Liver Transplantation for Primary Sclerosing Cholangitis (PSC) With or Without Inflammatory Bowel Disease (IBD)-A European Society of Organ Transplantation (ESOT) Consensus Statement.

Primary sclerosing cholangitis (PSC) is the classical hepatobiliary manifestation of inflammatory bowel disease (IBD) and a lead indication for liver transplantation (LT) in the western world. In this article, we present a Consensus Statement on LT practice, developed by a dedicated Guidelines' Taskforce of the European Society of Organ Transplantation (ESOT). The overarching goal is to provide practical guidance on commonly debated topics, including indications and timing of LT, management of bile duct stenosis in patients on the transplant waiting list, technical aspects of transplantation, immunosuppressive strategies post-transplant, timing and extension of intestinal resection and futility criteria for re-transplantation.

Can dietary fiber improve the technological characteristics and sensory acceptance of low-fat Italian type salami?

To meet the needs of new consumers, meat researchers need to develop healthier products. Dietary fibers can be added for structural purposes, to present functional characteristics or to change the composition of the final product. In this study, mixture design was used to investigate the effects of partial substitution of pork fat by inulin, fructooligosaccharides and α-cyclodextrin on the technological and sensory quality characteristics of low-fat Italian type salami. The partial substitution of fat using dietary fibers shows no effect on weight loss, Aw and pH during ripening time. However, the addition of up to 2% α-cyclodextrin increased lightness and reduced redness and yellowness. Up to 2% of inulin or fructooligosaccharides added improved the sensory acceptance, texture parameters and redness. Healthier low-fat Italian type salami can be produced using inulin or fructooligosaccharides as fat substitute for pork fat and still obtain good technological and sensorial results.

Intestinal Intussusception by Monophasic Synovial Sarcoma: Case Report and Literature Review.

INTRODUCTION: Synovial sarcomas are rare malignant tumors of soft tissues, arising mainly from periarticular structures. Gastrointestinal localizations are unusual presentation of these rare sarcomas. METHODS: We present the case of a 56- years old man with monophasic synovial sarcoma, arising primarily from the ileum, and causing intussusception. A review of the literature was conducted to gather information about this rare sarcoma. RESULTS: We found that the criteria normally used to determine the prognosis in patients with monophasic synovial sarcoma of soft tissue are poorly applicable for gastrointestinal localizations. CONCLUSIONS: A better characterization of these tumors could identify them as a distinct entity, compared with monophasic synovial sarcomas of soft tissues.

Effectiveness of different therapeutic strategies in preventing diverticulitis recurrence.

BACKGROUND: Colonic diverticulitis shows a high recurrence rate. AIMS: To assess the efficacy of three different therapeutic strategies in preventing diverticulitis recurrence. MATERIALS AND METHODS: One hundred thirty patients suffering from Acute Uncomplicated Diverticulitis (AUD) (81 males, 49 females, mean age 64.71 years, range 40-85) were prospectively assessed. After obtaining remission, considered present when both endoscopic and histological damage were absent, the patients were treated with mesalazine 1.6 g/day (59 patients, group A), or rifaximin 800 mg/day for 7 days every month (52 patients, group B). Clinical, endoscopic and histological follow-up was performed after 6, 12 and thereafter every 12 months after diagnosis of AUD. RESULTS: Seven patients were excluded from final evaluation because they were lost to follow-up. Fifty-five group A patients and 49 group B patients patients were available for the final assessment at the end of a 24-month follow-up. Sustained remission was significantly higher in group A with respect to group B. CONCLUSIONS: Patients taking mesalazine have lower risk of diverticulitis recurrence than patients taking rifaximin because of the lower prevalence of persisting endoscopic and histological inflammation.

Serum levels of selenium in patients with breast cancer before and after treatment of external beam radiotherapy.

BACKGROUND: To evaluate the influence of radiotherapy on the selenium serum levels of breast cancer patients. PATIENTS AND METHODS: This prospective study includes 209 breast cancer patients treated by external beam radiotherapy from December 2007 until August 2008. Plasma selenium concentrations were determined before and at the end of the radiotherapeutic treatment. Age, clinical stage, prior chemotherapy, body mass index (BMI) and personal habits (smoking and alcoholism) were recorded for each patient. RESULTS: The mean age was 61 years; the mean BMI was 28.7. One hundred and seventy-four patients (83.3%) were nonsmokers. One hundred and eighty-nine patients (90.4%) showed no drinking habits and 110 (52.6%) have no prior chemotherapy. Sixty patients (28.7%) were in clinical stage I, 141 (67.5%) in clinical stage II and 8 (3.8%) in clinical stage III. At the beginning of radiotherapy, the mean selenium value for all patients was 86.4 µg/l and after radiation this value dropped to 47.8 µg/l. Multivariate analysis showed statistically significant difference in the plasma selenium concentration before and after radiotherapy for age (P > 0.001), BMI (P > 0.001), smoking (P > 0.001), alcoholism (P > 0.001), chemotherapy (P > 0.001) and clinical stage (P > 0.001). CONCLUSIONS: Significant reduction in plasma levels of selenium is recorded in patients undergoing radiotherapy, suggesting attention to the nutritional status of this micronutrient and other antioxidant agents.

Performance evaluation of paediatric propofol pharmacokinetic models in healthy young children.

BACKGROUND: The performance of eight currently available paediatric propofol pharmacokinetic models in target-controlled infusions (TCIs) was assessed, in healthy children from 3 to 26 months of age. METHODS: Forty-one, ASA I-II children, aged 3-26 months were studied. After the induction of general anaesthesia with sevoflurane and remifentanil, a propofol bolus dose of 2.5 mg kg(-1) followed by an infusion of 8 mg kg(-1) h(-1) was given. Arterial blood samples were collected at 1, 2, 3, 5, 10, 20, 40, and 60 min post-bolus, at the end of surgery, and at 1, 3, 5, 30, 60, and 120 min after stopping the infusion. Model performance was visually inspected with measured/predicted plots. Median performance error (MDPE) and the median absolute performance error (MDAPE) were calculated to measure bias and accuracy of each model. RESULTS: Performance of the eight models tested differed markedly during the different stages of propofol administration. Most models underestimated propofol concentration 1 min after the bolus dose, suggesting an overestimation of the initial volume of distribution. Six of the eight models tested were within the accepted limits of performance (MDPE<20% and MDAPE<30%). The model derived by Short and colleagues performed best. CONCLUSIONS: Our results suggest that six of the eight models tested perform well in young children. Since most models overestimate the initial volume of distribution, the use for TCI might result in the administration of larger bolus doses than necessary.

Real-life efficacy and safety of Ustekinumab as second- or third-line therapy in Crohn's disease: results from a large Italian cohort study.

OBJECTIVE: Ustekinumab (UST) is an anti-IL12/23 antibody for the treatment of Crohn's Disease (CD). The aim of this study was to compare the efficacy and safety of UST in a large population-based cohort of CD patients who failed previous treatment with other biologics. PATIENTS AND METHODS: 194 CD patients (108 males and 86 females, mean age 48 years (range 38-58 years) were retrospectively reviewed. 147 patients were already treated with anti-TNFα (75.8%), and 47 (24.2%) patients were already treated with anti-TNFα and vedolizumab. Concomitant treatment with steroids was present in 177 (91.2%) patients. RESULTS: At week 12, clinical remission was achieved in 146 (75.2%) patients. After a mean follow-up of 6 months, clinical remission was maintained in 135 (69.6%) patients; at that time, mucosal healing was assessed in 62 (31.9%) patients, and it was achieved in 33 (53.2) patients. Three (1.5%) patients were submitted to surgery. Steroid-free remission was achieved in 115 (59.3%) patients. Both serum C-Reactive Protein and Fecal Calprotectin (FC) levels were significantly reduced with respect to baseline levels during follow-up. A logistic regression, UST therapy as third-line therapy (after both anti-TNFα and vedolizumab), FC >200 µg/g, and HBI ≥8 were significantly associated with lack of remission. Adverse events occurred in 5 (2.6%) patients, and four of them required suspension of treatment. CONCLUSIONS: UST seemed to be really effective and safe in CD patients unresponsive to other biologic treatments, especially when used as second-line treatment.

Cytotoxic T lymphocytes recognize an HLA-A2-restricted epitope within the hepatitis B virus nucleocapsid antigen.

The absence of readily manipulable experimental systems to study the cytotoxic T lymphocyte (CTL) response against hepatitis B virus (HBV) antigens has thus far precluded a definitive demonstration of the role played by this response in the pathogenesis of liver cell injury and viral clearance during HBV infection. To circumvent the problem that HBV infection of human cells in vitro for production of stimulator/target systems for CTL analysis is not feasible, a panel of 22 overlapping synthetic peptides covering the entire amino acid sequence of the HBV core (HBcAg) and e (HBeAg) antigens were used to induce and to analyze the HBV nucleocapsid-specific CTL response in nine patients with acute hepatitis B, six patients with chronic active hepatitis B, and eight normal controls. By using this approach, we have identified an HLA-A2-restricted CTL epitope, located within the NH2-terminal region of the HBV core molecule, which is shared with the e antigen and is readily recognized by peripheral blood mononuclear cells from patients with self-limited acute hepatitis B but less efficiently in chronic HBV infection. Our study provides the first direct evidence of HLA class I-restricted T cell cytotoxicity against HBV in humans. Furthermore, the different response in HBV-infected subjects who successfully clear the virus (acute patients) in comparison with patients who do not succeed (chronic patients) suggests a pathogenetic role for this CTL activity in the clearance of HBV infection.

Cytotoxic T lymphocyte response to a wild type hepatitis B virus epitope in patients chronically infected by variant viruses carrying substitutions within the epitope.

Mutations that abrogate recognition of a viral epitope by class I-restricted cytotoxic T lymphocyte (CTL) can lead to viral escape if the CTL response against that epitope is crucial for viral clearance. The likelihood of this type of event is low when the CTL response is simultaneously directed against multiple viral epitopes, as has been recently reported for patients with acute self-limited hepatitis B virus (HBV) infection. The CTL response to HBV is usually quite weak, however, during chronic HBV infection, and it is generally acknowledged that this is a major determinant of viral persistence in this disease. If such individuals were to produce a mono- or oligospecific CTL response, however, negative selection of the corresponding mutant viruses might occur. We have recently studied two HLA-A2-positive patients with chronic hepatitis B who, atypically, developed a strong HLA-A2-restricted CTL response against an epitope (FLPSDFFPSV) that contains an HLA-A2-binding motif located between residues 18-27 of the viral nucleocapsid protein, hepatitis B core antigen (HBcAg). These patients failed, however, to respond to any of other HLA-A2-restricted HBV-derived peptides that are generally immunogenic in acutely infected patients who successfully clear the virus. Interestingly, DNA sequence analysis of HBV isolates from these two patients demonstrated alternative residues at position 27 (V --> A and V --> I) and position 21 (S --> N, S --> A, and S --> V) that reduced the HLA and T cell receptor-binding capacities of the variant sequences, respectively. Synthetic peptides containing these alternative sequences were poorly immunogenic compared to the prototype HBc18-27 sequence, and they could not be recognized by CTL clones specific for the prototype peptide. While we do not know if the two patients were originally infected by these variant viruses or if the variants emerged subsequent to infection because of immune selection, the results are most consistent with the latter hypothesis. If this is correct, the data suggest that negative selection of mutant viral genomes might contribute to viral persistence in a subset of patients with chronic HBV infection who express a narrow repertoire of anti-HBV CTL responses.

Influence of obesity on propofol pharmacokinetics: derivation of a pharmacokinetic model.

BACKGROUND: The objective of this study was to develop a pharmacokinetic (PK) model to characterize the influence of obesity on propofol PK parameters. METHODS: Nineteen obese ASA II patients undergoing bariatric surgery were studied. Patients received propofol 2 mg kg(-1) bolus dose followed by a 5-20-40-120 min, 10-8-6-5 mg kg(-1) h(-1) infusion. Arterial blood samples were withdrawn at 1, 3, 5 min after induction, every 10-20 min during propofol infusion, and every 10-30 min for 2 h after stopping the propofol infusion. Arterial samples were processed by high-performance liquid chromatography. Time-concentration data profiles from this study were pooled with data from two other propofol PK studies available at http://www.opentci.org. Population PK modelling was performed using non-linear mixed effects model. RESULTS: The study involved 19 obese adults who contributed 163 observations. The pooled analysis involved 51 patients (weight 93 sd 24 kg, range 44-160 kg; age 46 sd 16 yr, range 25-81 yr; BMI 33 sd 9 kg m(-2), range 16-52 kg m(-2)). A three-compartment model was used to investigate propofol PK. An allometric size model using total body weight (TBW) was superior to all other models investigated (linear TBW, free fat mass, lean body weight, normal fat mass) for all clearance parameters. Variability in V2 and Q2 was reduced by a function showing a decrease in both parameters with age. CONCLUSIONS: We have derived a population PK model using obese and non-obese data to characterize propofol PK over a wide range of body weights. An allometric model using TBW as the size descriptor of volumes and clearances was superior to other size descriptors to characterize propofol PK in obese patients.

Safety and effectiveness of infliximab for inflammatory bowel diseases in clinical practice.

BACKGROUND AND OBJECTIVES: Our aim was to assess the efficacy and safety of infliximab (IFX) in clinical practice in three Primary Care, Hospital Centers. MATERIAL AND METHODS: From September 2004 to December 2008 62 patients (28 males, 34 females, mean age 30.25 years, range 15-55 years), affected by ulcerative colitis (UC) (23 pts) or by Crohn's disease (CD) (39 patients) were treated. Clinical efficacy, safety, mucosal healing and quality of life were assessed both in UC and CD. RESULTS: A total of 746 infusions were performed. IFX was administered for a mean of 26 months (range 8-44 months). 33/39 (84.61%) pts with CD were in remission under treatment with IFX for a mean time of 19 months (range 12-44 months). Mean Crohn Disease Activity Index (CDAI) score decreased from 295 (range 258-346) to 136 (range 98-136) (p < 0.005). Inflammatory Bowel Disease Quality of Life (IBDQL) improved from 48 (at entry) to 198 (at the end of the study) (p < 0.005). 20/23 (86.95%) patients with UC were in remission under treatment with IFX for a mean of 18 months (range 8-34 months). Mean Disease Activity Index (DAI) decreased from 11 (range 9-12) to < 3 (range 2-3) (p < 0.05). Mean Mayo Subscore for Endoscopy decreased from 3 to < 1 (range 0-1). IBDQL improved from 56 (at entry) to 194 (at the end of the study) (p < 0.005). Only 5 patients (8.06%) experienced side-effects. CONCLUSIONS: Long-term outpatients treatment with IFX seems to be safe and effective in managing patients affected by IBD in clinical practice.

[Preconditioning of the liver]. / Präkonditionierung der Leber.

Posthepatectomy liver failure (PHLF) still represents a severe complication after major liver resection associated with a high mortality. In addition to an insufficient residual liver volume various factors play an important role in the pathophysiology of PHLF. These include the quality of the parenchyma, liver function, perfusion, i.e. maintenance of adequate inflow and outflow, as well as the condition of the patient and comorbidities. While the liver volume is relatively easy to evaluate using modern imaging techniques, the evaluation of liver function and liver quality require a differentiated approach. Both factors can be influenced by the constitutional status of the patient, medical history and previous treatment and must be given sufficient consideration in the risk evaluation. An adequate perfusion, e.g. portal and arterial circulation and adequate outflow by at least one hepatic vein as well an adequate biliary drainage should be always guaranteed in order to allow regeneration of the residual liver tissue. Only the understanding of all these aspects will support the surgeon in a correct and safe evaluation of the resectability. Additionally, the liver surgeon should be aware of all available perioperative and postoperative options to treat and to prevent PHLF. In this review article the most important questions regarding the risk factors related to PHLF are presented and the potential therapeutic and prophylactic management is described. The main goal is to ensure functional operability of the patient if oncological resectability is possible. In other words: in the case of correct oncological indication, the liver surgeon should be able to resect what is resectable or, alternatively, make resectable what primarily was not resectable.

Molecular methods for cost-efficient monitoring of HAB (harmful algal bloom) dinoflagellate resting cysts.

Cyst abundance and identity are essential for understanding and predicting blooms, and for assessing the dispersal of toxic target dinoflagellate species by natural or human mediated ways, as with ballast waters. The aim of this study was to apply rapid, specific and sensitive qPCR assays to enumerate toxic dinoflagellate cysts in sediment samples collected from Adriatic harbours. The molecular standard curves of various target species allowed obtaining the rDNA copy number per cyst. The analytical sensitivity for specific standard curves was determined to be 2 or 10 rDNA copies per reaction. The abundance varied in the range of 1-747 dinoflagellate cysts g-1 dry weight. The assays showed greater sensitivity as compared to counts by light microscopy. This qPCR method revealed a powerful tool for the quantification of cysts from toxic dinoflagellate resting stages in sediment samples from Adriatic ports.

Detection and quantification of Prymnesium parvum (Haptophyceae) by real-time PCR.

AIMS: The ichthyotoxic species Prymnesium parvum (Haptophyceae) is difficult to quantify in a microscopy-based monitoring programme, because the cells are very small, fragile and their morphology can be distorted by the use of fixatives. In the attempt to overcome these problems, a real-time PCR-based method for the rapid and sensitive identification and quantification of P. parvum was developed. METHODS AND RESULTS: A quantitative real-time PCR assay was optimized with primers designed on the internal transcribed spacer 2 rDNA region of P. parvum. This PCR assay was specific, showing no amplification of DNA extracted from closely related species, and sensitive. Moreover, this method was able to detect and reliably quantify P. parvum cells in preserved environmental samples artificially spiked with known amounts of cultured cells. CONCLUSIONS: Considering the specificity, sensitivity and applicability to preserved environmental samples, this method may be a useful tool for the monitoring of this toxic species. SIGNIFICANCE AND IMPACT OF THE STUDY: The real-time PCR method described in this study may represent a progress towards the rapid detection and quantification of P. parvum cells in water-monitoring programmes, allowing the early application of strategies to control bloom events, such as the use of clay minerals.

The preS1 antigen of hepatitis B virus is highly immunogenic at the T cell level in man.

14 hepatitis B vaccine recipients who showed high titers of anti-hepatitis B surface antibodies in serum after booster immunization with a polyvalent hepatitis B surface antigen vaccine that contained trace amounts of hepatitis B virus (HBV) preS1 and preS2 envelope antigens were studied for their in vitro T cell response to these antigens. All 14 subjects displayed a significant proliferative T cell response to the S/p25 envelope region encoded polypeptide; 8 also responded to preS1, while only 1 showed a significant level of T cell proliferation to preS2. Limiting dilution analysis demonstrated that the frequency of preS-specific T cells in two of these vaccine recipients was higher than that of S/p25-specific T cells. T cell cloning was then performed and a total of 29 HBV envelope antigen-reactive CD4+ cloned lines were generated from two preS-responsive vaccines. 21 of these lines were S/p25 specific, 7 preS1 specific, and 1 preS2 specific. Taken together, all these results suggest that the preS1 antigen may function as a strong T cell immunogen in man.

Identification of immunodominant T cell epitopes of the hepatitis B virus nucleocapsid antigen.

Several lines of experimental evidence suggest that inclusion of core sequences in the hepatitis B vaccine may represent a feasible strategy to increase the efficacy of the vaccination. In order to identify immunodominant core epitopes, peripheral blood T cells purified from 23 patients with acute hepatitis B and different HLA haplotypes were tested with a panel of 18 short synthetic peptides (15 to 20 amino acids [AA]) covering the entire core region. All patients except one showed a strong T cell proliferative response to a single immunodominant 20 amino acid sequence located within the aminoterminal half of the core molecule. Two additional important sequences were also identified at the aminoterminal end and within the carboxyterminal half of the core molecule. These sequences were able to induce significant levels of T cell proliferation in 69 and 73% of the patients studied, respectively. T cell response to these epitopes was HLA class II restricted. The observations that (a) polyclonal T cell lines produced by PBMC stimulation with native HBcAg were specifically reactive with the relevant peptides and that (b) polyclonal T cell lines produced with synthetic peptides could be restimulated with native HBcAg, provide evidence that AA sequences contained within the synthetic peptides represent real products of the intracellular processing of the native core molecule. In conclusion, the identification of immunodominant T cell epitopes within the core molecule provides the molecular basis for the design of alternative and hopefully more immunogenic vaccines.

Long-lasting memory T cell responses following self-limited acute hepatitis B.

The molecular and cellular basis of long-term T cell memory against viral antigens is still largely undefined. To characterize anti-viral protection by memory T cells against non-cytopathic viruses able to cause acute self-limited and chronic infections, such as the hepatitis B virus (HBV), we studied HLA class II restricted responses against HBV structural antigens in 17 patients with acute hepatitis B, during the acute stage of infection and 2.2 to 13 yr after clinical resolution of disease. Results indicate that: (a) significant T cell proliferative responses to HBV nucleocapsid antigens were detectable in all patients during the acute phase of infection and in 14/17 also 2-13 yr after clinical resolution of disease; b) long-lasting T cell responses were sustained by CD45RO+T cells, predominantly expressing the phenotype of recently activated cells; c) limiting dilution analysis showed that in some patients the frequency of HBV-specific T cells was comparable to that observed in the acute stage of infection and, usually, higher than in patients with chronic HBV infection; d) the same amino acid sequences were recognized by T cells in the acute and recovery phases of infection; and e) HBV-DNA was detectable by nested-PCR in approximately half of the subjects. to conclusion, our results show that vigorous anti-viral T cell responses are detectable in vitro several years after clinical recovery from acute hepatitis B. Detection of minute amounts of virus in some recovered subjects suggests that long-term maintenance of an active anti-viral T cell response could be important not only for protection against reinfection but also for keeping the persisting virus under tight control.

Lamivudine treatment can restore T cell responsiveness in chronic hepatitis B.

High viral and/or antigen load may be an important cause of the T cell hyporesponsiveness to hepatitis B virus (HBV) antigens that is often observed in patients with chronic HBV infection. Reduction of viral and antigen load by lamivudine treatment represents an ideal model for investigating this hypothesis. HLA class II restricted T cell responses and serum levels of HBV-DNA, HBsAg, and HBeAg were studied before and during lamivudine treatment in 12 patients with hepatitis B e antigen positive chronic active hepatitis B to assess possible correlations between viral and/or antigen load and vigor of the T cell response. Cell proliferation to HBV nucleocapsid antigens and peptides and frequency of circulating HBV nucleocapsid-specific T cells were assessed to characterize CD4-mediated responses. A highly significant enhancement of the CD4-mediated response to HBV nucleocapsid antigens was already detectable in most patients 7-14 d after the start of lamivudine treatment. This effect was dramatic and persistent in 10 patients but undetectable in 2. It occurred concomitant with a rapid and marked reduction of viremia. Interestingly, lamivudine also enhanced the responses to mitogens and recall antigens, showing that its effect was not limited to HBV-specific T cells. In conclusion, an efficient antiviral T cell response can be restored by lamivudine treatment in patients with chronic hepatitis B concurrently with reduction of viremia, indicating the importance of viral load in the pathogenesis of T cell hyporesponsiveness in these patients. Since lamivudine treatment can overcome T cell hyporeactivity, combining lamivudine with treatments directed to stimulate the T cell response may represent an effective strategy to induce eradication of chronic HBV infection.

Water/cortical bone decomposition: A new approach in dual energy CT imaging for bone marrow oedema detection. A feasibility study.

INTRODUCTION: Many studies aimed at validating the application of Dual Energy Computed Tomography (DECT) in clinical practice where conventional CT is not exhaustive. An example is given by bone marrow oedema detection, in which DECT based on water/calcium (W/Ca) decomposition was applied. In this paper a new DECT approach, based on water/cortical bone (W/CB) decomposition, was investigated. MATERIALS AND METHODS: Eight patients suffering from marrow oedema were scanned with MRI and DECT. Two-materials density decomposition was performed in ROIs corresponding to normal bone marrow and oedema. These regions were drawn on DECT images using MRI informations. Both W/Ca and W/CB were considered as material basis. Scatter plots of W/Ca and W/CB concentrations were made for each ROI in order to evaluate if oedema could be distinguished from normal bone marrow. Thresholds were defined on the scatter plots in order to produce DECT images where oedema regions were highlighted through color maps. The agreement between these images and MR was scored by two expert radiologists. RESULTS: For all the patients, the best scores were obtained using W/CB density decomposition. CONCLUSIONS: In all cases, DECT color map images based on W/CB decomposition showed better agreement with MR in bone marrow oedema identification with respect to W/Ca decomposition. This result encourages further studies in order to evaluate if DECT based on W/CB decomposition could be an alternative technique to MR, which would be important when short scanning duration is relevant, as in the case of aged or traumatic patients.