Many studies have demonstrated the linkage between the IBD3 region(6p21.1-23),an area which encompasses the famous human leukocyte antigen(HLA) complex,and Crohn's disease(CD) or ulcerative colitis(UC).IBD3 is the...Many studies have demonstrated the linkage between the IBD3 region(6p21.1-23),an area which encompasses the famous human leukocyte antigen(HLA) complex,and Crohn's disease(CD) or ulcerative colitis(UC).IBD3 is the only region that meets genome-wide significance,and provides stronger evidence of the linkage than 16p13.1-16q12.2(IBD1),the locus that contains the susceptibility gene CARD15.However,despite these findings,IBD3 susceptibility genes remain elusive and unclear due to the strong linkage disequilibrium,extensive polymorphism,and high gene density that characterize this area and also due to varying allele frequencies in populations around the world.This area presents an extremely high abundance of genes,including the classical and non-classical major histocompatibility complex(MHC) class Ⅰ and Ⅱ genes,and other genes,namely MHC class Ⅲ genes tumor necrosis factor(TNF)-α and-β,and Hsp,whose proteins play key functions in immunological processes.To date,it is not clear which genes within the MHC family contribute to the IBD pathogenesis,although certain HLA alleles have been associated with IBD.Recent insights into the biological function of other genes encoded within the IBD3 region,such as the MHC class Ⅰ chain-related(MIC) genes,have led investigators to a more comprehensive exploration of this region.MHC class Ⅰ chain-related molecule A(MICA) is highly polymorphic and interacts with NKG2 D,its receptor on the surface of NK,Tγδ and T CD8+ cells.Increased expression of MICA in intestinal epithelial cells and increased expression of NKG2 D in CD4+ T cells(lamina propria) in patients with CD have also been reported.MICA alleles have also been associated with IBD,and a variation at amino acid position 129 of the α2-heavy chain domain seems to categorize MICA alleles into strong and weak binders of NKG2 D receptor,thereby influencing the effector cells' function.In this regard,a relevant role of MICA-129-Val/Met single nucleotide polymorphism has recently been implicated in the pathogenesis of IBD.TNF-α and-β also play an important role in inflammatory response.In fact,IBD is commonly treated with TNF-α inhibitors.Additionally,polymorphisms of TNF-α gene are known to affect the gene expression level and particular TNF-α genotypes may influence the response of IBD patients treated with TNF-α inhibitors.展开更多
AIM To detect hyper-conserved regions in the hepatitis B virus(HBV) X gene(HBX) 5' region that could be candidates for gene therapy.METHODS The study included 27 chronic hepatitis B treatmentnaive patients in vari...AIM To detect hyper-conserved regions in the hepatitis B virus(HBV) X gene(HBX) 5' region that could be candidates for gene therapy.METHODS The study included 27 chronic hepatitis B treatmentnaive patients in various clinical stages(from chronic infection to cirrhosis and hepatocellular carcinoma, both HBeA g-negative and HBeA g-positive), and infected with HBV genotypes A-F and H. In a serum sample from each patient with viremia > 3.5 log IU/m L, the HBX 5' end region [nucleotide(nt) 1255-1611] was PCRamplified and submitted to next-generation sequencing(NGS). We assessed genotype variants by phylogenetic analysis, and evaluated conservation of this region by calculating the information content of each nucleotide position in a multiple alignment of all unique sequences(haplotypes) obtained by NGS. Conservation at the HBx protein amino acid(aa) level was also analyzed.RESULTS NGS yielded 1333069 sequences from the 27 samples, with a median of 4578 sequences/sample(2487-9279, IQR 2817). In 14/27 patients(51.8%), phylogenetic analysis of viral nucleotide haplotypes showed a complex mixture of genotypic variants. Analysis of the information content in the haplotype multiple alignments detected 2 hyper-conserved nucleotide regions, one in the HBX upstream non-coding region(nt 1255-1286) and the other in the 5' end coding region(nt 1519-1603). This last region coded for a conserved amino acid region(aa 63-76) that partially overlaps a Kunitz-like domain.CONCLUSION Two hyper-conserved regions detected in the HBX 5' end may be of value for targeted gene therapy, regardless of the patients' clinical stage or HBV genotype.展开更多
Hepatitis delta virus(HDV) seems to strongly suppress hepatitis B virus(HBV)replication, although little is known about the mechanism of this interaction. Both these viruses show a dynamic distribution of mutants, res...Hepatitis delta virus(HDV) seems to strongly suppress hepatitis B virus(HBV)replication, although little is known about the mechanism of this interaction. Both these viruses show a dynamic distribution of mutants, resulting in viral quasispecies. Next-generation sequencing is a viable approach for analyzing the composition of these mutant spectra. As the regulatory hepatitis B X protein(HBx) is essential for HBV replication, determination of HBV X gene(HBX)quasispecies complexity in HBV/HDV infection compared to HBV monoinfection may provide information on the interactions between these two viruses.AIM To compare HBV quasispecies complexity in the HBX 5' region between chronic hepatitis delta(CHD) and chronic HBV mono-infected patients.METHODS Twenty-four untreated patients were included: 7/24(29.2%) with HBeAgnegative chronic HBV infection(CI, previously termed inactive carriers), 8/24(33.3%) with HBeAg-negative chronic hepatitis B(CHB) and 9/24(37.5%) with CHD. A serum sample from each patient was first tested for HBV DNA levels.The HBX 5' region [nucleotides(nt) 1255-1611] was then PCR-amplified for subsequent next-generation sequencing(MiSeq, Illumina, United States). HBV quasispecies complexity in the region analyzed was evaluated using incidencebased indices(number of haplotypes and number of mutations), abundancebased indices(Hill numbers of order 1 and 2), and functional indices(mutation frequency and nucleotide diversity). We also evaluated the pattern of nucleotide changes to investigate which of them could be the cause of the quasispecies complexity.RESULTS CHB patients showed higher median HBV-DNA levels [5.4 logIU/mL,interquartile range(IQR) 3.5-7.9] than CHD(3.4 logIU/mL, IQR 3-7.6)(P = n.s.)or CI(3.2 logIU/mL, IQR 2.3-3.5)(P < 0.01) patients. The incidence and abundance indices indicated that HBV quasispecies complexity was significantly greater in CI than CHB. A similar trend was observed in CHD patients, although only Hill numbers of order 2 showed statistically significant differences(CHB2.81, IQR 1.11-4.57 vs CHD 8.87, 6.56-11.18, P = 0.038). There were no significant differences in the functional indices, but CI and CHD patients also showed a trend towards greater complexity than CHB. No differences were found for any HBV quasispecies complexity indices between CHD and CI patients. G-to-A and C-to-T nucleotide changes, characteristic of APOBEC3 G, were higher in CHD and CI than in CHB in genotype A haplotypes, but not in genotype D. The proportion of nt G-to-A vs A-to-G changes and C-to-T vs T-to-C changes in genotype A and D haplotypes in CHD patients showed no significant differences. In CHB and CI the results of these comparisons were dependent on HBV genotype.CONCLUSION The lower-replication CHD and CI groups show a trend to higher quasispecies complexity than the higher-replication CHB group. The mechanisms associated with this greater complexity require elucidation.展开更多
AIM To determine the variability/conservation of the domain of hepatitis B virus(HBV) pre S1 region that interacts with sodium-taurocholate cotransporting polypeptide(hereafter, NTCP-interacting domain) and the preval...AIM To determine the variability/conservation of the domain of hepatitis B virus(HBV) pre S1 region that interacts with sodium-taurocholate cotransporting polypeptide(hereafter, NTCP-interacting domain) and the prevalence of the rs2296651 polymorphism(S267 F, NTCP variant) in a Spanish population. METHODS Serum samples from 246 individuals were included and divided into 3 groups: patients with chronic HBV infection(CHB)(n = 41, 73% Caucasians), patients with resolved HBV infection(n = 100, 100% Caucasians) and an HBV-uninfected control group(n = 105, 100% Caucasians). Variability/conservation of the amino acid(aa) sequences of the NTCPinteracting domain,(aa 2-48 in viral genotype D) and a highly conserved pre S1 domain associated with virion morphogenesis(aa 92-103 in viral genotype D) were analyzed by next-generation sequencing and compared in 18 CHB patients with viremia > 4 log IU/mL. The rs2296651 polymorphism was determined in all individuals in all 3 groups using an in-house real-time PCR melting curve analysis.RESULTS The HBV pre S1 NTCP-interacting domain showed a high degree of conservation among the examined viral genomes especially between aa 9 and 21(in the genotype D consensus sequence). As compared with the virion morphogenesis domain, the NTCPinteracting domain had a smaller proportion of HBV genotype-unrelated changes comprising > 1% of the quasispecies(25.5% vs 31.8%), but a larger proportion of genotype-associated viral polymorphisms(34% vs 27.3%), according to consensus sequences from Gen Bank patterns of HBV genotypes A to H. Variation/conservation in both domains depended on viral genotype, with genotype C being the most highly conserved and genotype E the most variable(limited finding, only 2 genotype E included). Of note, proline residues were highly conserved in both domains, and serine residues showed changes only to threonine or tyrosine in the virion morphogenesis domain. The rs2296651 polymorphism was not detected in any participant.CONCLUSION In our CHB population, the NTCP-interacting domain was highly conserved, particularly the proline residues and essential amino acids related with the NTCP interaction, and the prevalence of rs2296651 was low/null.展开更多
We report a case of acute severe hepatitis resulting from masitinib in a young amyotrophic lateral sclerosis patient. Hepatotoxicity induced by masitinib,a tyrosine kinase inhibitor,is usually transient with mild elev...We report a case of acute severe hepatitis resulting from masitinib in a young amyotrophic lateral sclerosis patient. Hepatotoxicity induced by masitinib,a tyrosine kinase inhibitor,is usually transient with mild elevation of transaminases,although acute hepatitis has been not reported to date. The hepatitis was resolved after masitinib was discontinued and a combination of prednisone and azathioprine was started. The transaminases returned to baseline normal values five months later. This is the first case in the hepatitis literature associated with masitinib. The autoimmune role of this drug-induced liver injury is discussed. Physicians should be aware of this potential complication.展开更多
Nonalcoholic fatty liver disease(NAFLD)is a heterogeneous and complex disease that is imprecisely diagnosed by liver biopsy.NAFLD covers a spectrum that ranges from simple steatosis,nonalcoholic steatohepatitis(NASH)w...Nonalcoholic fatty liver disease(NAFLD)is a heterogeneous and complex disease that is imprecisely diagnosed by liver biopsy.NAFLD covers a spectrum that ranges from simple steatosis,nonalcoholic steatohepatitis(NASH)with varying degrees of fibrosis,to cirrhosis,which is a major risk factor for hepatocellular carcinoma.Lifestyle and eating habit changes during the last century have made NAFLD the most common liver disease linked to obesity,type 2 diabetes mellitus and dyslipidemia,with a global prevalence of 25%.NAFLD arises when the uptake of fatty acids(FA)and triglycerides(TG)from circulation and de novo lipogenesis saturate the rate of FAβ-oxidation and verylow density lipoprotein(VLDL)-TG export.Deranged lipid metabolism is also associated with NAFLD progression from steatosis to NASH,and therefore,alterations in liver and serum lipidomic signatures are good indicators of the disease’s development and progression.This review focuses on the importance of the classification of NAFLD patients into different subtypes,corresponding to the main alteration(s)in the major pathways that regulate FA homeostasis leading,in each case,to the initiation and progression of NASH.This concept also supports the targeted intervention as a key approach to maximize therapeutic efficacy and opens the door to the development of precise NASH treatments.展开更多
Methionine adenosyltransferases(MATs)are essential enzymes for life as they produce S-adenosylmethionine(SAMe),the biological methyl donor required for a plethora of reactions within the cell.Mammalian systems express...Methionine adenosyltransferases(MATs)are essential enzymes for life as they produce S-adenosylmethionine(SAMe),the biological methyl donor required for a plethora of reactions within the cell.Mammalian systems express two genes,MAT1A and MAT2A,which encode for MATα1 and MATα2,the catalytic subunits of the MAT isoenzymes,respectively.A third gene MAT2B,encodes a regulatory subunit known as MATβwhich controls the activity of MATα2.MAT1A,which is mainly expressed in hepatocytes,maintains the differentiated state of these cells,whilst MAT2A and MAT2B are expressed in extrahepatic tissues as well as non-parenchymal cells of the liver(e.g.,hepatic stellate and Kupffer cells).The biosynthesis of SAMe is impaired in patients with chronic liver disease and liver cancer due to decreased expression and inactivation of MATα1.A switch from MAT1A to MAT2A/MAT2B occurs in multiple liver diseases and during liver growth and dedifferentiation,but this change in the expression pattern of MATs results in reduced hepatic SAMe level.Decades of study have utilized the Mat1a-knockout(KO)mouse that spontaneously develops non-alcoholic steatohepatitis(NASH)and hepatocellular carcinoma(HCC)to elucidate a variety of mechanisms by which MAT proteins dysregulation contributes to liver carcinogenesis.An increasing volume of work indicates that MATs have SAMe-independent functions,distinct interactomes and multiple subcellular localizations.Here we aim to provide an overview of MAT biology including genes,isoenzymes and their regulation to provide the context for understanding consequences of their dysregulation.We will highlight recent breakthroughs in the field and underscore the importance of MAT’s in liver tumorigenesis as well as their potential as targets for cancer therapy.展开更多
Biodegradable stents(BDSs)are an attractive option to avoid ongoing dilation or surgery in patients with benign stenoses of the small and large intestines.The experience with the currently the only BDS for endoscopic ...Biodegradable stents(BDSs)are an attractive option to avoid ongoing dilation or surgery in patients with benign stenoses of the small and large intestines.The experience with the currently the only BDS for endoscopic placement,made of Poly-dioxanone,have shown promising results.However some aspects should be improved as are the fact that BDSs lose their radial force over time due to the degradable material,and that can cause stent-induced mucosal or parenchymal injury.This complication rate and modest clinical efficacy has to be carefully considered in individual patients prior to placement of BDSs.Otherwise,the price of these stents therefore it is nowadays an important limitation.展开更多
Non-alcoholic fatty liver disease(NAFLD) is increasing considerably due to the current lifestyle,which means that it is becoming one of the main indications for liver transplantation.On the other hand,there is a stron...Non-alcoholic fatty liver disease(NAFLD) is increasing considerably due to the current lifestyle,which means that it is becoming one of the main indications for liver transplantation.On the other hand,there is a strong association between NAFLD and cardiovascular disease.This has been evidenced in many studies revealing a higher presence of carotid plaques or carotid intima-media thickness,leading to cardiovascular events and,ultimately,mortality.According to the liver transplant guidelines,screening for heart disease in transplant candidates should be performed by electrocardiogram and transthoracic echocardiography while a stress echocardiogram should be reserved for those with more than two cardiovascular risk factors or greater than 50 years old.However,there are no specific recommendations in NAFLD patients requiring a liver transplantation,despite its well-known cardiovascular risk association.Many studies have shown that these patients probably require a more exhaustive assessment and a global approach including other specialists such as cardiologists or nutritionists.Also,the incidence of cardiovascular disease is also increased in NAFLD patients in the post-transplantation period in comparison with other etiologies,because of the pre-existent risk factors together with the immunosuppressive therapy.Therefore,an early intervention on the lifestyle and the individualized selection of the immunosuppressive regimen could lead to a modification of the cardiovascular risk factors in NAFLD patients requiring a liver transplantation.展开更多
There have been major developments in endoscopic imaging techniques in recent years.Endoscopes with high definition and magnification can provide high quality images that allow for the histological estimation of lesio...There have been major developments in endoscopic imaging techniques in recent years.Endoscopes with high definition and magnification can provide high quality images that allow for the histological estimation of lesions in vivo and in situ when combined with ancillary enhancement techniques such as chromoendoscopy(CE)and virtual CE(narrow band imaging fujinon intelligent chromoendoscopy,or i-Scan).Despite the enormous potential for these advanced techniques,their value and feasibility in the clinic are still doubted,particularly in cases of colonic polyps that are slated for removal,where in vivo characterization may be deemed unnecessary.However,there are several advantages offered by such advanced endoscopic imaging.CE with or without magnification demonstrates highly accurate histology and invasion depth prediction,and virtual CE is a feasible and less cumbersome alternative to CE in terms of histological estimation,though not sufficiently accurate for depth invasion prediction.Furthermore,the supplementary information provided by advanced imaging systems can assist the endoscopist in the selection of a strategic approach,such as in deciding whether a colonic lesion should be resected,left in situ,or requires more intensive surgical treatment.Lastly,advanced high-resolution imaging techniques may be more cost effective,such that histopathology of lowrisk lesions following resection can be eliminated.The results of these evaluations and comparisons with traditional CE are presented and discussed.Taken together,the benefits provided by these advanced capabilities justify their development,and advocates their use for the treatment and management of colonic polyps.展开更多
Endoscopic retrograde cholangiopancreatography (ERCP) is an important tool for the diagnosis and treatment of the hepatobiliary system. The use of fluoroscopy to aid ERCP places both the patient and the endoscopy staf...Endoscopic retrograde cholangiopancreatography (ERCP) is an important tool for the diagnosis and treatment of the hepatobiliary system. The use of fluoroscopy to aid ERCP places both the patient and the endoscopy staff at risk of radiation-induced injury. Radiation dose to patients during ERCP depends on many factors, and the endoscopist cannot control some variables, such as patient size, procedure type, or fluoroscopic equipment used. Previous reports have demonstrated a linear relationship between radiation dose and fluoroscopy duration. When fluoroscopy is used to assist ERCP, the shortest fluoroscopy time possible is recommended. Pulsed fluoroscopy and monitoring the length of fluoroscopy have been suggested for an overall reduction in both radiation exposure and fluoroscopy times. Fluoroscopy time is shorter when ERCP is performed by an endoscopist who has many years experience of performing ERCP and carried out a large number of ERCPs in the preceding year. In general, radiation exposure is greater during therapeutic ERCP than during diagnostic ERCP. Factors associated with prolonged fluoroscopy have been delineated recently, but these have not been validated.展开更多
AIM: To implement a quick and simple test- rapid assessment faecal incontinence score(RAFIS) and show its reliability and validity.METHODS: From March 2008 through March 2010, we evaluated a total of 261 consecutive p...AIM: To implement a quick and simple test- rapid assessment faecal incontinence score(RAFIS) and show its reliability and validity.METHODS: From March 2008 through March 2010, we evaluated a total of 261 consecutive patients, including 53 patients with faecal incontinence. Demographic and comorbidity information was collected. In a single visit, patients were administered the RAFIS. The results obtained with the new score were compared with those of both Wexner score and faecal incontinence quality of life scale(FIQL) questionnaire. The patient withoutinfluence of the surgeon completed the test. The role of surgeon was explaining the meaning of each section and how he had to fill. Reliability of the RAFIS score was measured using intra-observer agreement and Cronbach's alpha(internal consistency) coefficient. Multivariate analysis of the main components within the different scores was performed in order to determine whether all the scores measured the same factor and to conclude whether the information could be encompassed in a single factor. A sample size of 50 patients with faecal incontinence was estimated to be enough to detect a correlation of 0.55 or better at 5% level of significance with 80% power.RESULTS: We analysed the results obtained by 53 consecutive patients with faecal incontinence(median age 61.55 ± 12.49 years) in the three scoring systems. A total of 208 healthy volunteers(median age 58.41 ± 18.41 years) without faecal incontinence were included in the study as negative controls. Pearson's correlation coefficient between "state" and "leaks" was excellent(r = 0.92, P < 0.005). Internal consistency in the comparison of "state" and "leaks" yielded also excellent correlation(Cronbach's α = 0.93). Results in each score were compared using regression analysis and a correlation value of r = 0.98 was obtained with Wexner score. As regards FIQL questionnaire, the values of "r " for the different subscales of the questionnaire were: "lifestyle" r =-0.87, "coping/behaviour" r =-0.91, "depression" r =-0.36 and "embarrassment" r =-0.90,(P < 0.01). A multivariate analysis showed that all the scoring systems measured the same factor. A single factor may explain 80.84% of the variability of FI, so all the scoring systems measure the same factor. Patient's continence improves when RAFIS and Jorge-Wexner scores show low values and when the values obtained in the FIQL questionnaire are high.CONCLUSION: RAFIS is a valid and reliable tool to assess Faecal Incontinence.展开更多
AIM To assess the relationship between the presence of toll-like receptor 4(TLR4) polymorphisms and bacterial infections in cirrhotic patients with ascites. METHODS We prospectively included consecutive patients with ...AIM To assess the relationship between the presence of toll-like receptor 4(TLR4) polymorphisms and bacterial infections in cirrhotic patients with ascites. METHODS We prospectively included consecutive patients with cirrhosis and ascites hospitalized during a 6-year period. Patients with human immunodeficiency virus(HIV) infection or any other immunodeficiency, patients with advanced hepatocellular carcinoma(beyond Milan's criteria) or any other condition determining poor short-term prognosis, and patients with a permanent urinary catheter were excluded. The presence of D299 G and/or T399 I TLR4 polymorphisms was determined by sequencing and related to the incidence and probability of bacterial infections, other complications of cirrhosis, hepatocellular carcinoma, and mortality during follow-up. A multivariate analysis to identify predictive variables of mortality in the whole series was performed. RESULTS We included 258 patients: 28(10.8%) were carriers of D299G and/or T399I TLR4 polymorphisms(polymorphism group) and 230 patients were not(wildtype group). The probability of developing any bacterial infection at one-year follow-up was 78% in the polymorphism group and 69% in the wild-type group(P = 0.54). The one-year probability of presenting infections caused by gram-negative bacilli(51% vs 44%, P = 0.68), infections caused by gram-positive cocci(49% vs 40%, P = 0.53), and spontaneous bacterial peritonitis(29% vs 34%, respectively, P = 0.99) did not differ between the two groups. The oneyear probability of transplant-free survival was 55% in the polymorphism group and 66% in the wild-type group(P = 0.15). Multivariate analysis confirmed that age, Child-Pugh score, active alcohol intake, previous hepatic encephalopathy, hepatocellular carcinoma and serum creatinine were associated with a higher risk of death during follow-up. CONCLUSION Genetic polymorphisms D299 G and/or T399 I of TLR4 do not seem to play a relevant role in the predisposition of cirrhotic patients with ascites to bacterial infections.展开更多
Colorectal cancer(CRC)is one of the most frequent neoplasms and an important cause of mortality in the developed world.This cancer is caused by both genetic and environmental factors although 35%of the variation in CR...Colorectal cancer(CRC)is one of the most frequent neoplasms and an important cause of mortality in the developed world.This cancer is caused by both genetic and environmental factors although 35%of the variation in CRC susceptibility involves inherited genetic differences.Mendelian syndromes account for about5%of the total burden of CRC,with Lynch syndrome and familial adenomatous polyposis the most common forms.Excluding hereditary forms,there is an important fraction of CRC cases that present familial aggregation for the disease with an unknown germline genetic cause.CRC can be also considered as a complex disease taking into account the common diseasecommom variant hypothesis with a polygenic model of inheritance where the genetic components of common complex diseases correspond mostly to variants of low/moderate effect.So far,30 common,low-penetrance susceptibility variants have been identified for CRC.Recently,new sequencing technologies including exomeand whole-genome sequencing have permitted to add a new approach to facilitate the identification of new genes responsible for human disease predisposition.By using whole-genome sequencing,germline mutations in the POLE and POLD1 genes have been found to be responsible for a new form of CRC genetic predisposition called polymerase proofreading-associated polyposis.展开更多
Crohn's disease is a chronic inflammatory condition that may involve any segment of the gastrointestinal tract. Although several drugs have proven efficacy in inducing and maintaining disease in remission, resecti...Crohn's disease is a chronic inflammatory condition that may involve any segment of the gastrointestinal tract. Although several drugs have proven efficacy in inducing and maintaining disease in remission, resectional surgery remains as a cornerstone in the management of the disease, mainly for the treatment of its stenosing and penetrating complications. However, the occurrence of new mucosal (endoscopic) lesions in the neoterminal ileum early after surgery is almost constant, it is followed in the mid-term by clinical symptoms and, in a proportion of patients, repeated intestinal resections are required. Pathogenesis of postoperative recurrence (POR) is not fully understood, but luminal factors (commensal microbes, dietary antigens) seem to play an important role, and environmental and genetic factors may also have a relevant influence. Many studies tried to identify clinical predictors for POR with heterogeneous results, and only smoking has repeatedly been associated with a higher risk of POR. Ileocolonoscopy remains as the gold standard for the assessment of appearance and severity of POR, although the real usefulness of the available endoscopic score needs to be revisited and alternative techniques are emerging. Several drugs have been evaluated to prevent POR with limited success. Smoking cessation seems to be one of the more beneficial therapeutic measures. Aminosalicylates have only proved to be of marginal benefit, and they are only used in low-risk patients. Nitroimidazolic antibiotics, although efficient, are associated with a high rate of intolerance and might induce irreversible side effects when used for a long-term. Thiopurines are not widely used after ileocecal resection, maybe because some concerns in giving immunomodulators in asymptomatic patients still remain. In the era of biological agents and genetic testing, a well-established preventive strategy for POR is still lacking, and larger studies to identify good clinical, serological, and genetic predictors of early POR as well as more effective drugs (or drug combinations) are needed.展开更多
AIM: To assess our experience with the use and management of everolimus-based regimens post-liver transplantation and to redefine the potential role of this drug in current clinical practice.METHODS: From October 1988...AIM: To assess our experience with the use and management of everolimus-based regimens post-liver transplantation and to redefine the potential role of this drug in current clinical practice.METHODS: From October 1988 to December 2012, 1023 liver transplantations were performed in 955 patients in our Unit. Seventy-four patients(7.74%) received immunosuppression with everolimus at some time post-transplantation. Demographic characteristics, everolimus indication, time elapsed from transplantation to the introduction of everolimus, doses and levels administered, efficacy, side effects, discontinuation andpost-conversion survival were analyzed. RESULTS: Mean age at the time of conversion to everolimus was 57.7 ± 10 years. Indications for conversion were: refractory rejection 31.1%, extended hepatocellular carcinoma in explanted liver 19%, post-transplant hepatocellular carcinoma recurrence 8.1%, de novo tumour 17.6%, renal insufficiency 8.1%, severe neurotoxicity 10.8%, and others 5.4%. Median time from transplantation to introduction of everolimus was 6 mo(range: 0.10-192). Mean follow-up post-conversion was 22 ± 19 mo(range: 0.50-74). The event for which the drug was indicated was resolved in 60.8% of patients, with the best results in cases of refractory rejection, renal insufficiency and neurotoxicity. Results in patients with cancer were similar to those of a historical cohort treated with other immunosuppressants. The main side effects were dyslipidemia and infections. Post-conversion acute rejection occurred in 14.9% of cases. The drug was discontinued in 28.4% of patients.CONCLUSION: Everolimus at low doses in combination with tacrolimus is a safe immunosuppressant with multiple early and late indications post-liver transplantation.展开更多
Hepatitis C virus(HCV)chronic infection is associated with fibrosis progression,end-stage liver complications and HCC.Not surprisingly,HCV infection is a leading cause of liver-related morbidity and mortality worldwid...Hepatitis C virus(HCV)chronic infection is associated with fibrosis progression,end-stage liver complications and HCC.Not surprisingly,HCV infection is a leading cause of liver-related morbidity and mortality worldwide.After sustained virological response(SVR),the risk of developing hepatocellular carcinoma is not completely eliminated in patients with established cirrhosis or with advanced fibrosis.Therefore,lifelong surveillance is currently recommended.This strategy is likely not universally cost-effective and harmless,considering that not all patients with advanced fibrosis have the same risk of developing HCC.Factors related to the severity of liver disease and its potential to improve after SVR,the molecular and epigenetic changes that occur during infection and other associated comorbidities might account for different risk levels and are likely essential for identifying patients who would benefit from screening programs after SVR.Efforts to develop predictive models and risk calculators,biomarkers and genetic panels and even deep learning models to estimate the individual risk of HCC have been made in the direct-acting antiviral agents era,when thousands of patients with advanced fibrosis and cirrhosis have reached SVR.These tools could help to identify patients with very low HCC risk in whom surveillance might not be justified.In this review,factors affecting the probability of HCC development after SVR,the benefits and risks of surveillance,suggested strategies to estimate individualized HCC risk and the current evidence to recommend lifelong surveillance are discussed.展开更多
The porphyries are a group of metabolic disorders characterized by deficiencies in the activity of enzymes involved in the biosynthesis of heme.In erythropoietic protoporphyria(EPP),in the majority of cases an autosom...The porphyries are a group of metabolic disorders characterized by deficiencies in the activity of enzymes involved in the biosynthesis of heme.In erythropoietic protoporphyria(EPP),in the majority of cases an autosomal dominant disease,there is a mutation of the gene that encodes ferrochelatase(FECH).FECH deficiency is associated with increased concentrations of protoporphyrin in erythrocytes,plasma,skin and liver.The prevalence of this inherited disorder oscillates between 1:75 000 and 1:200 000.Clinical manifestations of EPP appear in early infancy upon first exposure to the sun.Nevertheless,approximately 5%-20% of patients with EPP develop liver manifestations.Retention of protoporphyrin in the liver is associated with cholestatic phenomena and oxidative stress that predisposes to hepatobiliary disease of varying degrees of severity,such as cholelithiasis,mild parenchymal liver disease,progressive hepatocellular disease with end-stage liver disease and acute liver failure.Liver damage is the major risk in EPP patients,so surveillance and frequent clinical and biochemical liver follow-up is mandatory.The diagnostic approach consists in detecting increased levels of protoporphyrin,decreased activity of FECH and genetic analysis of the FECH gene.A variety of nonsurgical therapeutic approaches have been adopted for the management of EPP associated with liver disease,but none of these has been shown to be unequivocally efficacious.Nevertheless,some may have a place in preparing patients for liver transplantation.Liver transplantation does not correct the constitutional deficiency of FECH.Consequently,there is a risk of recurrence of liver disease after liver transplantation as a result of continuing overproduction of protoporphyrin.Some authors recommend that bone marrow transplantation should be considered in liver allograft recipients to prevent recurrence of hepatic disease.展开更多
AIM:To compare rifaximin and insulin-like growth factor(IGF)-1 treatment of hyperammonemia and brain edema in cirrhotic rats with portal occlusion.METHODS:Rats with CCl4-induced cirrhosis with ascites plus portal vein...AIM:To compare rifaximin and insulin-like growth factor(IGF)-1 treatment of hyperammonemia and brain edema in cirrhotic rats with portal occlusion.METHODS:Rats with CCl4-induced cirrhosis with ascites plus portal vein occlusion and controls were randomized into six groups:Cirrhosis;Cirrhosis + IGF-1;Cirrhosis + rifaximin;Controls;Controls + IGF-1;and Controls + rifaximin.An oral glutamine-challenge test was performed,and plasma and cerebral ammonia,glucose,bilirubin,transaminases,endotoxemia,brain water content and ileocecal cultures were measured and liver histology was assessed.RESULTS:Rifaximin treatment significantly reduced bacterial overgrowth and endotoxemia compared with cirrhosis groups,and improved some liver function parameters(bilirubin,alanine aminotransferase and aspartate aminotransferase).These effects were associated with a significant reduction in cerebral water content.Blood and cerebral ammonia levels,and area-underthe-curve values for oral glutamine-challenge tests were similar in rifaximin-treated cirrhotic rats and control group animals.By contrast,IGF-1 administration failed to improve most alterations observed in cirrhosis.CONCLUSION:By reducing gut bacterial overgrowth,only rifaximin was capable of normalizing plasma and brain ammonia and thereby abolishing low-grade brain edema,alterations associated with hepatic encephalopathy.展开更多
Pancreatic ductal adenocarcinoma(PDAC),the most common type of pancreatic tumor,is a highly aggressive human cancer with the lowest five-year survival rate of any human maligancy primarily due to its earlymetastasis a...Pancreatic ductal adenocarcinoma(PDAC),the most common type of pancreatic tumor,is a highly aggressive human cancer with the lowest five-year survival rate of any human maligancy primarily due to its earlymetastasis and lack of response to chemotherapy and radiation.Recent research suggests that PDAC cells comprise a hierarchy of tumor cells that develop around a population of cancer stem cells(CSCs),a small and distinct population of cancer cells that mediates tumoregenesis,metastasis and resistance to standard treatments.Thus,CSCs could be a target for more effective treatment options.Interestingly,pancreatic CSCs are subject to regulation by some of key embryonic stem cell(ESC)transctiption factors abberently expressed in PDAC,such as SOX2,OCT4 and NANOG.ESC transcription factors are important DNA-binding proteins present in both embryonic and adult somatic cells.The critical role of these factors in reprogramming processes makes them essential not only for embryonic development but also tumorigenesis.Here we provide an overview of stem cell transcription factors,particularly SOX2,OCT4,and NANOG,on their expression and function in pancreatic cancer.In contrast to embryonic stem cells,in which OCT4 and SOX2 are tightly regulated and physically interact to regulate a wide spectrum of target genes,de novo SOX2 expression alone in pancreatic cancer cells is sufficient to promote self-renewal,dedifferentiation and imparting stemness characteristics via impacting specific cell cycle regulatory genes and epithelial-mesnechymal transtion driver genes.Thus,targeting ESC factors,particularly SOX2,could be a worthy strategy for pancreatic cancer therapy.展开更多
基金Supported by The Projects from Foundation Seneca,No.05748/PI/07 and No.04487/GERM/06the Fondo de Investigación Sanitaria(FIS)projects CIBERehd,No.PI11/02644 and No.PI11/02686(in part)the ISCⅡ and Fundación para la Formación e Investigación Sanitarias de la Región de Murcia(FFIS),No.CA11/00034(to López-Hernández R)
文摘Many studies have demonstrated the linkage between the IBD3 region(6p21.1-23),an area which encompasses the famous human leukocyte antigen(HLA) complex,and Crohn's disease(CD) or ulcerative colitis(UC).IBD3 is the only region that meets genome-wide significance,and provides stronger evidence of the linkage than 16p13.1-16q12.2(IBD1),the locus that contains the susceptibility gene CARD15.However,despite these findings,IBD3 susceptibility genes remain elusive and unclear due to the strong linkage disequilibrium,extensive polymorphism,and high gene density that characterize this area and also due to varying allele frequencies in populations around the world.This area presents an extremely high abundance of genes,including the classical and non-classical major histocompatibility complex(MHC) class Ⅰ and Ⅱ genes,and other genes,namely MHC class Ⅲ genes tumor necrosis factor(TNF)-α and-β,and Hsp,whose proteins play key functions in immunological processes.To date,it is not clear which genes within the MHC family contribute to the IBD pathogenesis,although certain HLA alleles have been associated with IBD.Recent insights into the biological function of other genes encoded within the IBD3 region,such as the MHC class Ⅰ chain-related(MIC) genes,have led investigators to a more comprehensive exploration of this region.MHC class Ⅰ chain-related molecule A(MICA) is highly polymorphic and interacts with NKG2 D,its receptor on the surface of NK,Tγδ and T CD8+ cells.Increased expression of MICA in intestinal epithelial cells and increased expression of NKG2 D in CD4+ T cells(lamina propria) in patients with CD have also been reported.MICA alleles have also been associated with IBD,and a variation at amino acid position 129 of the α2-heavy chain domain seems to categorize MICA alleles into strong and weak binders of NKG2 D receptor,thereby influencing the effector cells' function.In this regard,a relevant role of MICA-129-Val/Met single nucleotide polymorphism has recently been implicated in the pathogenesis of IBD.TNF-α and-β also play an important role in inflammatory response.In fact,IBD is commonly treated with TNF-α inhibitors.Additionally,polymorphisms of TNF-α gene are known to affect the gene expression level and particular TNF-α genotypes may influence the response of IBD patients treated with TNF-α inhibitors.
基金Supported by the Instituto de Salud Carlos III,No.PI15/00856the European Regional Development Fund(ERDF),No.PI15/00856
文摘AIM To detect hyper-conserved regions in the hepatitis B virus(HBV) X gene(HBX) 5' region that could be candidates for gene therapy.METHODS The study included 27 chronic hepatitis B treatmentnaive patients in various clinical stages(from chronic infection to cirrhosis and hepatocellular carcinoma, both HBeA g-negative and HBeA g-positive), and infected with HBV genotypes A-F and H. In a serum sample from each patient with viremia > 3.5 log IU/m L, the HBX 5' end region [nucleotide(nt) 1255-1611] was PCRamplified and submitted to next-generation sequencing(NGS). We assessed genotype variants by phylogenetic analysis, and evaluated conservation of this region by calculating the information content of each nucleotide position in a multiple alignment of all unique sequences(haplotypes) obtained by NGS. Conservation at the HBx protein amino acid(aa) level was also analyzed.RESULTS NGS yielded 1333069 sequences from the 27 samples, with a median of 4578 sequences/sample(2487-9279, IQR 2817). In 14/27 patients(51.8%), phylogenetic analysis of viral nucleotide haplotypes showed a complex mixture of genotypic variants. Analysis of the information content in the haplotype multiple alignments detected 2 hyper-conserved nucleotide regions, one in the HBX upstream non-coding region(nt 1255-1286) and the other in the 5' end coding region(nt 1519-1603). This last region coded for a conserved amino acid region(aa 63-76) that partially overlaps a Kunitz-like domain.CONCLUSION Two hyper-conserved regions detected in the HBX 5' end may be of value for targeted gene therapy, regardless of the patients' clinical stage or HBV genotype.
基金Supported by the Instituto de Salud Carlos Ⅲ,grants PI15/00856 and PI17/02233co-financed by the European Regional Development Fund(ERDF)
文摘Hepatitis delta virus(HDV) seems to strongly suppress hepatitis B virus(HBV)replication, although little is known about the mechanism of this interaction. Both these viruses show a dynamic distribution of mutants, resulting in viral quasispecies. Next-generation sequencing is a viable approach for analyzing the composition of these mutant spectra. As the regulatory hepatitis B X protein(HBx) is essential for HBV replication, determination of HBV X gene(HBX)quasispecies complexity in HBV/HDV infection compared to HBV monoinfection may provide information on the interactions between these two viruses.AIM To compare HBV quasispecies complexity in the HBX 5' region between chronic hepatitis delta(CHD) and chronic HBV mono-infected patients.METHODS Twenty-four untreated patients were included: 7/24(29.2%) with HBeAgnegative chronic HBV infection(CI, previously termed inactive carriers), 8/24(33.3%) with HBeAg-negative chronic hepatitis B(CHB) and 9/24(37.5%) with CHD. A serum sample from each patient was first tested for HBV DNA levels.The HBX 5' region [nucleotides(nt) 1255-1611] was then PCR-amplified for subsequent next-generation sequencing(MiSeq, Illumina, United States). HBV quasispecies complexity in the region analyzed was evaluated using incidencebased indices(number of haplotypes and number of mutations), abundancebased indices(Hill numbers of order 1 and 2), and functional indices(mutation frequency and nucleotide diversity). We also evaluated the pattern of nucleotide changes to investigate which of them could be the cause of the quasispecies complexity.RESULTS CHB patients showed higher median HBV-DNA levels [5.4 logIU/mL,interquartile range(IQR) 3.5-7.9] than CHD(3.4 logIU/mL, IQR 3-7.6)(P = n.s.)or CI(3.2 logIU/mL, IQR 2.3-3.5)(P < 0.01) patients. The incidence and abundance indices indicated that HBV quasispecies complexity was significantly greater in CI than CHB. A similar trend was observed in CHD patients, although only Hill numbers of order 2 showed statistically significant differences(CHB2.81, IQR 1.11-4.57 vs CHD 8.87, 6.56-11.18, P = 0.038). There were no significant differences in the functional indices, but CI and CHD patients also showed a trend towards greater complexity than CHB. No differences were found for any HBV quasispecies complexity indices between CHD and CI patients. G-to-A and C-to-T nucleotide changes, characteristic of APOBEC3 G, were higher in CHD and CI than in CHB in genotype A haplotypes, but not in genotype D. The proportion of nt G-to-A vs A-to-G changes and C-to-T vs T-to-C changes in genotype A and D haplotypes in CHD patients showed no significant differences. In CHB and CI the results of these comparisons were dependent on HBV genotype.CONCLUSION The lower-replication CHD and CI groups show a trend to higher quasispecies complexity than the higher-replication CHB group. The mechanisms associated with this greater complexity require elucidation.
基金Supported by Instituto de Salud Carlos Ⅲ,No.PI14/01416 and No.PI15/00856cofinanced by the European Regional Development Fund(ERDF)the Gilead Fellowship Program,No.GLD14-00296
文摘AIM To determine the variability/conservation of the domain of hepatitis B virus(HBV) pre S1 region that interacts with sodium-taurocholate cotransporting polypeptide(hereafter, NTCP-interacting domain) and the prevalence of the rs2296651 polymorphism(S267 F, NTCP variant) in a Spanish population. METHODS Serum samples from 246 individuals were included and divided into 3 groups: patients with chronic HBV infection(CHB)(n = 41, 73% Caucasians), patients with resolved HBV infection(n = 100, 100% Caucasians) and an HBV-uninfected control group(n = 105, 100% Caucasians). Variability/conservation of the amino acid(aa) sequences of the NTCPinteracting domain,(aa 2-48 in viral genotype D) and a highly conserved pre S1 domain associated with virion morphogenesis(aa 92-103 in viral genotype D) were analyzed by next-generation sequencing and compared in 18 CHB patients with viremia > 4 log IU/mL. The rs2296651 polymorphism was determined in all individuals in all 3 groups using an in-house real-time PCR melting curve analysis.RESULTS The HBV pre S1 NTCP-interacting domain showed a high degree of conservation among the examined viral genomes especially between aa 9 and 21(in the genotype D consensus sequence). As compared with the virion morphogenesis domain, the NTCPinteracting domain had a smaller proportion of HBV genotype-unrelated changes comprising > 1% of the quasispecies(25.5% vs 31.8%), but a larger proportion of genotype-associated viral polymorphisms(34% vs 27.3%), according to consensus sequences from Gen Bank patterns of HBV genotypes A to H. Variation/conservation in both domains depended on viral genotype, with genotype C being the most highly conserved and genotype E the most variable(limited finding, only 2 genotype E included). Of note, proline residues were highly conserved in both domains, and serine residues showed changes only to threonine or tyrosine in the virion morphogenesis domain. The rs2296651 polymorphism was not detected in any participant.CONCLUSION In our CHB population, the NTCP-interacting domain was highly conserved, particularly the proline residues and essential amino acids related with the NTCP interaction, and the prevalence of rs2296651 was low/null.
基金Supported by Grants from the Spanish Fondo de Investigaciones Sanitarias no.PI13-01272(to Gamez J)an Interlaken Research Awards Program
文摘We report a case of acute severe hepatitis resulting from masitinib in a young amyotrophic lateral sclerosis patient. Hepatotoxicity induced by masitinib,a tyrosine kinase inhibitor,is usually transient with mild elevation of transaminases,although acute hepatitis has been not reported to date. The hepatitis was resolved after masitinib was discontinued and a combination of prednisone and azathioprine was started. The transaminases returned to baseline normal values five months later. This is the first case in the hepatitis literature associated with masitinib. The autoimmune role of this drug-induced liver injury is discussed. Physicians should be aware of this potential complication.
文摘Nonalcoholic fatty liver disease(NAFLD)is a heterogeneous and complex disease that is imprecisely diagnosed by liver biopsy.NAFLD covers a spectrum that ranges from simple steatosis,nonalcoholic steatohepatitis(NASH)with varying degrees of fibrosis,to cirrhosis,which is a major risk factor for hepatocellular carcinoma.Lifestyle and eating habit changes during the last century have made NAFLD the most common liver disease linked to obesity,type 2 diabetes mellitus and dyslipidemia,with a global prevalence of 25%.NAFLD arises when the uptake of fatty acids(FA)and triglycerides(TG)from circulation and de novo lipogenesis saturate the rate of FAβ-oxidation and verylow density lipoprotein(VLDL)-TG export.Deranged lipid metabolism is also associated with NAFLD progression from steatosis to NASH,and therefore,alterations in liver and serum lipidomic signatures are good indicators of the disease’s development and progression.This review focuses on the importance of the classification of NAFLD patients into different subtypes,corresponding to the main alteration(s)in the major pathways that regulate FA homeostasis leading,in each case,to the initiation and progression of NASH.This concept also supports the targeted intervention as a key approach to maximize therapeutic efficacy and opens the door to the development of precise NASH treatments.
基金National Institutes of Health,NIAAA,No.R01AA026759(Lu)National Institutes of Health,NIDDK,No.R01DK107288(Lu)+4 种基金National Institutes of Health,NCCIH,No.R01AT001576National Institutes of Health,NCI,No.R01CA172086(Lu and Mato)Agencia Estatal de Investigación MINECO,No.SAF 2017-88041-RISCiii PIE14/00031,No.CIBERehdISCiiiSevero Ochoa Excellence Accreditation,No.SEV-2016-0644)(Mato)
文摘Methionine adenosyltransferases(MATs)are essential enzymes for life as they produce S-adenosylmethionine(SAMe),the biological methyl donor required for a plethora of reactions within the cell.Mammalian systems express two genes,MAT1A and MAT2A,which encode for MATα1 and MATα2,the catalytic subunits of the MAT isoenzymes,respectively.A third gene MAT2B,encodes a regulatory subunit known as MATβwhich controls the activity of MATα2.MAT1A,which is mainly expressed in hepatocytes,maintains the differentiated state of these cells,whilst MAT2A and MAT2B are expressed in extrahepatic tissues as well as non-parenchymal cells of the liver(e.g.,hepatic stellate and Kupffer cells).The biosynthesis of SAMe is impaired in patients with chronic liver disease and liver cancer due to decreased expression and inactivation of MATα1.A switch from MAT1A to MAT2A/MAT2B occurs in multiple liver diseases and during liver growth and dedifferentiation,but this change in the expression pattern of MATs results in reduced hepatic SAMe level.Decades of study have utilized the Mat1a-knockout(KO)mouse that spontaneously develops non-alcoholic steatohepatitis(NASH)and hepatocellular carcinoma(HCC)to elucidate a variety of mechanisms by which MAT proteins dysregulation contributes to liver carcinogenesis.An increasing volume of work indicates that MATs have SAMe-independent functions,distinct interactomes and multiple subcellular localizations.Here we aim to provide an overview of MAT biology including genes,isoenzymes and their regulation to provide the context for understanding consequences of their dysregulation.We will highlight recent breakthroughs in the field and underscore the importance of MAT’s in liver tumorigenesis as well as their potential as targets for cancer therapy.
文摘Biodegradable stents(BDSs)are an attractive option to avoid ongoing dilation or surgery in patients with benign stenoses of the small and large intestines.The experience with the currently the only BDS for endoscopic placement,made of Poly-dioxanone,have shown promising results.However some aspects should be improved as are the fact that BDSs lose their radial force over time due to the degradable material,and that can cause stent-induced mucosal or parenchymal injury.This complication rate and modest clinical efficacy has to be carefully considered in individual patients prior to placement of BDSs.Otherwise,the price of these stents therefore it is nowadays an important limitation.
文摘Non-alcoholic fatty liver disease(NAFLD) is increasing considerably due to the current lifestyle,which means that it is becoming one of the main indications for liver transplantation.On the other hand,there is a strong association between NAFLD and cardiovascular disease.This has been evidenced in many studies revealing a higher presence of carotid plaques or carotid intima-media thickness,leading to cardiovascular events and,ultimately,mortality.According to the liver transplant guidelines,screening for heart disease in transplant candidates should be performed by electrocardiogram and transthoracic echocardiography while a stress echocardiogram should be reserved for those with more than two cardiovascular risk factors or greater than 50 years old.However,there are no specific recommendations in NAFLD patients requiring a liver transplantation,despite its well-known cardiovascular risk association.Many studies have shown that these patients probably require a more exhaustive assessment and a global approach including other specialists such as cardiologists or nutritionists.Also,the incidence of cardiovascular disease is also increased in NAFLD patients in the post-transplantation period in comparison with other etiologies,because of the pre-existent risk factors together with the immunosuppressive therapy.Therefore,an early intervention on the lifestyle and the individualized selection of the immunosuppressive regimen could lead to a modification of the cardiovascular risk factors in NAFLD patients requiring a liver transplantation.
基金Supported by The CIBERehd(Centro de Investigación Biomédica en Red,enfermedades hepaticas y digestivas)to Sanabria E
文摘There have been major developments in endoscopic imaging techniques in recent years.Endoscopes with high definition and magnification can provide high quality images that allow for the histological estimation of lesions in vivo and in situ when combined with ancillary enhancement techniques such as chromoendoscopy(CE)and virtual CE(narrow band imaging fujinon intelligent chromoendoscopy,or i-Scan).Despite the enormous potential for these advanced techniques,their value and feasibility in the clinic are still doubted,particularly in cases of colonic polyps that are slated for removal,where in vivo characterization may be deemed unnecessary.However,there are several advantages offered by such advanced endoscopic imaging.CE with or without magnification demonstrates highly accurate histology and invasion depth prediction,and virtual CE is a feasible and less cumbersome alternative to CE in terms of histological estimation,though not sufficiently accurate for depth invasion prediction.Furthermore,the supplementary information provided by advanced imaging systems can assist the endoscopist in the selection of a strategic approach,such as in deciding whether a colonic lesion should be resected,left in situ,or requires more intensive surgical treatment.Lastly,advanced high-resolution imaging techniques may be more cost effective,such that histopathology of lowrisk lesions following resection can be eliminated.The results of these evaluations and comparisons with traditional CE are presented and discussed.Taken together,the benefits provided by these advanced capabilities justify their development,and advocates their use for the treatment and management of colonic polyps.
文摘Endoscopic retrograde cholangiopancreatography (ERCP) is an important tool for the diagnosis and treatment of the hepatobiliary system. The use of fluoroscopy to aid ERCP places both the patient and the endoscopy staff at risk of radiation-induced injury. Radiation dose to patients during ERCP depends on many factors, and the endoscopist cannot control some variables, such as patient size, procedure type, or fluoroscopic equipment used. Previous reports have demonstrated a linear relationship between radiation dose and fluoroscopy duration. When fluoroscopy is used to assist ERCP, the shortest fluoroscopy time possible is recommended. Pulsed fluoroscopy and monitoring the length of fluoroscopy have been suggested for an overall reduction in both radiation exposure and fluoroscopy times. Fluoroscopy time is shorter when ERCP is performed by an endoscopist who has many years experience of performing ERCP and carried out a large number of ERCPs in the preceding year. In general, radiation exposure is greater during therapeutic ERCP than during diagnostic ERCP. Factors associated with prolonged fluoroscopy have been delineated recently, but these have not been validated.
基金CIBERehd was funded by the Instituto de Salud CarloⅢ
文摘AIM: To implement a quick and simple test- rapid assessment faecal incontinence score(RAFIS) and show its reliability and validity.METHODS: From March 2008 through March 2010, we evaluated a total of 261 consecutive patients, including 53 patients with faecal incontinence. Demographic and comorbidity information was collected. In a single visit, patients were administered the RAFIS. The results obtained with the new score were compared with those of both Wexner score and faecal incontinence quality of life scale(FIQL) questionnaire. The patient withoutinfluence of the surgeon completed the test. The role of surgeon was explaining the meaning of each section and how he had to fill. Reliability of the RAFIS score was measured using intra-observer agreement and Cronbach's alpha(internal consistency) coefficient. Multivariate analysis of the main components within the different scores was performed in order to determine whether all the scores measured the same factor and to conclude whether the information could be encompassed in a single factor. A sample size of 50 patients with faecal incontinence was estimated to be enough to detect a correlation of 0.55 or better at 5% level of significance with 80% power.RESULTS: We analysed the results obtained by 53 consecutive patients with faecal incontinence(median age 61.55 ± 12.49 years) in the three scoring systems. A total of 208 healthy volunteers(median age 58.41 ± 18.41 years) without faecal incontinence were included in the study as negative controls. Pearson's correlation coefficient between "state" and "leaks" was excellent(r = 0.92, P < 0.005). Internal consistency in the comparison of "state" and "leaks" yielded also excellent correlation(Cronbach's α = 0.93). Results in each score were compared using regression analysis and a correlation value of r = 0.98 was obtained with Wexner score. As regards FIQL questionnaire, the values of "r " for the different subscales of the questionnaire were: "lifestyle" r =-0.87, "coping/behaviour" r =-0.91, "depression" r =-0.36 and "embarrassment" r =-0.90,(P < 0.01). A multivariate analysis showed that all the scoring systems measured the same factor. A single factor may explain 80.84% of the variability of FI, so all the scoring systems measure the same factor. Patient's continence improves when RAFIS and Jorge-Wexner scores show low values and when the values obtained in the FIQL questionnaire are high.CONCLUSION: RAFIS is a valid and reliable tool to assess Faecal Incontinence.
基金Supported by(partially)from the Instituto de Salud CarlosⅢ,Madrid,Spain,No.PI0900357cofinanced by Fondos FEDER(Fondo Europeo de Desarrollo Regional)+3 种基金“Una manera de hacer Europa”,European Union,and CERCA Programme,Generalitat de CatalunyaSilvia Vidal was supported by Fondo de Investigaciones Sanitarias(FIS)a participant in the Program for Stabilization of Investigators of the Direcciód’Estrategia i Coordinaciódel Departament de Salut,Generalitat de CatalunyaEdilmar Alvarado-Tapias is a recipient of a“Río Hortega”fellowship grant from the Instituto de Salud CarlosⅢ,No.CM16/00133
文摘AIM To assess the relationship between the presence of toll-like receptor 4(TLR4) polymorphisms and bacterial infections in cirrhotic patients with ascites. METHODS We prospectively included consecutive patients with cirrhosis and ascites hospitalized during a 6-year period. Patients with human immunodeficiency virus(HIV) infection or any other immunodeficiency, patients with advanced hepatocellular carcinoma(beyond Milan's criteria) or any other condition determining poor short-term prognosis, and patients with a permanent urinary catheter were excluded. The presence of D299 G and/or T399 I TLR4 polymorphisms was determined by sequencing and related to the incidence and probability of bacterial infections, other complications of cirrhosis, hepatocellular carcinoma, and mortality during follow-up. A multivariate analysis to identify predictive variables of mortality in the whole series was performed. RESULTS We included 258 patients: 28(10.8%) were carriers of D299G and/or T399I TLR4 polymorphisms(polymorphism group) and 230 patients were not(wildtype group). The probability of developing any bacterial infection at one-year follow-up was 78% in the polymorphism group and 69% in the wild-type group(P = 0.54). The one-year probability of presenting infections caused by gram-negative bacilli(51% vs 44%, P = 0.68), infections caused by gram-positive cocci(49% vs 40%, P = 0.53), and spontaneous bacterial peritonitis(29% vs 34%, respectively, P = 0.99) did not differ between the two groups. The oneyear probability of transplant-free survival was 55% in the polymorphism group and 66% in the wild-type group(P = 0.15). Multivariate analysis confirmed that age, Child-Pugh score, active alcohol intake, previous hepatic encephalopathy, hepatocellular carcinoma and serum creatinine were associated with a higher risk of death during follow-up. CONCLUSION Genetic polymorphisms D299 G and/or T399 I of TLR4 do not seem to play a relevant role in the predisposition of cirrhotic patients with ascites to bacterial infections.
基金Supported by SCB is supported by a contract from the Fondo de Investigación Sanitaria,No.CP 03-0070CEJ and JM are supported by a contract from CIBERehd+7 种基金CIBERehd and CIB-ERER are funded by the Instituto de Salud Carlos IIIFondo de Investigación Sanitaria/FEDER,No.11/00219 and No.11/00681Instituto de Salud Carlos III(Acción Transversal de Cáncer),Xunta de Galicia,No.07PXIB9101209PRMinisterio de Cien-cia e Innovación,No.SAF2010-19273Asociación Espaola contra el Cáncer(Fundación Científica GCB13131592CAST y Junta de Barcelona)FundacióOlga Torres(SCB and CRP)FP7 CHIBCHA Consortium(SCB and ACar)COST Action BM1206(SCB and CRP)
文摘Colorectal cancer(CRC)is one of the most frequent neoplasms and an important cause of mortality in the developed world.This cancer is caused by both genetic and environmental factors although 35%of the variation in CRC susceptibility involves inherited genetic differences.Mendelian syndromes account for about5%of the total burden of CRC,with Lynch syndrome and familial adenomatous polyposis the most common forms.Excluding hereditary forms,there is an important fraction of CRC cases that present familial aggregation for the disease with an unknown germline genetic cause.CRC can be also considered as a complex disease taking into account the common diseasecommom variant hypothesis with a polygenic model of inheritance where the genetic components of common complex diseases correspond mostly to variants of low/moderate effect.So far,30 common,low-penetrance susceptibility variants have been identified for CRC.Recently,new sequencing technologies including exomeand whole-genome sequencing have permitted to add a new approach to facilitate the identification of new genes responsible for human disease predisposition.By using whole-genome sequencing,germline mutations in the POLE and POLD1 genes have been found to be responsible for a new form of CRC genetic predisposition called polymerase proofreading-associated polyposis.
文摘Crohn's disease is a chronic inflammatory condition that may involve any segment of the gastrointestinal tract. Although several drugs have proven efficacy in inducing and maintaining disease in remission, resectional surgery remains as a cornerstone in the management of the disease, mainly for the treatment of its stenosing and penetrating complications. However, the occurrence of new mucosal (endoscopic) lesions in the neoterminal ileum early after surgery is almost constant, it is followed in the mid-term by clinical symptoms and, in a proportion of patients, repeated intestinal resections are required. Pathogenesis of postoperative recurrence (POR) is not fully understood, but luminal factors (commensal microbes, dietary antigens) seem to play an important role, and environmental and genetic factors may also have a relevant influence. Many studies tried to identify clinical predictors for POR with heterogeneous results, and only smoking has repeatedly been associated with a higher risk of POR. Ileocolonoscopy remains as the gold standard for the assessment of appearance and severity of POR, although the real usefulness of the available endoscopic score needs to be revisited and alternative techniques are emerging. Several drugs have been evaluated to prevent POR with limited success. Smoking cessation seems to be one of the more beneficial therapeutic measures. Aminosalicylates have only proved to be of marginal benefit, and they are only used in low-risk patients. Nitroimidazolic antibiotics, although efficient, are associated with a high rate of intolerance and might induce irreversible side effects when used for a long-term. Thiopurines are not widely used after ileocecal resection, maybe because some concerns in giving immunomodulators in asymptomatic patients still remain. In the era of biological agents and genetic testing, a well-established preventive strategy for POR is still lacking, and larger studies to identify good clinical, serological, and genetic predictors of early POR as well as more effective drugs (or drug combinations) are needed.
文摘AIM: To assess our experience with the use and management of everolimus-based regimens post-liver transplantation and to redefine the potential role of this drug in current clinical practice.METHODS: From October 1988 to December 2012, 1023 liver transplantations were performed in 955 patients in our Unit. Seventy-four patients(7.74%) received immunosuppression with everolimus at some time post-transplantation. Demographic characteristics, everolimus indication, time elapsed from transplantation to the introduction of everolimus, doses and levels administered, efficacy, side effects, discontinuation andpost-conversion survival were analyzed. RESULTS: Mean age at the time of conversion to everolimus was 57.7 ± 10 years. Indications for conversion were: refractory rejection 31.1%, extended hepatocellular carcinoma in explanted liver 19%, post-transplant hepatocellular carcinoma recurrence 8.1%, de novo tumour 17.6%, renal insufficiency 8.1%, severe neurotoxicity 10.8%, and others 5.4%. Median time from transplantation to introduction of everolimus was 6 mo(range: 0.10-192). Mean follow-up post-conversion was 22 ± 19 mo(range: 0.50-74). The event for which the drug was indicated was resolved in 60.8% of patients, with the best results in cases of refractory rejection, renal insufficiency and neurotoxicity. Results in patients with cancer were similar to those of a historical cohort treated with other immunosuppressants. The main side effects were dyslipidemia and infections. Post-conversion acute rejection occurred in 14.9% of cases. The drug was discontinued in 28.4% of patients.CONCLUSION: Everolimus at low doses in combination with tacrolimus is a safe immunosuppressant with multiple early and late indications post-liver transplantation.
文摘Hepatitis C virus(HCV)chronic infection is associated with fibrosis progression,end-stage liver complications and HCC.Not surprisingly,HCV infection is a leading cause of liver-related morbidity and mortality worldwide.After sustained virological response(SVR),the risk of developing hepatocellular carcinoma is not completely eliminated in patients with established cirrhosis or with advanced fibrosis.Therefore,lifelong surveillance is currently recommended.This strategy is likely not universally cost-effective and harmless,considering that not all patients with advanced fibrosis have the same risk of developing HCC.Factors related to the severity of liver disease and its potential to improve after SVR,the molecular and epigenetic changes that occur during infection and other associated comorbidities might account for different risk levels and are likely essential for identifying patients who would benefit from screening programs after SVR.Efforts to develop predictive models and risk calculators,biomarkers and genetic panels and even deep learning models to estimate the individual risk of HCC have been made in the direct-acting antiviral agents era,when thousands of patients with advanced fibrosis and cirrhosis have reached SVR.These tools could help to identify patients with very low HCC risk in whom surveillance might not be justified.In this review,factors affecting the probability of HCC development after SVR,the benefits and risks of surveillance,suggested strategies to estimate individualized HCC risk and the current evidence to recommend lifelong surveillance are discussed.
文摘The porphyries are a group of metabolic disorders characterized by deficiencies in the activity of enzymes involved in the biosynthesis of heme.In erythropoietic protoporphyria(EPP),in the majority of cases an autosomal dominant disease,there is a mutation of the gene that encodes ferrochelatase(FECH).FECH deficiency is associated with increased concentrations of protoporphyrin in erythrocytes,plasma,skin and liver.The prevalence of this inherited disorder oscillates between 1:75 000 and 1:200 000.Clinical manifestations of EPP appear in early infancy upon first exposure to the sun.Nevertheless,approximately 5%-20% of patients with EPP develop liver manifestations.Retention of protoporphyrin in the liver is associated with cholestatic phenomena and oxidative stress that predisposes to hepatobiliary disease of varying degrees of severity,such as cholelithiasis,mild parenchymal liver disease,progressive hepatocellular disease with end-stage liver disease and acute liver failure.Liver damage is the major risk in EPP patients,so surveillance and frequent clinical and biochemical liver follow-up is mandatory.The diagnostic approach consists in detecting increased levels of protoporphyrin,decreased activity of FECH and genetic analysis of the FECH gene.A variety of nonsurgical therapeutic approaches have been adopted for the management of EPP associated with liver disease,but none of these has been shown to be unequivocally efficacious.Nevertheless,some may have a place in preparing patients for liver transplantation.Liver transplantation does not correct the constitutional deficiency of FECH.Consequently,there is a risk of recurrence of liver disease after liver transplantation as a result of continuing overproduction of protoporphyrin.Some authors recommend that bone marrow transplantation should be considered in liver allograft recipients to prevent recurrence of hepatic disease.
基金Supported by A grant from the Instituto de Salud CarlosTM,PI051371,PI080809
文摘AIM:To compare rifaximin and insulin-like growth factor(IGF)-1 treatment of hyperammonemia and brain edema in cirrhotic rats with portal occlusion.METHODS:Rats with CCl4-induced cirrhosis with ascites plus portal vein occlusion and controls were randomized into six groups:Cirrhosis;Cirrhosis + IGF-1;Cirrhosis + rifaximin;Controls;Controls + IGF-1;and Controls + rifaximin.An oral glutamine-challenge test was performed,and plasma and cerebral ammonia,glucose,bilirubin,transaminases,endotoxemia,brain water content and ileocecal cultures were measured and liver histology was assessed.RESULTS:Rifaximin treatment significantly reduced bacterial overgrowth and endotoxemia compared with cirrhosis groups,and improved some liver function parameters(bilirubin,alanine aminotransferase and aspartate aminotransferase).These effects were associated with a significant reduction in cerebral water content.Blood and cerebral ammonia levels,and area-underthe-curve values for oral glutamine-challenge tests were similar in rifaximin-treated cirrhotic rats and control group animals.By contrast,IGF-1 administration failed to improve most alterations observed in cirrhosis.CONCLUSION:By reducing gut bacterial overgrowth,only rifaximin was capable of normalizing plasma and brain ammonia and thereby abolishing low-grade brain edema,alterations associated with hepatic encephalopathy.
基金Supported by Universidad del Pais Vasco,Instituto Biodonostia,San Sebastian,and CIBERehd(red de enfermedades hepaticas y digestivas)American Cancer Society institutional awardMayo Clinic Pancreatic Cancer SPORE,No.CA102701
文摘Pancreatic ductal adenocarcinoma(PDAC),the most common type of pancreatic tumor,is a highly aggressive human cancer with the lowest five-year survival rate of any human maligancy primarily due to its earlymetastasis and lack of response to chemotherapy and radiation.Recent research suggests that PDAC cells comprise a hierarchy of tumor cells that develop around a population of cancer stem cells(CSCs),a small and distinct population of cancer cells that mediates tumoregenesis,metastasis and resistance to standard treatments.Thus,CSCs could be a target for more effective treatment options.Interestingly,pancreatic CSCs are subject to regulation by some of key embryonic stem cell(ESC)transctiption factors abberently expressed in PDAC,such as SOX2,OCT4 and NANOG.ESC transcription factors are important DNA-binding proteins present in both embryonic and adult somatic cells.The critical role of these factors in reprogramming processes makes them essential not only for embryonic development but also tumorigenesis.Here we provide an overview of stem cell transcription factors,particularly SOX2,OCT4,and NANOG,on their expression and function in pancreatic cancer.In contrast to embryonic stem cells,in which OCT4 and SOX2 are tightly regulated and physically interact to regulate a wide spectrum of target genes,de novo SOX2 expression alone in pancreatic cancer cells is sufficient to promote self-renewal,dedifferentiation and imparting stemness characteristics via impacting specific cell cycle regulatory genes and epithelial-mesnechymal transtion driver genes.Thus,targeting ESC factors,particularly SOX2,could be a worthy strategy for pancreatic cancer therapy.
