Chemokine Receptors CCR1, CCR3, CCR7 and Chemokines CX3CL1 and CCL5 are Significantly Up-Regulated and Very Reliable for Acute Rejection Diagnosis of Kidney Transplants

Background: The allo-immune response following organ transplantation constitutes one of the main determinants concerning both short- and long- term outcomes in renal graft recipients. Chemokines and their receptors play a diversified and important role, either homeostatic or inflammatory and direct different immune-competent cell types to the allograft. While deeply studied in the last two decades, controversy persists as a result of chemokines’ pleiotropic actions. We report our analysis of CCR1, CCR3, CCR7, CCL5 and CX3CL1 expression or synthesis by graft-infiltrating cells in human kidney transplants (KTx). At the same time, we tested their robustness in diagnosing acute rejection. Methods: Fine-needle aspiration biopsies (Fnab) were performed either on days 7 or 14 post-transplantation among stable KTx and on the day of acute rejection (AR) diagnosis. Fnab cytopreparations were studied by the enzymatic avidin-biotin complex staining for CCR1, CCR3, CCR7 and CX3CL1. From another subgroup of cases, Fnab samples were cultured for 48 hours and the supernatants were analysed for CCL5 by ELISA. Results: The group of AR cases showed a significantly up-regulated expression of CCR1, CCR3, CCR7 and CX3CL1 and a significantly higher synthesis of CCL5. The positive predictive values were respectively 92%, 97%, 85%, 76% and 78% and negative predictive values were by the same order, 100%, 73%, 100%, 98% and 83%. Conclusions: Our study permits us to advance that CCR1 and CCR3 play a significant and non-redundant role in acute rejection, and it is the first report of CCR3 association with rejection, probably related to CCL5. The presence inside the graft of significant up-regulation for CCR7 surmises that part of antigen presentation may be performed there without being restricted to secondary lymphoid sites. Our results with CX3CL1 confirm other reports.

Helicobacter pylori and microRNAs:Relation with innate immunity and progression of preneoplastic conditions

The accepted paradigm for intestinal-type gastric cancer pathogenesis is a multistep progression from chronic gastritis induced by Helicobacter pylori(H. pylori) to gastric atrophy, intestinal metaplasia, dysplasia and ultimately gastric cancer. The genetic and molecular mechanisms underlying disease progression are still not completely understood as only a fraction of colonized individuals ever develop neoplasia suggesting that bacterial, host and environmental factors are involved. Micro RNAs are noncoding RNAs that may influence H. pylori-related pathology through the regulation of the transcription and expression of various genes, playing an important role in inflammation, cell proliferation, apoptosis and differentiation. Indeed, H. pylori have been shown to modify micro RNA expression in the gastric mucosa and micro RNAs are involved in the immune host response to the bacteria and in the regulation of the inflammatory response. Micro RNAs have a key role in the regulation of inflammatory pathways and H. pylori may influence inflammation-mediated gastric carcinogenesis possibly through DNA methylation and epigenetic silencing of tumor suppressor micro RNAs. Furthermore, micro RNAs influenced by H. pylori also have been found to be involved in cell cycle regulation, apoptosis and epithelial-mesenchymal transition. Altogether, micro RNAs seem to have an important role in the progression from gastritis to preneoplastic conditions and neoplastic lesions and since each micro RNA can control the expression of hundreds to thousands of genes, knowledge of micro RNAs target genes and their functions are of paramount importance. In this article we present a comprehensive review about the role of micro RNAs in H. pylori gastric carcinogenesis, identifying the micro RNAs downregulated and upregulated in the infection and clarifying their biological role in the link between immune host response, inflammation, DNA methylation and gastric carcinogenesis.

Gastric cancer in a Caucasian population: Role of pepsinogen C genetic variants

瞄准：在胃蛋白酶原 C (PGC ) 基因学习插入 / 删除多型性的角色，为胃粘膜的终端区别的一个有效标记，在到胃的损害的开发的危险性。方法：没有肿瘤的疾病的证据，学习与已知的胃的损害的 99 件样品和 127 件样品被执行。PCR 被采用， 6 多态的等位基因被放大：等位基因 1 (510 bp ) ，等位基因 2 (480 bp ) ，等位基因 3/4 (450/460 bp ) ，等位基因 5 (400 bp ) 并且等位基因 6 (310 bp ) 。结果：我们的结果表明等位基因 6 搬运人似乎对任何胃的损害的发展有保护(或 = 0.34；P【0.001 ) ，与象萎缩或肠的组织变形那样的胃的腺癌联系的 non-dysplastic 损害(或 = 0.28；P【0.001 ) 或侵略 GC (或 = 0.39；P = 0.004 ) 。结论：我们的学习表明等位基因 6 搬运人地位在胃的损害的发展有一个保护的角色，可能由于它有 PGC 的更高的表示的协会。而且，在控制组的等位基因 6 搬运人的频率比在亚洲人口获得了高是远的，它可能代表在白种人和亚洲人口之间的基因差距。

Endoscopic mucosal resection and endoscopic submucosal dissection in the treatment of sporadic nonampullary duodenal adenomatous polyps

Although uncommon, sporadic nonampullary duodenal adenomas have a growing detection due to the widespread of endoscopy. Endoscopic therapy is being increasingly used for these lesions, since surgery, considered the standard treatment, carries significant morbidity and mortality. However, the knowledge about its risks and benefits is limited, which contributes to the current absence of standardized recommendations. This review aims to discuss the efficacy and safety of endoscopic mucosal resection(EMR) and endoscopic submucosal dissection(ESD) in the treatment of these lesions. A literature review was performed, using the Pubmed database with the query: "(duodenum or duodenal)(endoscopy or endoscopic) adenoma resection", in the human species and in English. Of the 189 retrieved articles, and after reading their abstracts, 19 were selected due to their scientific interest. The analysis of their references, led to the inclusion of 23 more articles for their relevance in this subject. The increased use of EMR in the duodenum has shown good results with complete resection rates exceeding 80% and low complication risk(delayed bleeding in less than 12% of the procedures). Although rarely used in the duodenum, ESD achieves close to 100% complete resection rates, but is associated with perforation and bleeding risk in up to one third of the cases. Even though literature is insufficient to draw definitive conclusions, studies suggest that EMR and ESD are valid options for the treatment of nonampullary adenomas. Thus, strategies to improve these techniques, and consequently increase the effectiveness and safety of the resection of these lesions, should be developed.

Current role and future perspectives of cardiac rehabilitation in coronary heart disease

Ischaemic heart disease(IHD)is a major cause of morbidity and mortality worldwide.While there have been major advances in this field,these patients are still a higher risk subgroup.As such,strategies to mitigate risk and tailor secondary prevention measures are of the utmost relevance.Cardiac rehabilitation(CR),encompassing several domains including exercise training,cardiovascular risk factor optimization,nutritional and psychological assessments,as well as other ancillary interventions has shown to be one of the pillars in the contemporary management of patients with IHD.Indeed,CR is associated with several benefits in this population,ranging from functional capacity to improvements in outcomes.Whilst this,there are still several issues concerning the optimal application of CR which are still not fully ascertained,such as lack of referral and completion,as well as questions related to programme design(particularly among patients with multiple comorbidities).In this review,we aim at presenting a pragmatic overview on the current role of CR in the management of individuals with IHD,while also discussing some of the caveats in the current data,as well as future concepts which could help improve the uptake and personalization of this pivotal time-tested intervention.

Effects of natural mineral-rich water consumption on the expression of sirtuin 1 and angiogenic factors in the erectile tissue of rats with fructose-induced metabolic syndrome

Consuming a high-fructose diet induces metabolic syndrome （MS）-Iike features, including endothelial dysfunction. Erectile dysfunction is an early manifestation of endothelial dysfunction and systemic vascular disease. Because mineral deficiency intensifies the deleterious effects of fructose consumption and mineral ingestion is protective against MS, we aimed to characterize the effects of 8weeks of natural mineral-rich water consumption on the structural organization and expression of vascular growth factors and receptors on the corpus cavernosum （CC） in 10% fructose-fed Sprague-Dawley rats （FRUCT）. Differences were not observed in the organization of the CC either on the expression of vascular endothelial growth factor （VEGF） or the components of the angiopoietins/Tie2 system. However, opposing expression patterns were observed for VEGF receptors （an increase and a decrease for VEGFR1 and VEGFR2, respectively） in FRUCT animals, with these patterns being strengthened by mineral-rich water ingestion. Mineral-rich water ingestion （FRUCTMIN） increased the proportion of smooth muscle cells compared with FRUCT rats and induced an upregulatory tendency of sirtuin I expression compared with the control and FRUCT groups. Western blot results were consistent with the dual immunofluorescence evaluation. Plasma oxidized low-density lipoprotein and plasma testosterone levels were similar among the experimental groups, although a tendency for an increase in the former was observed in the FRUCTMIN group. The mineral-rich water-treated rats presented changes similar to those observed in rats treated with MS-protective polyphenol-rich beverages or subjected to energy restriction, which led us to hypothesize that the effects of mineral-rich water consumption may be more vast than those directly observed in this study.

Capsule enteroscopy is useful for the therapeutic management of Crohn's disease

AIM: To analyze therapeutic changes in Crohn's disease(CD) patients following video capsule endoscopy(VCE) and to assess the usefulness of Lewis score and the Patency Capsule.METHODS: Patency Capsule was performed in every patient that had indication for VCE, and those with negative patency did not undergo VCE. Patients with established CD that underwent VCE between January 2011 and February 2014 were selected for this study; those with suspected CD were excluded, independent of VCE results, since our purpose was to address differences in therapeutic regimen in CD patients before and after VCE. Patients with inconclusive VCE were also excluded. Patients had to be free of non-steroidal anti-inflammatories for at least 1 mo. Those patients who met these criteria were allocated into one of three groups: Staging group(asymptomatic CD patients that underwent VCE for staging of CD), Flare group(patients with active CD), or Post-op group(CD patients evaluated for post-operative recurrence). Lewis score was calculated for every VCE procedure. Statisticalanalysis was performed to address the impact of VCE findings on the therapeutic management of CD patients and to evaluate the utility of the Lewis score.RESULTS: From a total of 542 VCEs, 135 were performed in patients with CD. Patency capsule excluded nearly 25% of the patients who were supposed to undergo VCE. No videocapsule retention during VCE was reported. From these 135 patients, 29 were excluded because CD diagnosis was not established at the time of VCE. Therefore, a total of 106 patients were included in the final analysis. From these, the majority were in the Staging group(n = 73, 69%), and the remaining were in the Flare(n = 23, 22%) or Post-op(n = 10, 9%) group. Median time between diagnosis and VCE was 5.5 years. Overall, VCE determined changes in the treatment of 40% of patients: only 21% remained free of immunosuppressors after VCE compared to 44% before VCE(P < 0.001). The differences in therapy before and after VCE achieved statistical significance in the Staging and Flare groups. In addition, patients were significantly different when stratified regarding time since diagnosis to the date of VCE. A higher Lewis score was associated with therapeutic modifications(P < 0.0001); where a score higher than 1354 was related to 90% probability of changing therapy [area under the receiver operative characteristic(AUROC) 0.80(95%CI: 0.69-0.88)]. CONCLUSION: VCE significantly changed the therapeutic management of CD patients, even in those with long-term disease. Systematic use of Patency capsule allowed for no videocapsule retention.

Diagnosis and treatment of iron-deficiency anemia in gastrointestinal bleeding:A systematic review

BACKGROUND Anemia is considered a public health issue and is often caused by iron deficiency.Iron-deficiency anemia(IDA)often originates from blood loss from lesions in the gastrointestinal tract in men and postmenopausal women,and its prevalence among patients with gastrointestinal bleeding has been estimated to be 61%.However,few guidelines regarding the appropriate investigation of patients with IDA due to gastrointestinal bleeding have been published.AIM To review current evidence and guidelines concerning IDA management in gastrointestinal bleeding patients to develop recommendations for its diagnosis and therapy.METHODS Five gastroenterology experts formed the Digestive Bleeding and Anemia Workgroup and conducted a systematic literature search in PubMed and professional association websites.MEDLINE(via PubMed)searches combined medical subject headings(MeSH)terms and the keywords“gastrointestinal bleeding”with“iron-deficiency anemia”and“diagnosis”or“treatment”or“management”or“prognosis”or“prevalence”or“safety”or“iron”or“transfusion”or“quality of life”,or other terms to identify relevant articles reporting the management of IDA in patients over the age of 18 years with gastrointestinal bleeding;retrieved studies were published in English between January 2003 and April 2019.Worldwide professional association websites were searched for clinical practice guidelines.Reference lists from guidelines were reviewed to identify additional relevant articles.The recommendations were developed by consensus during two meetings and were supported by the published literature identified during the systematic search.RESULTS From 494 Literature citations found during the initial literature search,17 original articles,one meta-analysis,and 13 clinical practice guidelines were analyzed.Based on the published evidence and clinical experience,the workgroup developed the following ten recommendations for the management of IDA in patients with gastrointestinal bleeding:(1)Evaluation of hemoglobin and iron status;(2)Laboratory testing;(3)Target treatment population identification;(4)Indications for erythrocyte transfusion;(5)Treatment targets for erythrocyte transfusion;(6)Indications for intravenous iron;(7)Dosages;(8)Monitoring;(9)Indications for intravenous ferric carboxymaltose treatment;and(10)Treatment targets and monitoring of patients.The workgroup also proposed a summary algorithm for the diagnosis and treatment of IDA in patients with acute or chronic gastrointestinal bleeding,which should be implemented during the hospital stay and follow-up visits after patient discharge.CONCLUSION These recommendations may serve as a starting point for clinicians to better diagnose and treat IDA in patients with gastrointestinal bleeding,which ultimately may improve health outcomes in these patients.

Could sport be part of pediatric obesity prevention and treatment? Expert conclusions from the 28th European Childhood Obesity Group Congress

The prevalence of pediatric obesity continues to increase worldwide,bringing with it various metabolic,functional,social,and psychological complications.1 Both the prevention and treatment of childhood obesity must be based on multidisciplinary approaches combining nutrition,physical activity(PA),and psychological support.2 As an essential element of these multicomponent strategies,regular physical activity has been acknowledged as having beneficial effects on children's and adolescents,body composition,physical fitness,and metabolic profile,as well as on their health-related quality of life,social and psychological health,and academic achievement.3,4 Given that only a relatively small proportion of children and adolescents meet the public health recommendations for PA,5 and given that weight loss exercise-based interventions suffer from a high attrition rate,there is a clear need for appropriate PAs.

Exosomal glypican-1 is elevated in pancreatic cancer precursors and can signal genetic predisposition in the absence of endoscopic ultrasound abnormalities

BACKGROUND Individuals within specific risk groups for pancreatic ductal adenocarcinoma(PDAC)[mucinous cystic lesions(MCLs),hereditary risk(HR),and new-late onset diabetes mellitus(NLOD)]represent an opportunity for early cancer detection.Endoscopic ultrasound(EUS)is a premium image modality for PDAC screening and precursor lesion characterization.While no specific biomarker is currently clinically available for this purpose,glypican-1(GPC1)is overexpressed in the circulating exosomes(crExos)of patients with PDAC compared with healthy subjects or those harboring benign pancreatic diseases.AIM To evaluate the capacity of GPC1+crExos to identify individuals at higher risk within these specific groups,all characterized by EUS.METHODS This cross-sectional study with a prospective unicentric cohort included 88 subjects:40 patients with MCL,20 individuals with HR,and 20 patients with NLOD.A control group(CG)was submitted to EUS for other reasons than pancreatic pathology,with normal pancreas and absence of hereditary risk factors(n=8).The inclusion period was between October 2016 and January 2019,and the study was approved by the Ethics Committee of Centro Hospitalar Universitário de São João,Porto,Portugal.All patients provided written informed consent.EUS and blood tests for quantification of GPC1+crExos by flow cytometry and carbohydrate antigen 19-9(CA 19-9)levels by ELISA were performed in all subjects.EUS-guided tissue acquisition was done whenever necessary.For statistical analysis,SPSS®27.0(IBM Corp.,Armonk,NY,United States)version was used.All graphs were created using GraphPad Prism 7.00(GraphPad Software,San Diego,CA,United States).RESULTS Half of MCLs harbored worrisome features(WF)or high-risk stigmata(HRS).Pancreatic abnormalities were detected by EUS in 10.0%and 35.0%in HR and NLOD individuals,respectively,all considered non-malignant and“harmless.”Median levels of GPC1+crExos were statistically different:MCL[99.4%,interquartile range(IQR):94.9%-99.8%],HR(82.0%,IQR:28.9%-98.2%),NLOD(12.6%,IQR:5.2%-63.4%),and CG(16.2%,IQR:6.6%-20.1%)(P<0.0001).Median levels of CA 19-9 were within the normal range in all groups(standard clinical cut-off of 37 U/mL).Within HR,individuals with a positive history of cancer had higher median levels of GPC1+crExos(97.9%;IQR:61.7%-99.5%),compared to those without(59.7%;IQR:26.3%-96.4%),despite no statistical significance(P=0.21).Pancreatic cysts with WF/HRS were statistically associated with higher median levels of GPC1+crExos(99.6%;IQR:97.6%-99.8%)compared to those without(96.5%;IQR:81.3%-99.5%)(P=0.011),presenting an area under the receiver operating characteristic curve value of 0.723(sensitivity 75.0%and specificity 67.7%,using a cutoff of 98.5%;P=0.012).CONCLUSION GPC1+crExos may act as biomarker to support the diagnosis and stratification of PDAC precursor lesions,and in signaling individuals with genetic predisposition in the absence of EUS abnormalities.

Lot to give,got to live-the restless minds of the“Liver on Tour”project

The Liver on Tour was a special project devoted to increase the public awareness on Liver Health and Liver Diseases that the Portuguese Association for the Study of Liver Diseases launched throughout the country in 2010.

Toll-Like Receptors as Biomarkers of Gastric Carcinogenesis:Implications for Diagnosis,Prognosis and Treatment

Toll-like receptors (TLR) are essential for Helicobacter pylori (Hp) recognition and subsequent innate and adaptive immunity responses. TLR2 appears to be the receptor responsible for most of the immunologic reaction against Hp infection. However, TLR4, TLR9 and eventually TLR5 may also have a synergic effect with TLR2 against Hp. It has been shown that gastric Hp infection increases TLR expression in the gastric mucosa. Moreover, recent studies have shown that human gastric carcinogenesis is associated not only with increased expression of TLR but also with decreased expression of their inhibitors such as Toll-Interacting Protein (TOLLIP) and peroxisome proliferator-activated receptor (PPAR)-g. Indeed, gastric dysplasia and adenocarcinoma are associated with high expression levels of TLR and low levels of TOLLIP and PPAR-g, suggesting increased activation of these receptors throughout human gastric carcinogenesis. In this article we discuss how these novels findings could be used not only for the diagnosis and prognosis of gastric lesions associated with Hp infection but also for their treatment. Specifically, we discuss the potential use of TLR agonists in addition to antibiotics to improve eradication rates of Hp and of TLR antagonists to slow the progression of gastric preneoplastic lesions. We also discuss the potential value of TLR signalling blockers and quantification of tumoral TLR expression, respectively, in the treatment and prognosis of gastric cancer. In conclusion, TLRs can be an important link between Hp and the sequence of gastric carcinogenesis and they can be used as biomarkers of gastric carcinogenesis. In this article, future lines of investigation related with these novel scientific findings are proposed and discussed.

Conscience imperative of providing information and knowledge in hepatology:The Portuguese approach

The last 25 years have been a thrilling time for the Portuguese hepatologists. Our national meetings have been providing the forum for the exchange of scientific ideas and the presentation of clinical research in clinical Hepatology, a growing world of knowledge in medical care. Bridging the gaps between technology and clinical daily practice, the latest development and the almost humble bedside care, has been a challenge for the increasing numbers of doctors devoted to the diagnostic and treatment of liver disease. We have been trying to be very persuasive among the Portuguese medical community in demonstrating that cultural vectors may influence the origin and pattern of liver disease among us. Viral hepatitis and alcoholic liver disease are paradigms of this assumption. Chronic liver disease is responsible for 3% of the deaths in Portugal, which accounts for the top ten causes of death in our country. The recognition by public health authorities of this fact along with the national net of hepatology outpatient consultation in public hospitals, has brought liver diseases under the lights of doctors concerns and an increased public awareness of its dimension.

Spondylodiscitis Caused by Streptococcus dysgalactiae Subspecies Equisimilis:A Case Report of an Increasingly Recognized Pathogenic Organism

Streptococcus dysgalactiae subspecies equisimilis (SDSE) is a β-hemolytic Streptococcus that possesses genetic and clinical similarities to Streptococcus pyogenes. It is increasingly recognized as the etiological microorganism of invasive diseases. We report a case of a 74-year-old male who was admitted to this hospital with lower back and neck pain and infected with leg ulcer. The diagnosis of spondylodiscitis C2-C3 and L1-L3 caused by Streptococcus dysgalactiae subsp. equisimilis was made. The present case demonstrates the risk of older patients of developing invasive disease upon skin infection with Streptococcus dysgalactiae subsp. equisimilis, even when risk factors are absent or well controlled (as was diabetes mellitus in this case), suggesting that the pathogenic potential of SDSE should not be underestimated.

国际糖尿病足工作组:指南的制定和方法学(2023)——《国际糖尿病足工作组:糖尿病相关的足病预防与管理指南(2023)》的一部分

糖尿病相关的足病是造成糖尿病患者经济负担和增加社会成本的主要原因之一。本指南以主要目标为导向,以循证医学为依据,且在全球得到合理实施。践行国际糖尿病相关的足病指南对于减轻患者经济负担和社会成本有着重要影响。国际糖尿病足工作组(IWGDF)从1999年起开始发布并随后更新国际指南。2023年更新版指南相关推荐均基于推荐、评估、发展和评价分级(GRADE)系统,包括制定相关临床问题和重要结局,完成系统的文献系统综述和荟萃分析,完成评判表汇总,并且给予具体、明确、操作性强的推荐以及理论依据。本文阐述了《国际糖尿病足工作组:糖尿病相关的足病预防和管理指南(2023版)》(以下简称为指南)的制定过程。指南由7个部分组成,包括预防、糖尿病相关的足溃疡分类、减压、周围动脉病变、感染、创面愈合干预以及活动性夏科神经骨关节病,分别由7个独立的国际专家工作组编写。IWGDF编辑委员会对7个章节进行了整合和简化,形成IWGDF实践指南。指南中的每条推荐均经过IWGDF编辑委员会成员和相关领域的独立的国际专家审阅通过。本文是IWGDF指南的制定和方法学。我们相信,医务人员、公共卫生机构和政策制定者采用和实施2023年IWGDF指南,将会改善糖尿病相关的足病的预防和管理水平,从而减少全球该疾病患者和减轻该疾病引起的全球社会负担。

Emergency Care for Children and Adolescents after Sexual Violence, in Brazil’s Capital, Brasilia

Objective: Sexual violence affects women of all ages but, more commonly, children and adolescents. This study aimed to identify the extent to which services are being provided at the hospitals responsible for the emergency care of children and adolescents who have suffered sexual violence and to determine whether there is any difference in the provision of such services as a function of the victim’s age. Method: This cross-sectional study investigated differences in the care received by female children and adolescents who are victims of sexual violence in a capital city, comparing the treatment given to girls under 15 with that given to adolescents of 15 to 19 years of age. The data were extracted from the State Department of Health database between 01/01/2012 and 31/12/2016. Results: Children under 15 were much less likely to receive prophylaxis against HIV, sexually transmitted infections and hepatitis B, with the number of adolescent girls treated adequately corresponding to between twice and almost three times the number of children treated prophylactically. Only 10% of girls under 15 received emergency contraception. Conclusion: The lack of standard care established by the Ministry of Health highlights the need for urgent debates both locally and probably throughout the country, as the situation may be similar in other regions of the country.

Solutions for submucosal injection: What to choose and how to do it

During the past decades, endoscopic resection techniques have gradually improved and gained more importance for the management of premalignant lesions and early cancers. These endoscopic resection techniques can be divided in 3 major groups: snare polipectomy, endoscopic mucosal resection(EMR) and endoscopic submucosal dissection(ESD). The use of submucosal injection is essential for the majority of EMR techniques and is an integral part of ESD,whereas during polipectomy it is not crucial in most cases except to prevent bleeding in large polyps and/or those with large stalks as an alternative to mechanical methods. Injection provides a lifting up effect of the lesion separating it from the muscular layer, thereby reducing thermal injury and the risk of perforation and bleeding while also facilitating en-bloc resection by improving technical feasibility. With this work, we aim to review the most common endoscopic resection techniques and the importance of submucosal injection in each one of them. For that, we present some of the most commonly used submucosal injection solutions, taking into account their advantages and disadvantages. We also discuss, based on current recommendations and our own experience, how and when to preform submucosal injection, depending on lesions features and endoscopic resection technique that′s being used, to assure complete resection and to prevent associated adverse events. Finally, we also present and discuss some new proposed submucosal injection solutions,endoscopic resection techniques and devices that may have a major impact on the future of therapeutic endoscopy.

-765G > C COX-2 polymorphism may be a susceptibility marker for gastric adenocarcinoma in patients with atrophy or intestinal metaplasia

AIM: To investigate the relationship between the -765G > C COX-2 polymorphism and the development of different gastric lesions: atrophy or intestinal metaplasia and gastric adenocarcinoma. METHODS: A cross-sectional study was performed involving 320 Portuguese individuals (210 without evidence of neoplastic disease, 73 patients with gastric adenocarcinomas and 37 with atrophy or intestinal metaplasia) using a PCR-RFLP method. RESULTS: -765C allele was overrepresented in the patients with gastric adenocarcinoma (51%) when compared either with the control group (38%) or patients with atrophy or intestinal metaplasia (27%). Callele was found to be very common in our population (0.22), and a multivariate logistic regression analysis revealed nearly 3-fold increased risk for the progression to gastric adenocarcinoma in patients with atrophy or intestinal metaplasia carrying the -765C allele (OR = 2.67, 95% CI = 1.03-6.93; P = 0.04).considered as another susceptibility marker for gastric adenocarcinoma development in patients with atrophy or intestinal metaplasia.

Venous thrombosis and prothrombotic factors in inflammatory bowel disease

Patients with inflammatory bowel disease(IBD)may have an increased risk of venous thrombosis(VTE).PubMed,ISI Web of Knowledge and Scopus were searched to identify studies investigating the risk of VTE and the prevalence of acquired and genetic VTE risk factors and prothrombotic abnormalities in IBD.Overall,IBD patients have a two-to fourfold increased risk of VTE compared with healthy controls,with an overall incidence rate of 1%-8%.The majority of studies did not show significant differences in the risk of VTE between Crohn’s disease and ulcerative colitis.Several acquired factors are responsible for the increased risk of VTEin IBD:inflammatory activity,hospitalisation,surgery,pregnancy,disease phenotype(e.g.,fistulising disease,colonic involvement and extensive involvement)and drug therapy(mainly steroids).There is also convincing evidence from basic science and from clinical and epidemiological studies that IBD is associated with several prothrombotic abnormalities,including initiation of the coagulation system,downregulation of natural anticoagulant mechanisms,impairment of fibrinolysis,increased platelet count and reactivity and dysfunction of the endothelium.Classical genetic alterations are not generally found more often in IBD patients than in nonIBD patients,suggesting that genetics does not explain the greater risk of VTE in these patients.IBD VTE may have clinical specificities,namely an earlier first episode of VTE in life,high recurrence rate,decreased efficacy of some drugs in preventing further episodes and poor prognosis.Clinicians should be aware of these risks,and adequate prophylactic actions should be taken in patients who have disease activity,are hospitalised,are submitted to surgery or are undergoing treatment.

Innate immunity and hepatocarcinoma:Can toll-likereceptors open the door to oncogenesis?

Hepatocarcinoma(HCC) is a highly prevalent cancer worldwide and its inflammatory background was established long ago.Recent studies have shown that innate immunity is closely related to the HCC carcinogenesis.An effective innate immunity response relies on the tolllike receptors(TLR) found in several different liver cells which,through different ligands and many signaling pathways can elicit,not only a pro-inflammatory but also an oncogenic or anti-oncogenic response.Our aim was to study the role of TLRs in the liver oncogenesis and as a consequence their value as potential therapeutic targets.We performed a systematic review of PubMed searching for original articles studying the relationship between HCC and TLRs until March 2015.TLR2 appears to be a fundamental stress-sensor as its absence reveals an augmented tendency to accumulate DNAdamages and to cell survival.However,pathways are still not fully understood as TLR2 up-regulation was also associated to enhanced tumorigenesis.TLR3 has a wellknown protective role influencing crucial processes like angiogenesis,cell growth or proliferation.TLR4 works as an interesting epithelial-mesenchymal transition's inducer and a promoter of cell survival probably inducing HCC carcinogenesis even though an anti-cancer role has already been observed.TLR9's influence on carcinogenesis is also controversial and despite a potential anticancer capacity,a pro-tumorigenic role is more likely.Genetic polymorphisms in some TLRs have been found and its influence on the risk of HCC has been reported.As therapeutic targets,TLRs are already in use and have a great potential.In conclusion,TLRs have been shown to be an interesting influence on the HCCs microenvironment,with TLR3 clearly determining an antitumour influence.TLR4 and TLR9 are considered to have a positive relationship with tumour development even though,in each of them anti-tumorigenic signals have been described.TLR2 presents a more ambiguous role,possibly depending on the stage of the inflammationHCC axis.