Evolution of tetraspanin antigens in the zoonotic Asian blood fluke Schistosoma japonicum

BACKGROUND: Despite successful control efforts in China over the past 60 years, zoonotic schistosomiasis caused by Schistosoma japonicum remains a threat with transmission ongoing and the risk of localised resurgences prompting calls for a novel integrated control strategy, with an anti-schistosome vaccine as a core element. Anti-schistosome vaccine development and immunisation attempts in non-human mammalian host species, intended to interrupt transmission, and utilising various antigen targets, have yielded mixed success, with some studies highlighting variation in schistosome antigen coding genes (ACGs) as possible confounders of vaccine efficacy. Thus, robust selection of target ACGs, including assessment of their genetic diversity and antigenic variability, is paramount. Tetraspanins (TSPs), a family of tegument-surface antigens in schistosomes, interact directly with the host's immune system and are promising vaccine candidates. Here, for the first time to our knowledge, diversity in S. japonicum TSPs (SjTSPs) and the impact of diversifying selection and sequence variation on immunogenicity in these protiens were evaluated. METHODS: SjTSP sequences, representing parasite populations from seven provinces across China, were gathered by baiting published short-read NGS data and were analysed using in silico methods to measure sequence variation and selection pressures and predict the impact of selection on variation in antigen protein structure, function and antigenic propensity. RESULTS: Here, 27 SjTSPs were identified across three subfamilies, highlighting the diversity of TSPs in S. japonicum. Considerable variation was demonstrated for several SjTSPs between geographical regions/provinces, revealing that episodic, diversifying positive selection pressures promote amino acid variation/variability in the large extracellular loop (LEL) domain of certain SjTSPs. Accumulating polymorphisms in the LEL domain of SjTSP-2, -8 and -23 led to altered structural, functional and antibody binding characteristics, which are predicted to impact antibody recognition and possibly blunt the host's ability to respond to infection. Such changes, therefore, appear to represent a mechanism utilised by S. japonicum to evade the host's immune system. CONCLUSION: Whilst the genetic and antigenic geographic variability observed amongst certain SjTSPs could present challenges to vaccine development, here we demonstrate conservation amongst SjTSP-1, -13 and -14, revealing their likely improved utility as efficacious vaccine candidates. Importantly, our data highlight that robust evaluation of vaccine target variability in natural parasite populations should be a prerequisite for anti-schistosome vaccine development

Dose assessment of melatonin in sepsis (DAMSEL2) study : Pharmacokinetics of two doses of oral melatonin in patients with sepsis

Open Access via the Wiley OA Agreement Funding The work was funded by the Scottish Government under the Experimental and Translational Medicine funding scheme of the Chief Scientist Office of Scotland, UK, reference number ETM/538Peer reviewedPublisher PD

Endoscopic biliary therapy in the era of bariatric surgery

There is an increasing demand and availability of bariatric surgery, with a range of procedures performed, some leading to altered upper gastrointestinal anatomy. The patient population undergoing bariatric surgery is also at increased risk of gallstones and biliary stone disease. Endoscopy (ie, endoscopic retrograde cholangiopancreatography) is the cornerstone of management of biliary stone disease, but may be challenging after bariatric surgery. In this review the endoscopic, surgery assisted, or percutaneous options that may be considered are discussed, based on the details of surgical anatomy and available expertise

Genomic Characterisation of a Multiple Drug Resistant IncHI2 ST4 Plasmid in Escherichia coli ST744 in Australia.

Antibiotic resistance genes (ARGs) including those from the blaCTX-M family and mcr-1 that encode resistance to extended spectrum β-lactams and colistin, respectively, have been linked with IncHI2 plasmids isolated from swine production facilities globally but not in IncHI2 plasmids from Australia. Here we describe the first complete sequence of a multiple drug resistance Australian IncHI2-ST4 plasmid, pTZ41_1P, from a commensal E. coli from a healthy piglet. pTZ41_1P carries genes conferring resistance to heavy-metals (copper, silver, tellurium and arsenic), β-lactams, aminoglycosides and sulphonamides. The ARGs reside within a complex resistance locus (CRL) that shows considerable sequence identity to a CRL in pSDE_SvHI2, an IncHI2:ST3 plasmid from an enterotoxigenic E. coli with serotype O157:H19 of porcine origin that caused substantial losses to swine production operations in Australia in 2007. pTZ41_1P is closely related to IncHI2 plasmids found in E. coli and Salmonella enterica from porcine, avian and human sources in Europe and China but it does not carry genes encoding resistance to clinically-important antibiotics. We identified regions of IncHI2 plasmids that contribute to the genetic plasticity of this group of plasmids and highlight how they may readily acquire new resistance gene cargo. Genomic surveillance should be improved to monitor IncHI2 plasmids

NbSi nanowire quantum phase-slip circuits: dc supercurrent blockade, microwave measurements, and thermal analysis

We present a detailed report of microwave irradiation of ultranarrow superconducting nanowires. In our nanofabricated circuits containing a superconducting NbSi nanowire, a dc blockade of current flow was observed at low temperatures below a critical voltage Vc, a strong indicator of the existence of quantum phase-slip (QPS) in the nanowire. We describe the results of applying microwaves to these samples, using a range of frequencies and both continuous-wave and pulsed drive, in order to search for dual Shapiro steps which would constitute an unambiguous demonstration of quantum phase-slip. We observed no steps, and our subsequent thermal analysis suggests that the electron temperature in the series CrO resistors was significantly elevated above the substrate temperature, resulting in sufficient Johnson noise to wash out the steps. To understand the system and inform future work, we have constructed a numerical model of the dynamics of the circuit for dc and ac bias (both continuous-wave and pulsed drive signals) in the presence of Johnson noise. Using this model, we outline important design considerations for device and measurement parameters which should be used in any future experiment to enable the observation of dual Shapiro steps at experimentally accessible temperatures and, thus, lead to the development of a QPS-based quantum current standard

Immunoglobulin G4-related sclerosing cholangitis

Immunoglobulin G4-related disease (IgG4-RD) is a systemic fibroinflammatory condition of which IgG4-related sclerosing cholangitis (IgG4-SC) is the biliary manifestation. In this review, we provide an overview of IgG4-RD, with a focus on the biliary manifestations. In particular, we describe the important differential diagnoses of IgG4-SC, namely, primary sclerosing cholangitis and cholangiocarcinoma, outline diagnostic criteria for IgG4-SC, provide insight into possible pathophysiological mechanisms underlying the disease and discuss short and long-term management options of this recently described disease

The endoscopist and malignant and non-malignant biliary obstruction

Patients with biliary strictures often represent a diagnostic and therapeutic challenge, due to the site and complexity of biliary obstruction and wide differential diagnosis. Multidisciplinary decision making is required to reach an accurate and timely diagnosis and to plan optimal care. Developments in endoscopic ultrasound and peroral cholangioscopy have advanced the diagnostic yield of biliary endoscopy, and novel optical imaging techniques are emerging. Endoscopic approaches to biliary drainage are preferred in most scenarios, and recent advances in therapeutic endoscopic ultrasound allow drainage where the previous alternatives were only percutaneous or surgical. Here we review recent advances in endoscopic practice for the diagnosis and management of biliary strictures. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by Jesus Banales, Marco Marzioni and Peter Jansen

Diagnosis of pancreaticobiliary malignancy by detection of minichromosome maintenance protein 5 in biliary brush cytology

Background: Biliary brush cytology is the standard method of evaluating biliary strictures, but is insensitive at detecting malignancy. In pancreaticobiliary cancer minichromosome maintenance replication proteins (MCM 2–7) are dysregulated in the biliary epithelium and MCM5 levels are elevated in bile samples. This study aimed to validate an immunocolorimetric ELISA assay for MCM5 as a pancreaticobiliary cancer biomarker in biliary brush samples. methods: Biliary brush specimens were collected prospectively at ERCP from patients with a biliary stricture. Collected samples were frozen at −80 °C. The supernatant was washed and lysed cells incubated with HRP-labelled anti-MCM5 mouse monoclonal antibody. Test positivity was determined by optical density absorbance. Patients underwent biliary brush cytology or additional investigations as per clinical routine. results: Ninety-seven patients were included in the study; 50 had malignant strictures. Median age was 65 years (range 21–94) and 51 were male. Compared with final diagnosis the MCM5 assay had a sensitivity for malignancy of 65.4% compared with 25.0% for cytology. In the 72 patients with paired MCM5 assay and biliary brush cytology, MCM5 demonstrated an improved sensitivity (55.6% vs 25.0%; P=0.0002) for the detection of malignancy. conclusions: Minichromosome maintenance replication protein5 is a more sensitive indicator of pancreaticobiliary malignancy than standard biliary brush cytology

Endoscopic versus percutaneous drainage of symptomatic pancreatic fluid collections: a 14-year experience from a tertiary hepatobiliary centre

INTRODUCTION: Endoscopic transmural drainage (ED) or percutaneous drainage (PD) has mostly replaced surgery for the initial management of patients with symptomatic pancreatic fluid collections (PFCs). This study aimed to compare outcomes for patients undergoing ED or PD of symptomatic PFCs. METHODS: Between January 2000 and December 2013, all patients who required PD or ED of a PFC were included. Rates of treatment success, length of hospital stay, adverse events, re-interventions and length of follow-up were recorded retrospectively in all cases. RESULTS: In total, 164 patients were included in the study; 109 patients underwent ED; and 55 had PD alone. During the 14-year study period, the incidence of ED increased and PD fell. In the 109 patients who were managed by ED, treatment success was considerably higher than in those managed by PD (70 vs. 31 %). Rates of procedural adverse events were higher in the ED cohort compared to the PD group (10 vs. 1 %), but patients managed by ED required fewer interventions (median of 1.8 vs. 3.3) had lower rates of residual collections (21 vs. 67 %) and need for surgical intervention (4 vs. 11 %). In the ED group, treatment success was similar for walled-off pancreatic necrosis (WOPN) and pseudocysts (67 vs. 72 %, P = 0.77). There were no procedure-related deaths. CONCLUSION: Compared with PD, ED of symptomatic PFCs was associated with higher rates of treatment success, lower rates of re-intervention, including surgery and shorter lengths of hospital stay. Outcomes in WOPN were comparable to those in patients with pseudocysts

Identification of potential serum peptide biomarkers of biliary tract cancer using MALDI MS profiling.

The aim of this discovery study was the identification of peptide serum biomarkers for detecting biliary tract cancer (BTC) using samples from healthy volunteers and benign cases of biliary disease as control groups. This work was based on the hypothesis that cancer-specific exopeptidase activities in serum can generate cancer-predictive peptide fragments from circulating proteins during coagulation