Reproductive ecology of muskellunge (Esox masquinongy), an introduced predator, in the lower Wolastoq/Saint John River, New Brunswick, Canada.

Introduced predators can have harmful top-down effects on their newly colonized system through competition with and direct predation on native species. Following an initial introduction of muskellunge in Lac Frontière, Québec in the 1970s at the headwaters of the Wolastoq/Saint John River, the species rapidly migrated downstream, expanding its range by ~500 km over ~20 years. Despite this expansive colonization and concern over possible threats to native species, little is known about the basic ecology of muskellunge in this system. The last downstream barrier is the hydroelectric facility, Mactaquac Generating Station (MGS), 150 km upstream of the sea. While there are no downstream fish passage facilities at MGS, adult muskellunge have been recorded downstream. In this study, muskellunge (n = 23) were surgically tagged with very-high-frequency (VHF) radio or combined acoustic radio telemetry (CART) tags and tracked over two spawning seasons. We sought to determine if there was a reproducing population downstream of MGS and tracked Tagged muskellunge over two spawning seasons. We tracked fish to locate and confirm spawning sites, and followed up with egg and/or juvenile sampling surveys. Tagged muskellunge (90%) moved upstream towards the MGS during the spawning period in each year (2016 and 2017), where they remained throughout the entire spawning period. No spawning or nursery sites were confirmed near MGS, but in 2016 three distinct spawning locations and six distinct nursery sites were confirmed 10-12 km downstream amongst a chain of flooded islands. In 2016, eggs, sac-fry and juveniles were collected and confirmed as muskellunge by genetic sequencing, providing the first empirical observation of successful spawning downstream of MGS.

A unique type of fully covered metal stent for the management of post liver transplant biliary anastomotic strictures.

BACKGROUND: We report our experience of treating anastomotic strictures using a novel type of fully covered metal stent (FCSEMS). This stent, known as the Kaffes Stent, is short-length with an antimigration waist and is easily removable due to long retrieval wires deployed within the duodenum. METHODS: Sixty-two patients underwent ERCP and Kaffes stent insertion for post-transplant anastomotic strictures following confirmation of a stricture on MRCP. These patients were retrospectively analysed for immediate and long-term stricture resolution, improvement in symptoms and liver function tests (LFTs), stricture recurrence and complication rates. RESULTS: Of the 56 patients who had their stent removed at the time of analysis, 54 (96%) had immediate stricture resolution and 42 continued to have long-term resolution (mean follow-up period was 548 days). Of the 16 patients with symptoms of biliary obstruction, 13 had resolution of their symptoms. Overall, there was a significant improvement in LFTs after stent removal compared to before stent insertion. Complication rates were 15% with only one patient requiring biliary reconstruction. CONCLUSIONS: The Kaffes stent is effective and safe at resolving post liver transplant biliary anastomotic strictures.

The combined molecular adjuvant CASAC enhances the CD8+ T cell response to a tumor-associated self-antigen in aged, immunosenescent mice.

BACKGROUND: Ineffective induction of T cell mediated immunity in older individuals remains a persistent challenge for vaccine development. Thus, there is a need for more efficient and sophisticated adjuvants that will complement novel vaccine strategies for the elderly. To this end, we have investigated a previously optimized, combined molecular adjuvant, CASAC (Combined Adjuvant for Synergistic Activation of Cellular immunity), incorporating two complementary Toll-like receptor agonists, CpG and polyI:C, a class-II epitope, and interferon (IFN)-γ in aged mice. FINDINGS: In aged mice with typical features of immunosenescence, antigen specific CD8+ T cell responses were stimulated after serial vaccinations with CASAC or Complete/Incomplete Freund's Adjuvant (CFA/IFA) and a class I epitope, deriving either from ovalbumin (SIINFEKL, SIL) or the melanoma-associated self-antigen, tyrosinase-related protein-2 (SVYDFFVWL, SVL). Pentamer analysis revealed that aged, CASAC/SIL-vaccinated animals had substantially higher frequencies of H-2K(b)/SIL-specific CD8+ T cells compared to the CFA/IFA-vaccinated groups. Similarly, higher frequencies of H-2K(b)/SVL-pentamer+ and IFN-γ+ CD8+ T cells were detected in the aged, CASAC + SVL-vaccinated mice than in their CFA/IFA-vaccinated counterparts. In both antigen settings, CASAC promoted significantly better functional CD8+ T cell activity. CONCLUSION: These studies demonstrate that functional CD8+ T cells, specific for both foreign and tumour-associated self-antigens, can be effectively induced in aged immunosenescent mice using the novel multi-factorial adjuvant CASAC.

Management of patients with decompensated cirrhosis.

During the assessment of a patient with liver disease, finding the patient has decompensated cirrhosis, as defined by the presence of jaundice, ascites, variceal haemorrhage or hepatic encephalopathy, has major implications regarding management and prevention of cirrhosis-related complications, as well as consideration for a referral for liver transplantation evaluation. Prognosis is markedly worse in patients with decompensated compared with compensated cirrhosis. In general, any patient with decompensated cirrhosis should receive evaluation and medical care by a hepatologist. Since patients frequently present with more than one facet of liver decompensation, such cases pose a complex management challenge requiring input from a multidisciplinary team and close liaison with a liver transplant centre.

Interaction of CarD with RNA polymerase mediates Mycobacterium tuberculosis viability, rifampin resistance, and pathogenesis.

Mycobacterium tuberculosis infection continues to cause substantial human suffering. New chemotherapeutic strategies, which require insight into the pathways essential for M. tuberculosis pathogenesis, are imperative. We previously reported that depletion of the CarD protein in mycobacteria compromises viability, resistance to oxidative stress and fluoroquinolones, and pathogenesis. CarD associates with the RNA polymerase (RNAP), but it has been unknown which of the diverse functions of CarD are mediated through the RNAP; this question must be answered to understand the CarD mechanism of action. Herein, we describe the interaction between the M. tuberculosis CarD and the RNAP ß subunit and identify point mutations that weaken this interaction. The characterization of mycobacterial strains with attenuated CarD/RNAP ß interactions demonstrates that the CarD/RNAP ß association is required for viability and resistance to oxidative stress but not for fluoroquinolone resistance. Weakening the CarD/RNAP ß interaction also increases the sensitivity of mycobacteria to rifampin and streptomycin. Surprisingly, depletion of the CarD protein did not affect sensitivity to rifampin. These findings define the CarD/RNAP interaction as a new target for chemotherapeutic intervention that could also improve the efficacy of rifampin treatment of tuberculosis. In addition, our data demonstrate that weakening the CarD/RNAP ß interaction does not completely phenocopy the depletion of CarD and support the existence of functions for CarD independent of direct RNAP binding.

Hepatitis delta virus.

Hepatitis delta virus (HDV) is a small, defective RNA virus that can infect only individuals who have hepatitis B virus (HBV); worldwide more than 15 million people are co-infected. There are eight reported genotypes of HDV with unexplained variations in their geographical distribution and pathogenicity. The hepatitis D virion is composed of a coat of HBV envelope proteins surrounding the nucleocapsid, which consists of a single-stranded, circular RNA genome complexed with delta antigen, the viral protein. HDV is clinically important because although it suppresses HBV replication, it causes severe liver disease with rapid progression to cirrhosis and hepatic decompensation. The range of clinical presentation is wide, varying from mild disease to fulminant liver failure. The prevalence of HDV is declining in some endemic areas but increasing in northern and central Europe because of immigration. Treatment of HDV is with pegylated interferon alfa; however, response rates are poor. Increased understanding of the molecular virology of HDV will identify novel therapeutic targets for this most severe form of chronic viral hepatitis.

Early predictors of corticosteroid treatment failure in icteric presentations of autoimmune hepatitis.

UNLABELLED: Autoimmune hepatitis (AIH) typically responds to treatment in 90% of patients. Early prediction of treatment outcome would be advantageous in clinical practice. We evaluated whether parameters at initiation of therapy or changes in these parameters at day 3 and day 7 following corticosteroid initiation predicted treatment failure. Treatment-naive, jaundiced patients presenting to our tertiary unit between 1999-2009 were identified and mathematical models of prognosis in liver disease scores calculated at day 0, day 3, and day 7. Overall, 72 patients were identified (48 women, 24 men). Treatment failure occurred in 18% (13/72) of patients. At diagnosis, higher median bilirubin (451 µmol/L versus 262 µmol/L, P = 0.02), INR (1.62 versus 1.33, P = 0.005), model for endstage liver (MELD) score (26 versus 20, P = 0.02), MELD-sodium (Na) score (27 versus 22, P = 0.03) and United Kingdom endstage liver disease score (UKELD) score (59 versus 57, P = 0.01) significantly correlated with treatment failure. Analysis of area under the receiver operator characteristic curve (AUROC) values at day 7 identified change (Δ) bilirubin (AUROC 0.68), Δ creatinine (0.69), Δ MELD (0.79), Δ MELD-Na (0.83) and Δ UKELD (0.83) best predicted treatment failure. Specifically, a fall in UKELD of less than 2 points predicted treatment failure with a sensitivity of 85% and specificity of 68%. Of 13 treatment failures, nine required second-line immunosuppression, three required emergency transplant, and one died of sepsis. In total, four patients died in the treatment failure group compared with one in the responder group (4/13 = 31% versus 1/59 = 1.7%, P = 0.003). CONCLUSION: Approximately 20% of icteric AIH presentations fail corticosteroid therapy. This is associated with significant mortality and the need for emergency transplantation. Treatment failure is best predicted by change in MELD-Na and UKELD at day 7. Early identification of nonresponders may allow timely escalation of immunosuppression to prevent clinical deterioration.

Pancreatic pseudocysts in children: treatment by endoscopic cyst gastrostomy.

AIM: The aim of the present study was to review the use of endoscopic cyst gastrostomy (E-CG) as a treatment option for pancreatic pseudocysts referred to a tertiary paediatric surgical centre. METHODS: Retrospective review during a 10-year period (January 2001-December 2010). Cyst gastrostomies were performed using 1 or 2 double pigtailed Zimmon stents (7-10 Fr) under general anaesthesia. Data are quoted as median (range). RESULTS: E-CG was performed in 7 (5 males) children (median age at presentation 11.7 [8.2-15.8] years). Pancreatic pseudocysts were caused by acute pancreatitis in 5 (gallstones n = 1, hereditary pancreatitis n = 1, pancreatic divisum n = 1, asparaginase induced n = 1, and idiopathic n = 1) and pancreatic trauma in 2 (motor vehicle accident n = 1, and handlebar injury n = 1). All of the cases were associated with a rise in serum amylase level, median 1028 (276-2077) IU/L at the peak of symptoms. Three children had pancreatic duct stent placement during endoscopic retrograde cholangiopancreatography as the initial therapeutic intervention, but went on to have E-CG later. One who had a huge pseudocyst at presentation had already undergone an open cyst gastrostomy, which had recurred at 1 month. Rescue E-CG was performed 38 days later. All of the stents were removed endoscopically at 8 (6-40) weeks. E-CG was uncomplicated and pseudocysts resolved completely in 5. One required repeat placement at 15 days due to catheter slippage with later full resolution. One child required open cyst gastrostomy due to reaccumulation two months following removal of the stent. Median hospital stay post E-CG was 3 (1-23) days. There has been no recurrence at median follow-up of 18 (5-108) months. CONCLUSIONS: Endoscopic cyst gastrostomy is a safe and effective alternative for the management of pancreatic pseudocysts in children and should now be considered as treatment of choice.

Nasobiliary drainage: an effective treatment for pruritus in cholestatic liver disease.

Introduction: Nasobiliary drains (NBDs) have been successfully used to manage intrahepatic cholestasis, bile leaks and obstructive cholangitis. It allows external drainage of bile, bypassing the ileum where bile salts are reabsorbed. We assessed the utility of placement with effect on markers of cholestasis and patient symptoms. Methods: Consecutive patients undergoing NBD over 12 years for the management of pruritus were retrospectively analysed. Recorded variables included patient demographics, procedural characteristics and response to therapy. Results: Twenty-three patients (14, 61% male) underwent 30 episodes of NBD. The median age was 26 years old (range 2-67 years old). A single procedure was carried out in 20. One patient each had two, three and five episodes of NBD. The most common aetiologies were hereditary cholestatic disease (n=17, 74%) and drug-induced cholestasis (n=5, 22%),NBD remained in situ for a median of 8 days (range 1-45 days). Significant improvement in bilirubin was seen at 7 days post-NBD (p=0.0324), maintained at day 30 (335 µmol/L vs 302 µmol/L vs 167 µmol/L). There was symptomatic improvement in pruritus in 20 (67%, p=0.0494) episodes. One patient underwent NBD during the first trimester of pregnancy after medical therapy failure with a good symptomatic response. The catheters were well tolerated in 27 (90%) of cases. Mild pancreatitis occurred in 4 (13%) cases. Conclusion: NBD can be used to provide symptomatic improvement to patients with pruritus associated with cholestasis. It is well tolerated by patients. They can be used in pregnancy where medical management has failed.

Intraductal fully covered self-expanding metal stents in the management of post-liver transplant anastomotic strictures: a UK wide experience.

Background: Fully covered intraductal self-expanding metal stents (IDSEMS) have been well described in the management of post-liver transplant (LT) anastomotic strictures (ASs). Their antimigration waists and intraductal nature make them suited for deployment across the biliary anastomosis. Objectives: We conducted a multicentre study to analyse their use and efficacy in the management of AS. Design: This was a retrospective, multicentre observational study across nine tertiary centres in the United Kingdom. Methods: Consecutive patients who underwent endoscopic retrograde cholangiopancreatography with IDSEMS insertion were analysed retrospectively. Recorded variables included patient demographics, procedural characteristics, response to therapy and follow-up data. Results: In all, 162 patients (100 males, 62%) underwent 176 episodes of IDSEMS insertion for AS. Aetiology of liver disease in this cohort included hepatocellular carcinoma (n = 35, 22%), followed by alcohol-related liver disease (n = 29, 18%), non-alcoholic steatohepatitis (n = 20, 12%), primary biliary cholangitis (n = 15, 9%), acute liver failure (n = 13, 8%), viral hepatitis (n = 13, 8%) and autoimmune hepatitis (n = 12, 7%). Early AS occurred in 25 (15%) cases, delayed in 32 (20%) cases and late in 95 (59%) cases. Age at transplant was 54 years (range, 12-74), and stent duration was 15 weeks (range, 3 days-78 weeks). In total, 131 (81%) had complete resolution of stricture at endoscopic re-evaluation. Stricture recurrence was observed in 13 (10%) cases, with a median of 19 weeks (range, 4-88 weeks) after stent removal. At removal, there were 21 (12%) adverse events, 5 (3%) episodes of cholangitis and 2 (1%) of pancreatitis. In 11 (6%) cases, the removal wires unravelled, and 3 (2%) stents migrated. All were removed endoscopically. Conclusion: IDSEMS appears to be safe and highly efficacious in the management of post-LT AS, with low rates of AS recurrence.

Non-invasive assessment of fibrosis in liver grafts due to hepatitis C virus recurrence.

Hepatitis C virus (HCV) infection has become the most common indication for liver transplantation in the United States and Europe. Recurrence of HCV is universal in all liver graft recipients, but the natural history of the disease is variable with some patients displaying slowly progressive liver injury, while approximately 30% become cirrhotic within five yr of surgery. Currently, liver biopsy is the reference standard to assess liver injury in the post-transplant setting. But biopsy is associated with complications such as bleeding and pain, as well as the risk of sampling error and discordance in reporting between histopathologists. Thus, as in the pre-transplant setting, there is increasing attention being drawn to the use of non-invasive tests of liver fibrosis. This review examines the role of non-invasive assessment of hepatic fibrosis in the post-transplant setting including simple tests such as aspartate aminotransferase-to-platelet ratio index, the Benlloch formula, London Transplant Centre score, and finally transient elastography. The authors assess the respective advantages and disadvantages of the tests and consider how non-invasive tests of liver fibrosis can be utilized in the future management of post-transplant HCV infection.

Evaluation of risk factors in the development of hepatocellular carcinoma in autoimmune hepatitis: Implications for follow-up and screening.

UNLABELLED: Hepatocellular carcinoma (HCC) has traditionally been considered a rare complication of cirrhosis secondary to autoimmune hepatitis (AIH), yet the true incidence remains unknown due to a lack of published data. Consequently, some professional guidelines do not mandate routine surveillance for HCC in this condition. Our aims were to evaluate the rate at which HCC develops among a large, prospectively obtained cohort of patients with AIH at a single center. Demographic, clinical, and laboratory indices associated with the development of HCC were also identified. HCC was discovered in 15 of 243 patients with AIH, all of whom had type 1 AIH equating to 1090 cases per 100,000 patient follow-up years. HCC occurred in the same proportion of females as males, 6.1% versus 6.4%, P = 0.95. HCC occurred more frequently in patients who had cirrhosis at presentation, 9.3% versus 3.4%, P = 0.048, or who had a variceal bleed as the index presentation of AIH, 20% versus 5.3%, P = 0.003. The median duration from time of confirmed cirrhosis to a diagnosis of HCC was 102.5 months, range 12-195 months. Median survival in patients whose HCC was diagnosed on surveillance was 19 months (range 6-36 months) compared with 2 months (range 0-14 months) for patients presenting symptomatically (P = 0.042). CONCLUSION: Cirrhosis in AIH is the sine qua non for HCC development, which subsequently occurs at a rate of 1.1% per year and affects men and women in equal proportions.

Selective use of endoscopic retrograde cholangiopancreatography in the diagnosis of biliary atresia in infants younger than 100 days.

OBJECTIVES: We investigated the role and safety of endoscopic retrograde cholangiopancreatography (ERCP) in diagnosing biliary atresia (BA) in prolonged neonatal cholestasis, when standard workup was inconclusive. PATIENTS AND METHODS: We reviewed notes of 48 cholestatic infants younger than 100 days undergoing ERCP from 1997 to 2007. RESULTS: Amongst approximately 3300 infants evaluated for liver disease during the study, 224 (6.8%) were diagnosed with BA. Forty-eight children underwent ERCP. Findings at liver biopsy (n=47) included nonspecific cholestasis (n=19, 40%), giant-cell hepatitis (n=12, 26%), "large bile duct obstruction" (n=9, 19%) in the presence of pigmented stools, and mixed cholestatic/hepatitic features (n=7, 15%). ERCP demonstrated a patent biliary tree in 20 infants (42%). BA was confirmed at exploratory laparotomy in all 3 infants (6%) in whom cannulation failed. The remaining 25 infants (52%) also proceeded to exploratory laparotomy, in which BA was confirmed in 22 (46%). Amongst the 20 children in whom ERCP ruled out BA, 8 (17%) had normal biliary anatomy, whilst 12 (25%) had an abnormal biliary tree, including 6 (12.5%) with neonatal sclerosing cholangitis. After ERCP none developed clinical pancreatitis or peritonitis. CONCLUSIONS: ERCP is a safe procedure for diagnosing BA even in the smallest infants with high positive and negative predictive values.

Fibular Reconstruction of the Maxilla and Mandible with Immediate Implant-Supported Prosthetic Rehabilitation: Jaw in a Day.

The fibula free flap is a workhorse flap used to reconstruct ablative, osseous defects in the upper and lower jaws. Traditionally, the fibula free flap is inset into the defect freehand; dental implants are placed secondarily; and final prosthetic rehabilitation often occurs more than 1 year after ablative surgery. Virtual surgical planning and rapid prototyping of cutting guides and guide stents for head and neck reconstruction have facilitated improved accuracy in fibular transfer. This article describes the Jaw in a Day technique, allowing maxillary or mandibular resection, fibular free flap reconstruction, immediate implant placement, and prosthetic rehabilitation in a single operation.

Transcriptional regulation of the hepatocyte growth factor gene by pyrrolidine dithiocarbamate.

Hepatocyte growth factor (HGF) mediates cancer cell invasion and metastasis. This study characterised the down-regulation of HGF expression by pyrrolidine dithiocarbamate (PDTC), which markedly reduced HGF mRNA expression and protein production in MRC-5 cells. Reporter gene studies revealed that PDTC inhibited HGF gene transcription and that the response element is located in the region -75 to +42 bp flanking the transcription initiation site. Electrophoretic mobility shift assay identified three specific protein complexes binding in this region, which were abrogated by exposure of cells to PDTC. PDTC deserves further investigation as a novel therapeutic agent for HGF-driven cancers.

Non-invasive markers for the prediction of fibrosis in chronic hepatitis C infection.

Liver fibrosis occurs as a result of chronic liver injury and is the hallmark of chronic liver disease. The final stage of progressive liver fibrosis is cirrhosis, which is implicated in portal hypertension, end-stage liver disease and hepatocellular carcinoma. Liver biopsy has historically been the gold standard test for the assessment of liver fibrosis for liver diseases such as viral hepatitis, autoimmune hepatitis and primary biliary cirrhosis. Improved serological tests have enhanced the diagnosis of these conditions and reduced the need for liver biopsy. Liver biopsy is unpopular among patients and clinicians. It is associated with morbidity and mortality, and in addition is subject to sampling error, inter- and intra-observer variability. There is therefore a need for non-invasive markers of liver fibrosis that are accurate, reliable, cheap and easy to use. The aim of this review is to examine the different non-invasive methods that can be used to estimate the severity of fibrosis. The methods evaluated include clinical examination, routine laboratory investigations, imaging tests, specialized tests of liver function and finally serum extra-cellular matrix markers of fibrosis. The review mainly focuses on fibrogenesis in the context of chronic hepatitis C infection.

Day case 'treat and transfer' ERCP service under general anaesthesia.

OBJECTIVE: General anaesthesia (GA) has been increasingly used for advanced endoscopic procedures in particular endoscopic retrograde cholangiopancreatography (ERCP). Given the increasing pressure on many hospitals, the delivery of such service on a regular basis may not always be possible. We established a new day case 'GA ERCP' service. We describe our experience in evaluating the safety and overall feasibility of this new service. DESIGN: Prospective database has been interrogated for the period from March 2015 to December 2016. We documented patients' demographics, ERCP indications, American Society of Anesthesiologists (ASA) status, Cotton grade and complications. RESULTS: 67 patients were referred to endoscopy unit at King's College Hospital (KCH), for urgent day case GA ERCP from nine referring hospitals. The main indications were failed ERCP under sedation 47.8% (32/67), and unavailability of ERCP locally 41.8% (28/67). A total of 64 patients were actually transferred to KCH; 57.8% (37/64) women with a median age 55.8 years (range 23-90). 78.1% (50/64) of patients had a virgin papilla, with 39% (25/64) were ASA ≥3. The Cotton grade was ≥ 3 in 50% (32/64) patients. ERCP was completed successfully in 87.5% (56/64). For patients with previous failed ERCP, repeat ERCP under GA was successful in 75% (24/32). All patients were safely discharged back to their referring hospitals after the short observation period post-ERCP. CONCLUSIONS: Urgent inpatient transfers between hospitals for performing ERCP under GA as a day case is safe and feasible. The new GA ERCP pathway can be replicated by other UK centres.

Chronic mesenteric venous thrombosis: evaluation and determinants of survival during long-term follow-up.

BACKGROUND & AIMS: The natural history of chronic portomesenteric (PM) and portosplenomesenteric (PSM) venous thrombosis is defined poorly. Therapeutic options are limited, and are directed at the prevention of variceal bleeding and the control of abdominal pain related to gastrointestinal hyperemia. METHODS: Patients with extensive PM and PSM thrombosis were reviewed retrospectively to evaluate the efficacy of medical therapy and to determine which clinical variables had prognostic significance regarding long-term survival. RESULTS: Sixty patients, with a median age at diagnosis of 44 years (range, 18-68 y), were assessed. The median follow-up period was 3.5 years (range, 0.2-32.0 y). The overall survival rate was 73.3%, with 1- and 5-year survival rates of 81.6%, and 78.3%, respectively. One- and 5-year survival rates, excluding patients who died from malignancy-related causes, were 85.7% and 82.1%, respectively. Factors associated with improved survival included treatment with beta-blockers (P = .02; odds ratio [OR], .09; 95% confidence interval [CI], 0.01-0.70) and anticoagulation (P = .005; OR, 0.01; 95% CI, <0.01 to 0.26). Eighteen patients in total were anticoagulated, including 8 patients who had variceal bleeding, all of whom underwent endoscopic band ligation of esophageal varices before anticoagulation. By using Cox regression analysis, variables associated with reduced survival were the presence of ascites (P = .001; OR, 42.6; 95% CI, 5.03-360), and hyperbilirubinemia (P = .01; OR, 13.8; 95% CI, 1.9-100) at presentation. Six patients died of variceal hemorrhage. CONCLUSIONS: Patients with chronic PM and PSM venous thrombosis without underlying malignancy have an acceptable long-term survival. Treatment with beta-blockers and anticoagulation appears to improve outcome.