunfo de um estilo de investiga����o em medicina com ra��zes nos trabalhos pioneiros da microbiologia do s��culo XIX. Para outros, ainda, o significado da distin����o residia no facto de, dessa vez, o Pr��mio Nobel consagrar um trabalho com um impacto vis��vel e significativo nas vidas e no bem-estar de milh��es de doentes pelo mundo fora. N��o deixou de ser notado que, na ocasi��o, pouco se falou de genes, de genomas ou de temas ou tecnologias ���de ponta���. Warren e Marshall haviam procedido �� identifica����o, isolamento e cultura de um agente infeccioso e demonstrado as rela����es causais entre este e algumas patologias comuns do est��mago, como a gastrite cr��nica ou a ��lcera p��ptica, abrindo assim caminho ao diagn��stico e a terapias eficazes dessas patologias. Os dois australianos mostraram que havia caminhos modestos que tamb��m levavam ao Nobel, sem a necessidade de ceder ��s modas cient��ficas ou de procurar aparecer nas manchetes. Em todo o caso, tratava-se do coroar de um longo processo, iniciado em finais da d��cada de 1970, que levou a bact��ria Helicobacter pylori a tornar-se num ponto de passagem obrigat��rio para os gastroenterologistas e para os que eram afectados por doen��as g��stricas. Warren e Marshall tornavam-se, assim, os principais porta-vozes da bact��ria e das associa����es que permitiam que o que outrora fora considerado como uma entidade inexistente se tornasse uma entidade biom��dica real.

Infection and childhood leukemia: review of evidence

OBJECTIVE : To analyze studies that evaluated the role of infections as well as indirect measures of exposure to infection in the risk of childhood leukemia, particularly acute lymphoblastic leukemia. METHODS : A search in Medline, Lilacs, and SciELO scientific publication databases initially using the descriptors &#8220;childhood leukemia&#8221; and &#8220;infection&#8221; and later searching for the words &#8220;childhood leukemia&#8221; and &#8220;maternal infection or disease&#8221; or &#8220;breastfeeding&#8221; or &#8220;daycare attendance&#8221; or &#8220;vaccination&#8221; resulted in 62 publications that met the following inclusion criteria: subject aged &#8804; 15 years; specific analysis of cases diagnosed with acute lymphoblastic leukemia or total leukemia; exposure assessment of mothers&#8217; or infants&#8217; to infections (or proxy of infection), and risk of leukemia. RESULTS : Overall, 23 studies that assessed infections in children support the hypothesis that occurrence of infection during early childhood reduces the risk of leukemia, but there are disagreements within and between studies. The evaluation of exposure to infection by indirect measures showed evidence of reduced risk of leukemia associated mainly with daycare attendance. More than 50.0% of the 16 studies that assessed maternal exposure to infection observed increased risk of leukemia associated with episodes of influenza, pneumonia, chickenpox, herpes zoster, lower genital tract infection, skin disease, sexually transmitted diseases, Epstein-Barr virus, and Helicobacter pylori . CONCLUSIONS : Although no specific infectious agent has been identified, scientific evidence suggests that exposure to infections has some effect on childhood leukemia etiology.

Mecanismos biopatol��gicos da metastiza����o ganglionar no carcinoma g��strico. Implica����es para a cirurgia radical

RESUMO A constata����o de que o carcinoma g��strico continua a ser a segunda causa de morte por doen��a oncol��gica no mundo em geral e em particular em Portugal, assim como a verifica����o da elevada incid��ncia e letalidade no nosso pa��s, justifica uma particular aten����o a esta doen��a. Apesar de avan��os recentes na ac����o adjuvante e neo-adjuvante de terap��uticas n��o cir��rgicas, com algumas refer��ncias a melhorias na sobreviv��ncia, estas terap��uticas n��o t��m efic��cia curativa. Sendo assim, a cirurgia continua a constituir a ��nica esperan��a de cura no carcinoma g��strico. Em consequ��ncia, a correcta selec����o da t��cnica a aplicar, assim como a sua correcta execu����o, v��o ter influ��ncia marcante na sobreviv��ncia do doente. Os estudos dos centros oncol��gicos diferenciados em v��rias zonas geogr��ficas demonstram que a cirurgia radical, com adequada extens��o da gastrectomia e com linfadenectomia alargada permite obter as melhores sobreviv��ncias. O tipo de cirurgia mais praticado nos referidos centros oncol��gicos diferenciados �� a gastrectomia com linfadenectomia D2, ou seja, com excis��o da segunda esta����o ganglionar. Este tipo de cirurgia n��o aumenta a mortalidade, mas aumenta a morbilidade. No entanto, verifica-se que muitos doentes n��o desenvolvem metastiza����o que atinja a esta����o ganglionar de n��vel 2 e, por outro lado, muitos outros ultrapassam esta esta����o ganglionar. Ou seja, a linfadenectomia D2 �� exagerada para alguns doentes, �� necess��ria e suficiente para muitos, mas pelo contr��rio, �� insuficiente para outros. A quest��o radica na necessidade de equil��brio em oferecer a cada doente a cirurgia necess��ria para obter a melhor sobreviv��ncia, ainda que �� custa de maior morbilidade e, por outro lado, conseguir identificar os factores que determinam que alguns doentes n��o necessitem de ser submetidos a uma terap��utica t��o agressiva. Se a primeira quest��o �� eminentemente fisiopatol��gica e consiste em compreender os mecanismos da metastiza����o ganglionar no carcinoma g��strico, de modo a poder prever a incid��ncia e extens��o da metastiza����o ganglionar em cada doente em particular e, assim, adequar a terap��utica. No estudo de 50 doentes, que elabor��mos, a interpreta����o fisiopatol��gica apoia-se na avalia����o de par��metros aceites como convencionais e de par��metros oncol��gicos. Dentro dos par��metros convencionais estud��mos a localiza����o do tumor, a sua dimens��o, a classifica����o de Borrmann, as altera����es metab��licas, a gastrina s��rica, a citologia peritoneal, a infec����o pelo Helicobacter pylori (Hp), a metaplasia intestinal, a classifica����o de Ming, a classifica����o de Lauren, a invas��o em profundidade da parede g��strica (T), a metastiza����o no ���early gastric c��ncer���, a classifica����o TNM, o CEA 19.9 e o CA 72.4 s��ricos. Para identificar quais os marcadores oncobiol��gicos mais adequados, efectu��mos uma revis��o da literatura relativamente a: Ki-67, p53, caderina-E, ERBB2, Instabilidade de Microssat��lites, MUC 1, Sialil Tn e Sialil Lewis X. De acordo com os resultados referidos na literatura, seleccion��mos para estudo os seguintes marcadores: Ki-67, p53, caderina-E, ERBB2 e Instabilidade de Microssat��lites. Relacion��mos todos estes par��metros com a metastiza����o ganglionar, nos aspectos de frequ��ncia da metastiza����o, n��mero de g��nglios metastizados (classifica����o N da UICC) e metastiza����o das cadeias ganglionares distais (classifica����o N japonesa). No que se refere �� execu����o do programa cir��rgico, foram obtidos n��veis de radicalidade semelhantes ou superiores aos referidos na literatura internacional, com frequ��ncia de complica����es ao n��vel da referida na literatura europeia. No que se refere ao estudo dos factores de metastiza����o ganglionar verific��mos que os par��metros que apresentam maior rela����o com a frequ��ncia da metastiza����o s��o: a dimens��o ��� 5 cm; a profundidade de invas��o da parede (T) atingindo as camadas profundas; o tipo infiltrativo na classifica����o de Borrmann; a express��o de Ki-67 > 75%; a express��o de p53 positiva; a express��o de caderina-E anormal; a associa����o de Ki-67 ��� 50% + caderina-E anormal + p53 positiva; a associa����o de dimens��o ��� 5 cm + p53 positiva; a associa����o de T3/T4 + p53 positiva; a presen��a de marcadores tumorais elevados. A aus��ncia de metastiza����o ganglionar ou metastiza����o limitada �� primeira esta����o ganglionar, em que �� suficiente uma cirurgia conservadora de tipo D1, relaciona-se com a dimens��o < 5 cm; a invas��o em profundidade da parede (T) limitada ��s camadas superficiais; a aus��ncia de express��o de p53; a aus��ncia de n��veis elevados de marcadores tumorais. Recorrendo ao estudo dos quatro par��metros que podem ser determinados no pr��-operat��rio ��� dimens��o, invas��o em profundidade, express��o de p53 e marcadores tumorais convencionais foi poss��vel identificar 75% dos tumores N0 e 50% do conjunto dos tumores N0 + N1, ou seja, os tumores que n��o carecem de linfadenectomia alargada. Estudando a dimens��o, a presen��a de Hp, a invas��o em profundidade, os n��veis elevados de marcadores tumorais, a express��o de p53, Ki-67, de Caderina-E e de Instabilidade de Microssat��lites foi poss��vel caracterizar os tumores que envolvem maior risco de invadir as cadeias ganglionares distais e que, portanto, carecem de linfadenectomia alargada. Verifica-se assim que, com esta metodologia, �� poss��vel identificar uma percentagem significativa dos casos que n��o carecem de linfadenectomia alargada assim como daqueles que necessitam deste tipo de cirurgia.

Novel insights into the action of antimicrobial agents against human pathogens

Dissertation presented to obtain the Ph.D degree in Biochemistry