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Over the last 5 years, therapies for hepatitis C virus (HCV) infection have improved significantly, achieving sustained virologic response (SVR) rates of up to 100% in clinical trials in patients with HCV genotype 1. We investigated the effectiveness and safety of ombitasvir/paritaprevir/ritonavir±dasabuvir in an early access programme. This was a retrospective, multicentre, national study that included 291 treatment-naïve and treatment-experienced patients with genotype 1 or 4 HCV infection. Most patients (65.3%) were male, and the mean age was 57.5 years. The mean baseline viral load was 6.1 log, 69.8% had HCV 1b genotype, 72.9% had cirrhosis and 34.7% were treatment-naïve. SVR at 12 weeks posttreatment was 96.2%. Four patients had virological failure (1.4%), one leading to discontinuation. There were no statistical differences in virological response according to genotype or liver fibrosis. Thirty patients experienced serious adverse events (SAEs) (10.3%), leading to discontinuation in six cases. Hepatic decompensation was observed in five patients. Four patients died during treatment or follow-up, three of them directly related to liver failure. Multivariate analyses showed a decreased probability of achieving SVR associated with baseline albumin, bilirubin and Child-Pugh score B, and a greater probability of developing SAEs related to age and albumin. This combined therapy was highly effective in clinical practice with an acceptable safety profile and low rates of treatment discontinuation., (© 2016 John Wiley & Sons Ltd.)

Introduction: Vitamin D (VD) is known to have multiple extra-skeletal health functions. There is emerging interest in exploring the relationship between vitamin D and chronic liver disease (CLD)., Objectives: To determine the prevalence of VD deficiency in patients with CLD in our setting and to assess whether VD supplementation influences plasma levels and is associated with improved liver function., Material and Methods: We conducted a study in 2 phases. First, we analysed clinical and epidemiological characteristics in 94 patients with CLD; second, different doses of calcifediol (25-OH-VD) were administered to patients with VD deficiency (<20ng/mL) and insufficiency (20-30ng/mL). Plasma concentrations and liver function (Child-Pugh and MELD) at the end of treatment were compared with baseline data., Results: Deficient or insufficient VD levels were found in 87% of the patients, with an average concentration of 18.8ng/mL. Levels were lower in patients with cirrhosis (15.9ng/mL) (P=.002) and in alcoholic liver disease. VD levels were inversely proportional to the degree of liver function: Child A (16.52ng/mL) vs C (7.75ng/mL). After VD supplementation, optimal serum levels were achieved in 94% of patients and significant improvements were observed in platelet count, albumin levels (P<.05) and functional status assessed by the Child-Pugh scale (P<.05)., Conclusion: Given the high prevalence of VD deficiency or insufficiency, the need for screening should be considered in the population with CLD. VD supplementation could be safe and effective., (Copyright © 2015 Elsevier España, S.L.U. and AEEH y AEG. All rights reserved.)

Aim: Few studies have investigated the course of liver stiffness after treatment with protease inhibitors. We evaluated the impact of this therapy on liver fibrosis measured by transient elastography., Methods: This multicenter observational, cohort, prospective study included 90 patients with hepatitis C genotype 1 treated with telaprevir or boceprevir who had advanced fibrosis evidenced by liver stiffness (≥9.5 kPa). Liver stiffness was measured at baseline and 24 weeks after treatment ended, and was compared with virological responses at week 12., Results: Liver stiffness decreased in 89% of patients who achieved sustained virological response. The median intrapatient liver stiffness value at the end of follow-up decreased by 5.1 kPa (35%) from baseline compared with 0.1 kPa (0.5%) in those who did not achieve a sustained virological response (P<0.001). The liver stiffness level fell below 9.5 kPa in 58% of patients with sustained virological response, and 71% of those with sustained virological response and cirrhosis evidenced by liver stiffness at baseline achieved regression below 12.5 kPa by the end of follow-up. Sustained virological response was the only variable associated with improved liver stiffness in multivariate analysis (odds ratio: 17.3; 95% confidence interval: 4.4-67.6; P<0.001)., Conclusion: In patients with advanced fibrosis measured by transient elastography at the beginning of protease inhibitor-based therapy with sustained virological response, liver stiffness was significantly reduced 24 weeks after treatment. This suggests the possibility of liver cirrhosis evidenced by liver stiffness regression after sustained virological response in a significant proportion of patients.

Aim: To evaluates the effectiveness and safety of the first generation, NS3/4A protease inhibitors (PIs) in clinical practice against chronic C virus, especially in patients with advanced fibrosis., Methods: Prospective study and non-experimental analysis of a multicentre cohort of 38 Spanish hospitals that includes patients with chronic hepatitis C genotype 1, treatment-naïve (TN) or treatment-experienced (TE), who underwent triple therapy with the first generation NS3/4A protease inhibitors, boceprevir (BOC) and telaprevir (TVR), in combination with pegylated interferon and ribavirin. The patients were treatment in routine practice settings. Data on the study population and on adverse clinical and virologic effects were compiled during the treatment period and during follow up., Results: One thousand and fifty seven patients were included, 405 (38%) were treated with BOC and 652 (62%) with TVR. Of this total, 30% (n = 319) were TN and the remaining were TE: 28% (n = 298) relapsers, 12% (n = 123) partial responders (PR), 25% (n = 260) null-responders (NR) and for 5% (n = 57) with prior response unknown. The rate of sustained virologic response (SVR) by intention-to-treatment (ITT) was greater in those treated with TVR (65%) than in those treated with BOC (52%) (P < 0.0001), whereas by modified intention-to-treatment (mITT) no were found significant differences. By degree of fibrosis, 56% of patients were F4 and the highest SVR rates were recorded in the non-F4 patients, both TN and TE. In the analysis by groups, the TN patients treated with TVR by ITT showed a higher SVR (P = 0.005). However, by mITT there were no significant differences between BOC and TVR. In the multivariate analysis by mITT, the significant SVR factors were relapsers, IL28B CC and non-F4; the type of treatment (BOC or TVR) was not significant. The lowest SVR values were presented by the F4-NR patients, treated with BOC (46%) or with TVR (45%). 28% of the patients interrupted the treatment, mainly by non-viral response (51%): this outcome was more frequent in the TE than in the TN patients (57% vs 40%, P = 0.01). With respect to severe haematological disorders, neutropaenia was more likely to affect the patients treated with BOC (33% vs 20%, P ≤ 0.0001), and thrombocytopaenia and anaemia, the F4 patients (P = 0.000, P = 0.025, respectively)., Conclusion: In a real clinical practice setting with a high proportion of patients with advanced fibrosis, effectiveness of first-generation PIs was high except for NR patients, with similar SVR rates being achieved by BOC and TVR.

Background: The presence of a family history implies an increased risk for developing colorectal cancer (CRC), and may require a different screening strategy. The aim of this study was to evaluate lesions found during colonoscopies of patients that had a family history of CRC., Material and Methods: A retrospective study was conducted that included consecutive colonoscopies performed on patients with a family history of CRC at a referral center within the period from April 2000 to January 2012. The colonoscopic findings were analyzed in relation to sex, age, and the presence or absence of symptoms., Results: Data from 3,792 colonoscopies were collected. The mean age of the patients was 53.14 years (SD 12.22), and 57.4% were women. Colonoscopy was normal in 71.7% of the cases, with hyperplastic polyps being detected in 7.1%, and adenomatous polyps in 19.8% (39.4% of them were high risk). There was a 1.5% presence of adenocarcinomas in the subjects. Polyps and CRC were predominant in men (P=.001 and P=.027, respectively) and there was a linear increase with age. Symptomatic patients had a higher CRC detection rate (P<.001), but no differences were observed in relation to polyp diagnosis., Conclusions: Age and male sex increased the risk for presenting with CRC or adenomas in the group of patients with a family history of CRC, and the presence of symptoms was associated with a greater risk for presenting with CRC., (Copyright © 2014 Asociación Mexicana de Gastroenterología. Published by Masson Doyma México S.A. All rights reserved.)

Background and Rational: Telaprevir-based therapy (TBT) has been extensively evaluated in clinical trials. So we designed a study to compare the efficacy and safety of TBT between patients with moderate fibrosis and those suffering from advanced fibrosis in clinical practice. A multicenter observational and ambispective study was conducted. It included 582 patients with chronic hepatitis C genotype 1, 214 with fibrosis F2, and 368 with F3/F4 (F3: 148; F4: 220)., Results: The mean patient age was 55 years, 67% male. Type of prior response was 22% naïve, 57% relapsers, and 21% partial/null responders, 69% had high viral load (> 800,000 IU/mL). HCV genotypes were 1a (19%), 1b (69%), and 1 (12%), respectively. Sixty-five percent were non-CC IL28B genotype. Week-12 sustained virologic response (SVR12) was significantly higher among F2-naïve patients (78%) compared with F3/F4-naïve patients (60%; p = 0.039) and among F2 non-responders (67%) compared with F3/F4 non-responders (42%; p = 0.014). SVR12 among relapsers was remarkably high in both groups (F2:89% vs. F3/F4:78%). Severe anemia and thrombocytopenia were more frequent among patients with F3/F4 than those with F2 (p < 0.01). Overall, 132 patients (22%) discontinued treatment: 58 due to adverse effects, 42 due to the stopping-rule, and 32 due to breakthrough. Premature discontinuation was more frequent among patients with F3/F4 (p = 0.028), especially due to breakthrough (p < 0.001)., Conclusions: This multicenter study demonstrates high efficacy and an acceptable safety profile with regard to TBT in F2-patients in clinical practice.

Cereals are considered a basic food. Through the development of cooking, the human being has produced high- gluten-content food, so that it could make the most of its nutritional properties. Wheat is becoming one of the key elements of the Mediterranean diet. Amongst gluten- intake-related pathologies- gluten is present mainly in wheat, barley and rye- celiac disease (CD) is the most well-known. CD is a chronic inflammatory condition which affects gastrointestinal tract which develops in genetically predisposed individuals. The most common manifestation of CD is nutrients malabsorption. This protein trigger other pathology, wheat allergy (WA), which is an adverse immunological effect to gluten due to E immunoglobulin. A recent increased in non celiac gluten sensitivity (NCGS) has also been noticed, defined as the emergence of a range of gluten-intake related symptoms in patients for which celiac disease and wheat allergy have been ruled out. This article discusses these three conditions with their phatogenic mecanisms and the different clinic manifestations., (Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.)

Background & Aims: (i) To describe the demographic, clinical, virological and histological characteristics of the patients undergoing evaluation for indication of triple therapy against hepatitis C virus genotype 1, and to identify the reasons why candidate patients are excluded; and (ii) to evaluate the characteristics of the healthcare environment related to treatment., Methods: Observational, prospective and multi-centred study involving 16 hospitals of Spain. Data were collected on 1122 patients receiving attention in the outpatient clinics between June and December 2012., Results: Of the 1122 patients evaluated, 769 were finally included in this study; 27% (211/769) had contraindications to the therapy. Of those without contraindications, 54% (301/558) did not receive the treatment, and so, only about a third of the patients (33%-257/769) underwent therapy. The reasons for not initiating therapy were as follows: patient refusal (30%), mild disease/awaiting new treatments (34%), restrictions by the health service (30%), other reasons (6%). In univariate analyses, the probability of receiving treatment was related to: age <60 years, male gender, high education level, advanced fibrosis, having had previous treatment, being assessed in a centre of excellence. In multivariate analyses, the factors independently related to the probability of receiving treatment were as follows: high education level of the patients (P = 0.004), advanced fibrosis (P < 0.001) and centres of excellence (P = 0.009)., Conclusion: Despite the high efficacy of triple therapy, only a small proportion of patients receive the treatment. The causes related to non-treatment depend on patient factors, disease stage and characteristics of the health-service provision., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Morbidly obese patients usually present vitamin D deficiency or secondary hyperparathyroidism. Low vitamin D levels have been recently related to non-alcoholic fatty liver disease (NAFLD). The aim of this study was to analyse the relationship between vitamin D, bone turnover markers and non-alcoholic fatty liver disease and metabolic syndrome in severely obese patients., Methods: One hundred and ten patients who underwent bariatric surgery were included. Liver biopsy was taken during surgery. Two univariate analyses were carried out in order to i) analyse the relationship between liver histology and vitamin D-bone turnover markers (intact parathyroid hormone (PTH), osteocalcin and Carboxy-terminal collagen crosslinks) and ii) establish the association between metabolic syndrome components-insulin resistance (HOMA) and vitamin D-bone turnover markers., Results: 70% of the patients had lower levels of vitamin D or secondary hyperparathyroidism. None of the components of liver histology were associated with levels of vitamin D or with bone turnover parameters. Patients with metabolic syndrome showed lower levels of PTH and osteocalcin (72,42 (29,47) vs 61.25(19.59) p-Value: 0.022; 19.79 (10.43) vs 16.87(10.25) p-Value: 0,028, respectively). HOMA was not related to Vitamin D or bone turnover markers., Conclusion: Low levels of vitamin D or hyperparathyroidism are common in severely obese patients. Vitamin D and bone metabolism markers were associated neither to NAFLD nor with metabolic syndrome in our series of obese morbid patients., (Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.)

The treatment plan for chronic hepatitis C in special populations varies according to comorbidity and the current evidence on treatment. In patients with hepatitis C virus and HIV coinfection, the results of dual therapy (pegylated interferon plus ribavirin) are poor. In patients with genotype 1 infection, triple therapy (dual therapy plus boceprevir or telaprevir) has doubled the response rate, but protease inhibitors can interact with some antiretroviral drugs and provoke more adverse effects. These disadvantages are avoided by the new, second-generation, direct-acting antiviral agents. In patients who are candidates for liver transplantation or are already liver transplant recipients, the optimal therapeutic option at present is to combine the new antiviral agents, with or without ribavirin and without interferon. The treatment of patients under hemodialysis due to chronic renal disease continues to be dual therapy (often with reduced doses of pegylated interferon and ribavirin), since there is still insufficient information on triple therapy and the new antiviral agents. In mixed cryoglobulinemia, despite the scarcity of experience, triple therapy seems to be superior to dual therapy and may be used as rescue therapy in non-responders to dual therapy. However, a decision must always be made on whether antiviral treatment should be used concomitantly or after immunosuppressive therapy., (Copyright © 2014 Elsevier España, S.L.U. All rights reserved.)

There is experimental evidence that some antioxidant flavonoids show therapeutic potential in the treatment of hepatitis C through inhibition of hepatitis C virus (HCV) replication. We examined the effect of treatment with the flavonols quercetin and kaempferol, the flavanone taxifolin and the flavone apigenin on HCV replication efficiency in an in vitro model. While all flavonoids studied were able to reduce viral replication at very low concentrations (ranging from 0.1 to 5 μM), quercetin appeared to be the most effective inhibitor of HCV replication, showing a marked anti-HCV activity in replicon-containing cells when combined with interferon (IFN)α. The contribution of oxidative/nitrosative stress and lipogenesis modulation to inhibition of HCV replication by quercetin was also examined. As expected, quercetin decreased HCV-induced reactive oxygen and nitrogen species (ROS/RNS) generation and lipoperoxidation in replicating cells. Quercetin also inhibited liver X receptor (LXR)α-induced lipid accumulation in LXRα-overexpressing and replicon-containing Huh7 cells. The mechanism underlying the LXRα-dependent lipogenesis modulatory effect of quercetin in HCV-replicating cells seems to involve phosphatidylinositol 3-kinase (PI3K)/AKT pathway inactivation. Thus, inhibition of the PI3K pathway by LY294002 attenuated LXRα upregulation and HCV replication mediated by lipid accumulation, showing an additive effect when combined with quercetin. Inactivation of the PI3K pathway by quercetin may contribute to the repression of LXRα-dependent lipogenesis and to the inhibition of viral replication induced by the flavonol. Combined, our data suggest that oxidative/nitrosative stress blockage and subsequent modulation of PI3K-LXRα-mediated lipogenesis might contribute to the inhibitory effect of quercetin on HCV replication.

Introduction: Less than half of patients with chronic hepatitis C genotype 3 (G3) and high viral load (HVL) without a rapid virological response (RVR) achieve a sustained virological response (SVR) when treated with peginterferon plus ribavirin (RBV)., Objectives: To assess the impact of high doses of RBV on SVR in patients with G3 and HVL., Methods: Ninety-seven patients were randomized to receive peginterferon α-2a+RBV 800 mg/day (A; n=42) or peginterferon α-2a+RBV 1600 mg/day+epoetin β 400 IU/kg/week SC (B; n=55). Patients allocated to group B who achieved RVR continued on RBV (800mg/day) for a further 20 weeks (B1; n=42) while non-RVR patients received a higher dose of RBV (1600 mg/day)+epoetin β (B2; n=13)., Results: RVR was observed in 64.3% of patients in A and in 76.4% in B (p=0.259). Intention-to-treat (ITT) analysis showed SVR rates of 64.3% (A) and 61.8% (B), with a reduction of -2.5% (-21.8% to 16.9%) (p=0.835). The SVR rate was 61.9% in arm B1 and 61.5% in arm B2. No serious adverse events were reported, and the rate of moderate adverse events was < 5%., Conclusions: G3 patients with high viral load without RVR did not obtain a benefit from a higher dose of RBV. Higher doses of RBV plus epoetin β were safe and well tolerated (Clin Trials Gov NCT00830609)., (Copyright © 2013 Elsevier España, S.L. and AEEH y AEG. All rights reserved.)

Molecular mechanisms contributing to hepatitis C virus (HCV)-associated steatosis are not well established, although HCV gene expression has been shown to alter host cell cholesterol/lipid metabolism. As liver X receptors (LXRs) play a role as key modulators of metabolism signaling in the development of steatosis, we aimed to investigate in an HCV in vitro model the effect of HCV NS5A protein, core protein, and viral replication on the intracellular lipid accumulation and the LXRα-regulated expression of lipogenic genes. The effects of LXRα siRNA or agonist GW3965 treatment on lipogenesis and HCV replication capacity in our HCV replicon system were also examined. NS5A- and core-expressing cells and replicon-containing cells exhibited an increase of lipid accumulation by inducing the gene expression and the transcriptional activity of LXRα, and leading to an increased expression of its lipogenic target genes sterol regulatory element binding protein-1c, peroxisome proliferator-activated receptor-γ, and fatty acid synthase. Transcriptional induction by NS5A protein, core protein, and viral replication occurred via LXR response element activation in the lipogenic gene promoter. No physical association between HCV proteins and LXRα was observed, whereas NS5A and core proteins indirectly upregulated LXRα through the phosphatidylinositol 3-kinase pathway. Finally, it was found that LXRα knockdown or agonist-mediated LXRα induction directly regulated HCV-induced lipogenesis and HCV replication efficiency in replicon-containing cells. Combined, our data suggest that LXRα-mediated regulation of lipogenesis by core and NS5A proteins may contribute to HCV-induced liver steatosis and to the efficient replication of HCV.

Background: There is an excess incidence of colorectal cancer (CRC) and mortality from this disease in the health area of Leon. The aim of the present study was to determine trends in CRC and its geographical distribution., Methods: Cases included in the Hospital Registry of Tumors of the Centro Asistencial Universitario de León from 1994-2008 and occurring in patients residing in the health area of Leon were studied. Time trends were evaluated with a Poisson regression model. To analyze geographical distribution, the smoothed relative risks (RR) of the municipalities adjusted by the Besag, York and Mollié model were calculated, and their subsequent probability of an RR>1 (PP) was calculated using Bayesian methods., Results: A total of 4,136 cases were included. Rates standardized to the European standard population ranged from 49.6 (1994-6) to 63.5 new cases per 100,000 inhabitants in men (2006-8) and from 29.6 to 33.8 in women. An annual 2% increase was found for all localizations, ranging from 1.8% in the rectum to 3.6% in the proximal colon. In all localizations, the increase was greater in men than in women. Several municipalities in the health area of Leon showed an excess risk. The geographical pattern observed was due especially to the distribution of colon cancer., Conclusions: The incidence rates observed were high and were increasing. Special attention should be paid to CRC in the health area of Leon, mainly in the municipalities with excess risk., (Copyright © 2011 Elsevier España, S.L. and AEEH y AEG. All rights reserved.)

Hepatocyte apoptosis plays an important role in the development of fulminant hepatic failure (FHF). The objective of this study was to investigate the antiapoptotic effect of melatonin in an animal model of FHF of viral origin induced by the rabbit hemorrhagic disease virus (RHDV). Rabbits were experimentally infected with 2 × 10(4) hemagglutination units of a RHDV isolate and received melatonin at two concentrations of 10 and 20 mg/kg at 0, 12, and 24 hr postinfection. RHDV infection induced liver apoptosis, with increased caspase-3 immunoexpression and activity and poly(ADP-ribose)polymerase-1 (PARP-1) proteolysis. These effects were attenuated by melatonin in a concentration-dependent manner. Antiapoptotic effects of melatonin were related to a reduced expression of Bax and cytosolic cytochrome c release, increased expression of Bcl-2 and Bcl-xL, and inhibition of caspase-9 activity. Increased thiobarbituric reactive acid substances concentration and oxidized-to-reduced glutathione ratio were significantly prevented by melatonin administration. Melatonin treatment also resulted in a reduction in caspase-8 activity, tumor necrosis factor receptor-1 (TNF-R1) expression, and phosphorylated Janus kinase (JNK) expression, and increased expression of cellular FLICE-inhibitory protein (c-FLIP). Our findings show that inhibition of apoptotic mechanisms contributes to the beneficial effects of melatonin in rabbits with experimental infection by RHDV and supports a potential hepatoprotective role of melatonin in FHF., (© 2010 The Authors. Journal of Pineal Research © 2010 John Wiley & Sons A/S.)

Management of fulminant hepatic failure (FHF) continues to be one challenging problem, and experimental animal models resembling its clinical conditions are still needed. Rabbit hemorrhagic disease (RHD) fullfils many requirements of an animal model of FHF. This work investigated changes in MAPK, NF-kappaB, AP-1 and STAT pathways during RHD-induced liver injury. Rabbits were infected with 2 x 10(4) hemagglutination units of an RHD virus isolate. Apoptosis was documented by the presence of caspase-3 activity and substantial PARP proteolysis at 36 and 48 h postinfection (pi). Infection induced a marked and maintained expression of TNF-alpha from 12 h pi, while there was only a transitory increase in IL-6 expression. Expression of phosphorylated (p)-JNK, p-p38 and p-ERK1/2 was significantly elevated at 12 h pi. At 48 h pi p-JNK expression was maintained at a maximum level, while that of p-p38 returned to normality and there was no p-ERK1/2 expression. Activation of NF-kappaB and AP-1 and increased expression of VCAM-1 and COX-2 were observed. No significant changes were detected in activation of STAT1 and STAT3, while SOCS3 expression increased significantly. The current findings suggest that activation of JNK is an essential component in liver injury mediated by the RHD virus and that lack of activation of STAT3, probably mediated by SOCS3 over-expression, would contribute to the inhibition of the regenerative response. Data show the presence of molecular mechanisms contributing to liver damage and the lack of regeneration and they support the usefulness of this model to investigate novel therapeutical modalities in FHF.

We present the case of a 57-year-old man with mononeuritis multiplex and high transaminase levels. After investigations, the patient was diagnosed with acute hepatitis B infection and polyarteritis nodosa (PAN). The symptoms of PAN are nonspecific. Nervous system involvement in the form of mononeuritis multiplex can be one of the forms of presentation. PAN is one of the extrahepatic manifestations of hepatitis B, but since the introduction of the hepatitis B vaccine, its incidence has markedly declined. After 1 year of follow-up, the patient is asymptomatic following treatment with antiviral drugs and steroids.

Melatonin reduces proliferation in many different cancer cell lines. However, studies on the oncostatic effects of melatonin in the treatment of hepatocarcinoma are limited. In this study, we examined the effect of melatonin administration on HepG2 human hepatocarcinoma cells, analyzing cell cycle arrest, apoptosis and mitogen-activated protein kinase (MAPK) signalling pathways. Melatonin was dissolved in the cell culture media in 0.2% dimethyl sulfoxide and administered at different concentrations for 2, 4, 6, 8 and 10 days. Melatonin at concentrations 1000-10,000 microM caused a dose- and time-dependent reduction in cell number. Furthermore, melatonin treatment induced apoptosis with increased caspase-3 activity and poly(ADP-ribose) polymerase proteolysis. Proapoptotic effects of melatonin were related to cytosolic cytochrome c release, upregulation of Bax and induction of caspase-9 activity. Melatonin treatment also resulted in increased caspase-8 activity, although no significant change was observed in Fas-L expression. In addition, JNK 1,-2 and -3 and p38, members of the MAPK family, were upregulated by melatonin treatment. Growth inhibition by melatonin altered the percentage or cells in G0-G1 and G2/M phases indicating cell cycle arrest in the G2/M phase. The reduced cell proliferation and alterations of cell cycle were coincident with a significant increase in the expression of p53 and p21 proteins. These novel findings show that melatonin, by inducing cell death and cell cycle arrest, might be useful as adjuvant in hepatocarcinoma therapy.

Objectives: We analyzed the characteristics of patients with gastric tumors diagnosed with multiple malignant primary neoplasm (MMPN) in the Health District of León., Material and Methods: Using the information in the Tumor Registry at León Hospital patients selected were those with gastric neoplasms diagnosed between 1993 and 2002. A follow-up was performed until December 31, 2004, and the characteristics of patients diagnosed with a second neoplasm were analyzed., Results: MMPN prevalence was 1,96%; 56% of patients had a history of cancer in first-degree relatives. The most frequent second neoplasms were digestive (26%) and urologic (21%); 87% of patients were diagnosed with a second neoplasm within the first two years. No significative differences in survival were observed among patients with synchronous or metachronous MMPN., Conclusions: MMPN in patients with gastric neoplasms is a relevant problem. While external carcinogenic agents could act as promoters in the development of second neoplasms, these patients seem to have a genetic background favoring the development of MMPN. Secondary prevention is the best measure to avoid MMPN development.

We have studied the effect of low doses of two widely used antidepressants, fluoxetine (Flx) and reboxetine (Rbx), on excitatory synapses of rat brain cortex and hippocampus. After 15 days of Flx treatment (0.67 mg/kg/day), its plasma level was 20.7+/-5.6 ng/ml. Analysis of postsynaptic densities (PSDs) by immunoblotting revealed no changes in the glutamate receptor subunits GluR1, NR1, NR2A/B, mGluR1alpha nor in the neurotrophin receptor p75(NTR). However, the brain-derived neurotrophic factor (BDNF) receptor TrkB decreased by 42.8+/-6%, and remained decreased after 6 weeks of treatment. The BDNF and TrkB content in homogenates of cortex and hippocampus began to rise at 9 and 15 days, respectively, and remained high for up to 6 weeks. Similar results were obtained following chronic Rbx administration at 0.128 mg/kg/day. We propose that BDNF, whose synthesis is increased by antidepressants, and which is in part released at synaptic sites, binds to TrkB in PSDs, leading to the internalization of the BDNF-TrkB complex and, thus, to a decrease of TrkB in the PSDs. This was paralleled by greater levels of phosphorylated (ie activated) TrkB in the light membrane fraction, that contains signaling endosomes. The retrograde transport of endocyted BDNF/TrkB complexes from spines to cell bodies, where it activates the synthesis of more BDNF, is a protracted process, potentially requiring several cycles of TrkB/BDNF complex endocytosis and transport. This positive feedback mechanism may help explain the time-lag between drug administration and its therapeutic effect, that is, the antidepressant drug paradox.

Objective: We analyzed the characteristics of the patients with bladder neoplasms who developed a multiple malignant primary neoplasm (MMPN) in the health district of León, the impact on survival and the prognostic variables., Material and Methods: We have used the data from the Tumor Registry of the Hospital of León and selected all those patients who were diagnosed of a bladder tumor between 1993 and 2002. They were classified into two groups: the first with 71 patients with MMPN and a second group with 159 patients with single bladder tumors diagnosed between 1996 and 1997., Results: Incidence of MMPN was of 7.1 percent. More than half of the patients had familial oncologic background. The second most frequently diagnosed neoplasms were urologic, followed by gastrointestinal and respiratory. Survival of patients with MMPN was 21 percent lower than single neoplasms. Variables with prognosis significance were the stage of the second neoplasm, diagnosis of a second urologic neoplasm and surgery treatment for the second tumor., Conclusions: MMPN in patients with bladder tumors are frequent in our geographic area. The high frequency of familial oncologic antecedents in these patients suggest a genetic background. Prognosis of MMPN patients is worse than single tumors patients, but no differences were observed regarding prognosis in patients with synchronous or metachronous MMPN.

Background: Malignant gastrointestinal obstruction is a secondary complication of cancers in an advanced state. Treatment has consisted of gastrojejunostomy. However, the endoscopic placement of metallic stents has provided positive results. This study aimed to compare the efficiency of both therapeutic options., Methods: A total of 41 patients with gastrointestinal obstruction caused by inoperable neoplasm were treated endoscopically with enteral stent (24 patients) or gastrojejunostomy (17 patients)., Results: In the endoscopic group (EG) 24 patients (100%) achieved efficient gastric emptying, as compared with 82.3% in the surgical group (SG). The difference was not significant. The average time for initiating oral food tolerance was 2.4 days for the EG and 5 days for the SG (p < 0.001). The average inpatient time was 7.1 days for the EG and 11.5 days for the SG (p < 0.001). Mortality at 30 days was lower in the EG (16.6%) than in the SG (29.4%) (p < 0.05). The survival time was 20 weeks for the EG and 21.6 weeks for the SG. The difference was not significant. The rate of complications was 4% in the (EG) and 17.6% in the (SG), with the difference was not significant., Conclusion: Endoscopic treatment of malignant gastrointestinal obstruction provides an adequate palliation of the symptoms. It is less invasive, avoids the morbidity associated with open gastrojejunostomy, and achieves a faster start to oral food and a shorter hospital stay, leading to a higher quality of life.

Objective: Needle-knife sphincterotomy (NKS) is used to achieve biliary access when routine cannulation methods have been unsuccessful. The aim of this study was to analyze the results of NNS in patients with an inaccessible common bile duct (difficult cannulation) using standard techniques in endoscopic retrograde cholangiopancreatography and the factors associated with the success of this procedure and complications., Material and Methods: We performed a prospective study of 72 patients who underwent NKS performed by the same endoscopist (J.E.) because of difficult cannulation of the common bile duct between January 1998 and December 2004. The results were analyzed in terms of successful biliary access, whether this was achieved in one or more sessions, its possible association with the underlying disease, and the incidence and severity of complications., Results: Seventy-two NKS were performed from a total of 1062 sphincterotomies (6.7%). A total of 77.7% of the patients underwent prior implantation of a pancreatic prosthesis (NKS-PP). The final diagnosis was: choledocholithiasis (31.9%), cancer of the pancreas (16.6%), cholangiocarcinoma (13.8%), benign stenosis (8.3%), dysfunction of the sphincter of Oddi (6.9%), normal (6.9%), and miscellaneous (13.8%). Cannulation was successful in 87.5% (63/72), and was achieved in the first session in 73% (46/63). Biliary access was achieved in 72.7% of patients (16/22) with biliopancreatic neoplasms versus 94% (47/50) of those with other diagnoses (p = 0.03). Eleven patients (15.2%) presented 12 complications (16.6%) (6 pancreatitis, 4 cholangitis, 1 papillary hemorrhage, and 1 portal vein filling). The use of a pancreatic prosthesis was related to a higher success rate and significantly fewer complications (p = 0.03)., Conclusions: NKS-PP can be a safe procedure in patients with difficult cannulation of the common bile duct. The presence of biliopancreatic neoplasm is a risk factor for failure to achieve biliary access compared with other diagnoses. The complication rate was similar to that found in other studies. No cases of severe pancreatitis or perforations were found.

Background: Glutamine, a nonessential amino acid, has received increasing attention because it becomes essential during stress and catabolic conditions. Many investigations have shown that during severe stress, the consumption of glutamine exceeds glutamine synthesis, resulting in depletion of glutamine stores. The aim of this study was to evaluate the effects of supplementing parenteral diets with a glutamine-containing dipeptide, L-alanyl-L-glutamine, on rat nutrition status., Methods: Male Wistar rats were used. Animals (n = 36) were centrally catheterized and randomly assigned to 1 of the following groups based on method of parenteral nutrition (PN): control group with oral nutrition and IV infusion of a saline solution; standard parenteral nutrition (SPN) group; or alanyl-glutamine-supplemented PN (ALA-GLN PN) group (20 g/L). Parenteral nutrition was isocaloric and isonitrogenous. Infusions were administered at a rate of 2.0 mL/h over 5 days. Nutrition status was assessed by body weight change, plasma proteins, accumulated urinary creatinine, and nitrogen balance., Results: Accumulated urinary creatinine increased significantly after day 4 in the ALA-GLN PN group, compared with the SPN group and the controls. Body weight change significantly differed on day 5 between the ALA-GLN PN and SPN groups. After 3 days, nitrogen balance was significantly lower and nitrogen retention higher in the ALA-GLN PN group when compared with the SPN group. Albumin and transferrin concentrations decreased significantly in the SPN group, but did not differ from the controls in the ALA-GLN PN group., Conclusions: Weight, plasma proteins, urinary accumulated creatinine, and nitrogen retention showed a better evolution in the group supplemented with the glutamine dipeptide when compared with the SPN group. Our results suggest a more suitable nutrition support in animals receiving L-alanyl-L-glutamine.

Aim: To investigate the relationship between serum levels of ferritin and bile acids (BA) and the response to antiviral treatment in chronic hepatitis C (HCV)., Methods: A retrospective study was carried out on 35 control volunteers and 50 patients receiving interferon alpha-2b alone or plus ribavirin for 48 weeks. These were classified as sustained responders (SR) for >6 months after therapy (n = 17), non-responders (NR) (n = 27) and relapsers (RL) (n = 6). Before treatment, serum ferritin levels were determined by immunoturbidometry, 3alpha-hydroxyl-BA levels (S-3alpha-OH-BA) were assayed enzymatically and total (desulfated, deglucuronidated and deamidated) BA concentrations (STBA) by gas chromatography-mass spectrometry., Results: STBA were lower in controls than in patients (SR < NR + RL). The highest levels of cholic acid and chenodeoxycholic acid families were found in NR + RL. Levels of cholic acid family were similar in controls and SR, whereas those of chenodeoxycholic acid family were higher in SR than in controls. A significant correlation between STBA (but not S-3alpha-OH-BA) and ferritin was found. Apparent value to predict the absence of a sustained response was calculated by combining elevated ferritin (>300 microg/mL) and STBA or individual BA species at different cut-off values. The best degree of certainty (100% specificity) was obtained using STBA >15 microM., Conclusion: These results recommend that larger prospective trials should be performed in chronic HCV patients to evaluate the usefulness of combined measuring of STBA and ferritin as additional prognostic markers to predict the existence of a very low probability of a sustained response to the current standard treatment, i.e. pegylated interferon in combination with ribavirin.

Malignant gastroduodenal obstruction may cause significant morbidity. Insertion of enteral prostheses as a palliative treatment is an acceptable option to achieve an appropriate gastric voiding without the morbidity associated to palliative surgery, with a lesser procedure-related mortality and a lower cost, while providing a better quality of life. Its is important to unify and consolidate the endoscopic procedure for the placement of enteral prostheses, avoiding variations that may preclude an adequate analysis of this procedure outcome.

Objective: We analyze the characteristics of the patients with prostate tumours who developed a multiple malignant primary neoplasms (MMPN) in the health district of León, the impact on survival and the prognostic variables., Material and Methods: We have used the data from the Tumour Registry of the Hospital of León and we have selected all those patients who were diagnosed of a prostate tumor between 1993 and 2002. Later we made two groups: the first with 67 patients with MMPN and a second group with 145 patients with single prostate tumours diagnosed during 1996 and 1997., Results: Prevalence of MMPM was of 5.57 percent. Patients with MMPN were 3 years younger than those with single tumours, with a high frequency (41 percent) of familial oncologic antecedents on first degree parents. The more frequent association was the synchronous urologic neoplasm. During the next two years from diagnosed of prostate tumour, 86 percent of patients with MMPN were diagnosed of their second neoplasm. Survival of metachronous MMPN patients was lower than synchronous MMPN patients, being the variables with prognosis significance the age, metachronous MMPN, stage of second neoplasms and if the second neoplasms was or not urologic., Conclusions: MMPN in patients with prostatic tumours are frequent in our medium. A genetic base may be associated in these patients. Prognosis of metachronous MMPN patients is worse. No differences were observed about prognosis with single tumour patients.

Goals: The goal of this study is to assess the effect that supplementing parenteral diets with L-glutamine or with L-alanyl-L-glutamine has on the balance of oxidants/antioxidants in the liver and on detoxification systems mediated by P-450 cytochrome in rats., Material and Methods: Central catheters were inserted in the animals (n = 60) and they were randomly assigned to one of the following groups: a control group (C) with oral feeding and I.V. infusion of saline solution, a total parenteral nutrition group without glutamine (TPN without GLN), a parenteral nutrition group with glutamine supplement (TPN GLN), and a total parenteral nutrition group with a supplement of alanine-glutamine dipeptide (20 g/L) (TPN ALA-GLN). The parenteral nutrition provided was all isocaloric and isonitrogenated, and the infusions were administered at a speed of 2 ml/h over 5 days., Results: In the animals of the group without GLN, the liver concentration of glutathione was reduced while the levels of thiobarbituric acid reaction products (TBARS) increased. Supplementing with either glutamine or alanine-glutamine normalized the levels of glutathione but the TBARS levels only fell in the group with the dipeptide. This effect was parallel to the partial recovery of the antioxidant enzyme activities analyzed. The liver concentrations of P-450 cytochrome, P-450 cytochrome dependent mono-oxygenases and the clearance of antipyrine were not modified by the supplements of glutamine or alanine-glutamine., Conclusions: Our data suggest a greater protection by alanine-glutamine supplements against the injury produced by free radicals during TPN and the absence of any effect with either glutamine or alanine-glutamine supplements on the oxidative metabolism of the liver.

Objective: To prospectively analyze the results obtained with papillary balloon dilatation (PBD) in the treatment of common bile duct stones in patients at risk of complications if endoscopic sphincterotomy (ES) were performed., Patients and Method: Thirty-three patients were included between January 2001 and June 2003 (mean age 76.2 years). The criteria for PBD were: choledocholithiasis < or =10 mm in patients with peripapillary diverticula, hemostatic alterations, Billroth-II, and preservation of Oddi's sphincter. In 79% of the patients sedation was performed by an anesthetist. PBD was performed with a balloon catheter dilator with a diameter of 8 or 10 mm for 2 minutes. The efficacy and duration of the procedure as well as complications at 30 days and patient satisfaction were evaluated., Results: Stone extraction was achieved in all patients (100%). The mean duration of the procedure was 26 minutes. Two patients (6%) presented mild pancreatitis. Serum amylase was elevated in 16 patients (48%): > or =3 times (post-PBD hyperamylasemia) in 11 (33%). The procedure caused no discomfort in 25/26 (96%) of the patients sedated by an anesthetist vs 2/5 patients (49%) who underwent endoscopic sedation., Conclusions: PBD is an effective and simple therapeutic option in the treatment of small common bile duct stones (< or =10 mm) and in patients at high risk. The duration of endoscopic retrograde cholangiopancreatography is not prolonged. Complications are infrequent (6%) and mild. Post-PBD hyperamylasemia is frequent and generally without clinical importance. Sedation by an anesthetist improves patient satisfaction.

The objective of this study is to determine if treatment with the angiogenesis inhibitor TNP-470 results in impairment of oxidative stress, inhibition of nuclear factor kappa B (NF-kappaB) activation and decrease of nitric oxide production in an experimental model of rat hepatocarcinogenesis. Tumour was induced by diethylnitrosamine and promoted by two-thirds hepatectomy plus acetaminofluorene administration. Experiments were carried out at 28 weeks after initiating the treatment. TNP-470 was administered at 30mg/kg, three times per week from 20 to 28 weeks. Carcinomatous tissue growing outside dysplastic nodules and a marked expression of placental glutathione S-transferase were detected in rats with induced carcinogenesis. Liver concentrations of thiobarbituric acid reactive substances, reduced glutathione (GSH) and glutathione disulfide (GSSG) were significantly higher than those of controls and there was a significant increase in the GSSG/GSH ratio. Tumour growth was accompanied by augmented expression of inducible nitric oxide synthase, activation of (NF-kappaB) and proteolysis of IkappaB. All these effects were absent in animals receiving TNP-470. Our results indicate that TNP-470 inhibits oxidative stress, nitric oxide production and NF-kappaB activation induced by experimental hepatocarcinogenesis. These changes would contribute to the beneficial effects of TNP-470 in cancer treatment.

In this study we sought to characterize a novel model of fulminant liver failure (FLF) by means of experimental infection of rabbits with the rabbit hemorrhagic disease virus (RHDV). Thirty-seven 9-week-old rabbits were injected intramuscularly with 2 x 10(4) hemagglutination units of an RHDV isolate. Eighty-five percent of rabbits died 36 to 54 hours after infection. From 36 hours after infection we noted marked increases in transaminases, lactate dehydrogenase, and total bilirubin. The rabbits exhibited hypoglycemia and coagulation abnormalities, with a significant decrease in factor V, factor VII, and prothrombin. Plasma aromatic amino acids and taurine showed progressive increases, and the Fischer index was significantly reduced. Expression of hepatocyte growth factor messenger RNA was inhibited from 36 hours after infection. Prostration and side recumbency were present at later stages, and neurologic symptoms rapidly progressed to coma. Onset of brain death was associated with a significant increase in intracranial pressure and blood ammonia. RHDV infection reproduces clinical, biochemical, and histologic features of the FLF syndrome and satisfies criteria for a suitable animal model. Rabbit hemorrhagic viral disease could provide a useful tool for the study of FLF and the evaluation of new liver-support technologies in human subjects.

This study was aimed to determine whether administration of an inhibitor of caspase-3 protects hepatocellular function in rats with hemorrhagic shock and whether caspases are important pharmacological targets in attenuating liver injury induced by hemorrhagic shock and resuscitation. Male adult rats were subjected to hemorrhagic shock by bleeding to a mean arterial blood pressure of 35-40 mmHg for 1 h and were then resuscitation with 60% shed blood and lactated Ringers solution. A subgroup of animals was injected i.v. with 2 mg/kg caspase inhibitor, Z-DEVD-FMK, prior to blood withdrawal. Fas ligand expression was markedly elevated and caspase-3 activity increased by 3-fold in hemorrhagic untreated rats. The increase in caspase-3 activity was prevented by administration of Z-DEVD-FMK prior to shock and resuscitation. Poly (adenosine diphosphate ribose) polymerase proteolysis was reduced in rats treated with the caspase-3 inhibitor compared with hemorrhagic untreated animals. Plasma aspartate aminotransferase and alanine aminotransferase values showed a significant increase at 6 h of shock in untreated animals (+360% and +515% as compared with sham-operated animals, respectively). Administration of the caspase-3 inhibitor did not prevent the increase in plasma transaminases. The cytosolic concentration of thiobarbituric acid-reactive substances (TBARS) and the oxidized:reduced glutathione ratio increased in the animals with hemorrhagic shock (+94% and +170%, respectively). These parameters were not significantly modified by pretreatment with Z-DEVD-FMK. It appears that caspase inhibition does not attenuate hepatocellular depression and liver injury induced by hemorrhagic shock and resuscitation.

Abdominal pain associated with nausea and vomiting in a young patient led to a diagnosis of median arcuate ligament syndrome. The presence of mild haematuria was associated with a concomitant Nutcracker syndrome. Diagnosis was achieved by a computed tomography scan, which showed compression of the vessels of the coeliac axis and left renal vein. These syndromes are very rare, and their association in the same patient has not been described before. There is no relationship in the aetiology of these entities. In this report we discuss the diagnosis and therapeutic options, and review the literature.

Primary leiomyosarcoma of the liver is a rare entity and fewer than 100 cases have been reported in the medical literature. Even more unusual is the association with another previous tumour. We report the case of a 84-year-old man who had been treated for a gastric non-Hodgkin lymphoma two years previously. He presented with a painful mass in the right upper abdomen. An ultrasound scan showed a large mass in the right lobe of the liver and chest radiography showed pulmonary metastases. Liver biopsy was performed and immunohistochemical analysis revealed a malignant leiomyosarcoma. We discuss this case and review the available literature.

Unlabelled: Sterilization is the reference method recommended to ensure the asepsia of an instrument used to perform cures. Chemical disinfection has shown itself to be highly effective in this process for endoscope equipment without there being definitive references about its efficiency on instruments used for cures., Objective: Evaluate the efficiency of chemical disinfection on instruments used for cures, with the reference method being sterilization., Methods: Prospective study in which the efficiency of glutaraldehyde-phenolate is compared to sterilization on 9 sets of instruments used for cures, each one having a dissection clamp and a Kocher clamp, used in 122 cures carried out in different wards at the León Hospital. Their efficiency was evaluated by means of microbiological studies after cures were performed and after disinfection or sterilization occurred., Results: There were no positive cultures after either the disinfection or the sterilization. The existence of positive cultures after cures was related to the type of wound treated, clean wounds were always negative while dirty wounds were frequently positive (p < 0.05)., Conclusion: Chemical disinfection with glutaraldehyde-phenolate is as efficient as sterilization in assuring the asepsia of instruments, while offering some clear advantages compared to sterilization since this chemical disinfection has a low cost, its use avoids the need to have duplicate instrument sets, it provides a longer life for these instruments and does not require moving instruments from their work site, thus preventing their loss.

Aim: To determine the degree of association between serum alpha-1-antitrypsin levels and its phenotypes as well as its clinical expression., Patients and Methods: The alpha-1-antitrypsin genotype was identified using polymerase chain reaction followed by restriction enzyme digest in 212 patients in whom serum alpha-1-antitrypsin determination had been requested. The reasons for the request, the existence of pulmonary or liver disease, clinical diagnoses and functional repercussions were analyzed., Results: Two hundred and twelve patients were evaluated (68% males; mean age: 34 20 years). In 23 patients (10.8%) a deficiency variant was found (one or two M alleles were lacking) and in 8 patients (3.8%) the genotype was ZZ. All patients with MM genotype had alpha-1-antitrypsin levels of 75 mg/dl or higher while none of the patients with ZZ genotype had levels higher than 40 ml/dl. All the patients with ZZ genotype showed alterations: 3 had pulmonary emphysema, 1 had chronic obstructive pulmonary disease and 4 had hypertransaminasemia. One patient with pulmonary emphysema had severe respiratory insufficiency while in the remaining patients with respiratory problems, respiratory insufficiency was slight or moderate. None of the patients with hypertransaminasemia showed echographic signs of portal hypertension or clinical or laboratory signs of reduced liver function., Conclusions: There is a close association between alpha-1-antitrypsin levels and the different genotypes. Consequently, in basal conditions with serum alpha-1-antitrypsin levels higher than 75 mg/dl genotyping is not required. The functional repercussions of deficiency variants in young adults is slight.

Aim: To determine the current status of endoscopic retrograde cholangiopancreatography (ERCP) and the effects of the introduction of magnetic resonance cholangiography (MRC) on ERCP and to evaluate the diagnostic yield of MRC since its introduction in obstructive biliary disease., Material and Methods: We performed a retrospective analysis of the ERCP carried out between January 1998 and December 2000 and of the MRC performed for suspected obstructive biliary disease from May 1999 to December 2000. When both techniques were performed, the diagnostic yield of MRC was evaluated., Results: We performed 927 ERCP. A total of 45.3% of the patients were men. Mean age was 69.2 14.6 years. Treatment was performed on 688 occasions (77%), mainly sphincterotomy (69.9%) and placement of polyethylene (21.8%) or self-expanding (9.9%) prostheses. The number of ERCP performed each year was 261, 330 and 336 in 1998, 1999 and 2000, respectively; of these 76.6%, 80% and 76.9% were therapeutic. MRC was performed in 63 patients with suspected biliary disease. In 27 of 59 patients (45.8%) MRC was sufficient for diagnosis, avoiding the need for ERCP. In the 35 patients in whom both techniques (MRC and ERCP) were performed, the diagnostic yield of MRC compared with that of ERCP was: sensitivity 100%, specificity 50%, positive predictive value 87.1%, negative predictive value 100% and overall value 89%. The cases responsible for the low specificity (all due to choledocholithiases) were analyzed and a significant time lapse was found between the performance of MRC and ERCP (range: 7-35 days) during which choledocholithiasis probably resolved spontaneously., Conclusions: a) Contrary to what could be expected, the number of ERCP seems to be increasing with a high percentage of endoscopic treatment; b) Because of its diagnostic sensitivity, MRC is the ideal technique for eliminating the need for diagnostic ERCP, thus allowing greater development of the therapeutic aspect of ERCP.