PAEDIATRIC-ONSET PRIMARY SCLEROSING CHOLANGITIS: CLINICAL COURSE AND OUTCOME

ABSTRACT BACKGROUND AND AIMS The natural history of paediatric onset PSC and PSC/AIH overlap syndrome is poorly known. Thus, this study was aimed at evaluating the clinical course and outcome of patients with a paediatric onset of disease. MATERIALS AND METHODS Between December 1993 and December 2011, thirty-five patients (median age at diagnosis 15 years), with confirmed PSC by cholangiography (ERC) and PSC/AIH by cholangiography and the modified score for AIH, were traced at Helsinki University Central Hospital. Clinical characteristics (symptoms and signs, associated diseases), diagnostic procedures (lab tests, liver biopsy, ERC) and long-term follow-up (mortality, liver transplantation, recurrence of the disease in the graft, malignancy) were reassessed until December 2013. RESULTS The original diagnosis was PSC in 22 children (63%) and PSC/AIH overlap syndrome in 13 (37%). At diagnosis most of the children had an insidious onset and most an associated IBD, being UC the most common form. Still, 4/35 (11%) had cirrhosis. Endoscopic retrograde cholangiography during follow-up was available for all of the patients and images showed a progression of intra-hepatic disease in 13/28 (46.4%) (p=0.0102). In the last follow-up (median 8 years), all patients were alive. Twenty-eight out of 35 patients (80%) and 13/35 patients (40%) were taken UDCA and immunosuppressive therapy, respectively; 3 patients were without treatment. Transaminases and GGT improved significantly. Four patients (11%) had undergone liver transplantation (after a median 7.5 years) and one was listed; and additional patient was transplanted because of Budd-Chiari syndrome. No difference in graft free survival was seen between patients with PSC and PSC/AIH. Three patients (two with PSC and one with PSC/AIH overlap syndrome) presented with cirrhosis. No malignancy occurred. CONCLUSION The clinical outcome of primary sclerosing cholangitis and overlap syndrome seems comparable including their progression to cirrhosis and requirement for liver transplantation. \u200

Surveillance of primary sclerosing cholangitis with ERC and brush cytology : risk factors for cholangiocarcinoma

Objective: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease leading to bile duct strictures and fibrosis, and predisposing to cholangiocarcinoma (CCA). Biliary dysplasia is a known precursor of CCA. In our unit, PSC patients undergo regular surveillance with ERC and brush cytology (BC), and liver transplantation is an option in case with biliary dysplasia. We evaluated the risk factors for biliary dysplasia and CCA based on ERC imaging, BC and liver function tests. Patients and methods: Seven hundred and eighty-eight ERCs were performed with BC for 447 PSC patients. ERC images were evaluated using the modified Amsterdam score, neutrophilic inflammation was assessed in BC, and liver function tests were collected. Ploidy analysis with DNA flow cytometry was performed in cases with advanced PSC or previous suspicious BC/aneuploidy. The endpoint was either a benign disease course (follow-up for >= 2.4 years after the latest ERC), benign histology, biliary dysplasia or CCA. Results: Benign disease course was seen in 424/447 (including 23 cases with biliary dysplasia), and CCA in 17 (3.8%) patients. Gallbladder carcinoma/carcinoma in situ was diagnosed in three patients. Advanced ERC findings, male gender, suspicious BC, aneuploidy in flow cytometry, inflammation, and elevation of ALP, bilirubin, ALT, AST, GGT, CEA and CA19-9 represented significant risk factors for CCA in univariate analysis. Conclusions: PSC patients with advanced bile duct disease and elevated liver enzymes, CEA or CA19-9, inflammation or suspicious BC are most likely to develop CCA. These patients may benefit from surveillance with BC if early liver transplantation is possible.Peer reviewe

An operational strategy to produce Bio-hydrogen : the use of digestate for process control

A semi-continuous digester was fed twice a day with a concentrated solution of glucose (100 g l-1) and monitored for a 30-days period, with the aim of testing the possibility of utilizing the digestate of a traditional biogas plant, after a heat-shock at 100\ubaC, for controlling process parameters (organic loading rate OLR, pH, volatile fatty acids VFA concentration), by adding it to the fresh substrate at a ratio R of the total feeding volume. The process resulted instable for OLR=10 gVS L-1and R=0.7, while more stable for OLR of 5 gVS L-1and R=0.85. The maximum bio-hydrogen production rate in stable conditions was 100 NmLH2 h-1 and the conversion yields were 1.7 - 1.8 molH2 mol-1glucose. The produced biogas showed always complete absence of methane

A farm-scale pilot plant for biohydrogen and biomethane production by two-stage fermentation

Hydrogen is considered one of the possible main energy carriers for the future, thanks to its unique environmental properties. Indeed, its energy content (120 MJ/kg) can be exploited virtually without emitting any exhaust in the atmosphere except for water. Renewable production of hydrogen can be obtained through common biological processes on which relies anaerobic digestion, a well-established technology in use at farm-scale for treating different biomass and residues. Despite two-stage hydrogen and methane producing fermentation is a simple variant of the traditional anaerobic digestion, it is a relatively new approach mainly studied at laboratory scale. It is based on biomass fermentation in two separate, seuqential stages, each maintaining conditions optimized to promote specific bacterial consortia: in the first acidophilic reactorhydrogen is produced production, while volatile fatty acids-rich effluent is sent to the second reactor where traditional methane rich biogas production is accomplished. A two-stage pilot-scale plant was designed, manufactured and installed at the experimental farm of the University of Milano and operated using a biomass mixture of livestock effluents mixed with sugar/starch-rich residues (rotten fruits and potatoes and expired fruit juices), afeedstock mixture based on waste biomasses directly available in the rural area where plant is installed. The hydrogenic and the methanogenic reactors, both CSTR type, had a total volume of 0.7m3 and 3.8 m3 respectively, and were operated in thermophilic conditions (55 2 °C) without any external pH control, and were fully automated. After a brief description of the requirements of the system, this contribution gives a detailed description of its components and of engineering solutions to the problems encountered during the plant realization and start-up. The paper also discusses the results obtained in a first experimental run which lead to production in the range of previous laboratory results, with a typical hydrogen and methane specific productivity of 2.2 and 0.5 Nm3/m3reactor per day, in the first and second stage of the plant respectively. At our best knowledge, this plant is one of the very first prototypes producing biohydrogen at farm scale, and it represents a distributed, small scale demonstration to obtain hydrogen from renewable waste-sources

Using olive mill wastewate to improve performance in producing electricity from domestic wastewater by using single-chamber microbial fuel cell

Improving electricity generation from wastewater (DW) by using olive mill wastewater (OMW) was evaluated using single-chamber microbial fuel cells (MFC). Doing so single-chambers air cathode MFCs with platinum anode were fed with domestic wastewater (DW) alone and mixed with OMW at the ratio of 14:1 (w/w). MFCs fed with DW + OMW gave 0.38 V at 1 kO, while power density from polarization curve was of 124.6mW m 2. The process allowed a total reduction of TCOD and BOD5 of 60% and 69%, respectively, recovering the 29% of the coulombic efficiency. The maximum voltage obtained from MFC fed with DW + OMW was 2.9 times higher than that of cell fed with DW. DNA-fingerprinting showed high bacterial diversity for both experiments and the presence on anodes of exoelectrogenic bacteria, such as Geobacter spp. Electrodes selected peculiar consortia and, in particular, anodes of both experiments showed a similar specialization of microbial communities independently by feeding used

Yield of prolonged wireless pH monitoring in achalasia patients successfully treated with pneumatic dilation

Background: Gastro-oesophageal reflux disease (GORD) is a long-term complication of achalasia treatments. The aim of our study was to evaluate the yield of prolonged wireless pH monitoring in patients with successfully treated achalasia and its influence on proton pump inhibitor (PPI) use. Methods: Twenty-five patients with achalasia who underwent prolonged wireless pH monitoring after a successful treatment with pneumatic dilation were enrolled. pH variables were analysed in the first 24 hours of monitoring to determine if tracings were indicative of GORD; the same variables were analysed in the following 24-hour period in order to obtain a worst-day diagnosis of GORD. PPI therapy before and after the test was recorded. Results: Five out of 25 patients had GORD diagnosis during the first day of monitoring and four of them had oesophagitis at endoscopy. During the following days of monitoring four more patients had a diagnosis of GORD. Out of the 25 patients, PPIs were started after the test in six asymptomatic GORD-positive ones, whereas prescription of PPIs was stopped without detrimental effect on symptoms in three GORD-negative patients. Conclusions: Prolonged wireless pH monitoring is a useful test to be added to endoscopy in order to evaluate GORD and to optimise antisecretory treatment in successfully treated achalasia patients

Drf1-dependent Kinase Interacts with Claspin through a Conserved Protein Motif

The Dbf4/Drf1-dependent kinase (DDK) is required for the initiation of DNA replication in eukaryotes. Another protein, Claspin, mediates the activation of a cellular checkpoint response to stalled replication forks and is also a regulator of replication. In this study, we found that DDK phosphorylates Claspin in vitro and forms a nuclear complex containing Cdc7, Drf1, and Claspin in Xenopus egg extracts. In addition, purified Claspin and DDK are capable of a direct in vitro interaction. We identified a conserved binding site on Claspin required for its interaction with DDK. This site corresponds to the first of two sequence repeats in the Chk1-binding domain of Claspin. Furthermore, we have established that two amino acids in this motif, Asp^(861) and Gln^(866), are essential for the interaction between Claspin and DDK. We found that mutant forms of Claspin incapable of interacting with DDK are still able to associate with and activate Chk1 in response to DNA replication blockages. However, Claspin-depleted egg extracts that have been reconstituted with these mutants of Claspin undergo DNA replication more slowly. These findings suggest that the interaction of DDK with Claspin mediates a checkpoint-independent function of Claspin related to DNA replication

An effector region in Eps8 is responsible for the activation of the Rac-specific GEF activity of Sos-1 and for the proper localization of the Rac-based actin-polymerizing machine

Genetic and biochemical evidence demonstrated that Eps8 is involved in the routing of signals from Ras to Rac. This is achieved through the formation of a tricomplex consisting of Eps8-E3b1-Sos-1, which is endowed with Rac guanine nucleotide exchange activity. The catalytic subunit of this complex is represented by Sos-1, a bifunctional molecule capable of catalyzing guanine nucleotide exchange on Ras and Rac. The mechanism by which Sos-1 activity is specifically directed toward Rac remains to be established. Here, by performing a structure-function analysis we show that the Eps8 output function resides in an effector region located within its COOH terminus. This effector region, when separated from the holoprotein, activates Rac and acts as a potent inducer of actin polymerization. In addition, it binds to Sos-1 and is able to induce Rac-specific, Sos-1-dependent guanine nucleotide exchange activity. Finally, the Eps8 effector region mediates a direct interaction of Eps8 with F-actin, dictating Eps8 cellular localization. We propose a model whereby the engagement of Eps8 in a tricomplex with E3b1 and Sos-1 facilitates the interaction of Eps8 with Sos-1 and the consequent activation of an Sos-1 Rac-specific catalytic ability. In this complex, determinants of Eps8 are responsible for the proper localization of the Rac-activating machine to sites of actin remodeling

Barrett's esophagus: proton pump inhibitors and chemoprevention II.

The following on proton pump inhibitors (PPIs) and chemoprevention in relation to Barrett's esophagus includes commentaries on 48-h pH monitoring, pH-impedence, bile acid testing, dyspepsia, long/short segment Barrett's esophagus, nonerosive reflux disease (NERD), functional heartburn, dual-release delivery PPIs, immediate-release PPIs, long-term PPI use, prokinetic agents, obesity, baclofen, nocturnal acid breakthrough, nonsteroidal anti-inflammatory drugs (NSAIDs), and new PPIs