Insulin secretion in liver transplant recipients following conversion to a prolonged release tacrolimus formulation.

Background: Post liver transplant diabetes mellitus (PLTDM) occurs in 10-40% of liver transplant recipients and is associated with increased morbidity and mortality. An important cause of PLTDM is tacrolimus induced, concentration-dependent, inhibition of insulin secretion.

Objective: To determine if a newly licenced formulation of tacrolimus (Envarsus-PA), which achieves peak tacrolimus concentrations 20-30% lower than other tacrolimus formulations has less of an inhibitory effect on insulin secretion.

COVID-19 infection in liver transplant recipients: Clinical features and outcomes from a Canadian multicentre cohort.

Prior studies have assessed risk factors and clinical outcomes in liver transplant (LT) recipients infected with COVID-19 globally; however, there is a paucity of Canadian data. Our multicentre study aims to examine the characteristics and clinical outcomes of LT patients with COVID-19 infection in Canada. Adult LT recipients with reverse transcription-polymerase chain reaction (RT-PCR) confirmed COVID-19, from Canadian tertiary care centres between March 2020 and June 2021 were included.

Post-transplant diabetes mellitus in Canadian liver and renal transplant recipients.

Post-transplant diabetes mellitus (PTDM) occurs in 10%-40% of liver and renal transplant recipients. Whether the risk factors for PTDM in liver and renal transplant recipients are similar and whether Indigenous Canadians, who have a high underlying prevalence of diabetes mellitus (DM), are at increased risk of developing PTDM have yet to be determined. To describe and compare those variables associated with PTDM in adult Canadian liver and renal transplant recipients.

Pharmacokinetics of a once-daily tacrolimus formulation in first nations and caucasian liver transplant recipients.

Patient ethnicity may influence the pharmacokinetics (PK) of tacrolimus. Because the Canadian First Nations (FN) constitute a large and increasing segment of the liver transplant population, we undertook to determine whether PK differences exist for a once-daily, extended release formulation of tacrolimus (Advagraf) in FN compared to Caucasian (CAUC) liver transplant recipients. Following achievement of a steady state with Advagraf, blood samples were drawn at 0, 1, 2, 4, 6, 8 and 24 hours for whole blood tacrolimus levels by commercial immunoassay and CYP3A4 and CYP3A5 allele analyses were performed by polymerase chain reactions.

The Psychological and Financial Impact of Long-distance Travel for Liver Transplantation.

Background: Patients who travel long distances to undergo liver transplantation have limited opportunities to develop confidence in their new healthcare providers and experience fewer support visits from family and friends at the transplant site. The objectives of this study were to document the psychological and financial impact of having to travel long distances for liver transplantation in adult liver disease patients.

Methods: This was a single-center, prospective study that used a 7-question survey, including Likert scales, patient recall, and administrative databases.

Epidemiology, clinical treatment patterns, and survival of hepatocellular carcinoma in Manitoba.

Background: Hepatocellular carcinoma (HCC) has a very poor survival rate, especially for those who do not receive a potentially curative therapy.

Methods: Treatment details were collected for 320 HCC patients diagnosed in Manitoba between January 2011 and December 2015. Patients had a mean age of 67.

Spontaneous Flares of Chronic Hepatitis B Virus in Hepatitis Be Antigen Negative Carriers Who Subsequently Clear Hepatitis B Surface Antigen.

Background: Acute exacerbations of chronic hepatitis B virus (HBV) infections can occur in HBV-infected, hepatitis e antigen (HBeAg)-negative patients in the absence of recent withdrawal of antiviral or immunosuppressive therapies. Whether these spontaneous "flares" predict subsequent loss of hepatitis B surface antigen (HBsAg) has yet to be determined.

Objectives: To document the percent of patients who experience spontaneous HBV flares and severity of the flares in chronic HBeAg-negative carriers.

Predicting Pre-transplant Abstinence in Patients with Alcohol-Induced Liver Disease.

Background: Some patients with alcohol-induced liver failure will succumb to their disease prior to demonstrating compliance with the six months abstinence rule for liver transplantation.

Purpose: The purpose of this study was to determine whether a patient's self-reported, longest period of abstinence predicts subsequent abstinence.

Methods: Adult patients (n=63) with alcohol-induced liver disease were asked to recall their longest period of abstinence prior to their initial hepatology visit.

Concomitant nonalcoholic fatty liver disease does not alter the activity, severity or course of primary biliary cholangitis.

Background & Aims: The impact of nonalcoholic fatty liver disease (NAFLD) on the natural history of primary biliary cholangitis (PBC) has yet to be described. The aim of this study was to document the activity, severity and progression of PBC in patients with concomitant NAFLD and compare the findings to those with PBC alone.

Methods: Disease activity was assessed by serum liver enzyme levels; severity, by Fib-4 scores and percent of patients with APRI >1.

Circulating Levels of Interleukin 1-Receptor Antagonist and Risk of Cardiovascular Disease: Meta-Analysis of Six Population-Based Cohorts.

Objective: Interleukin (IL)-1β represents a key cytokine in the development of cardiovascular disease (CVD). IL-1β is counter-regulated by IL-1 receptor antagonist (IL-1RA), an endogenous inhibitor. This study aimed to identify population-based studies on circulating IL-1RA and incident CVD in a systematic review, estimate the association between IL-1RA and incident CVD in a meta-analysis, and to test whether the association between IL-1RA and incident CVD is explained by other inflammation-related biomarkers in the MONICA/KORA Augsburg case-cohort study (Multinational Monitoring of Trends and Determinants in Cardiovascular Disease/Cooperative Health Research in the Region of Augsburg).

Predicting propulsive forces using distributed sensors in a compliant, high DOF, robotic fin.

Engineered robotic fins have adapted principles of propulsion from bony-finned fish, using spatially-varying compliance and complex kinematics to produce and control the fin's propulsive force through time. While methods of force production are well understood, few models exist to predict the propulsive forces of a compliant, high degree of freedom, robotic fin as it moves through fluid. Inspired by evidence that the bluegill sunfish (Lepomis macrochirus) has bending sensation in its pectoral fins, the objective of this study is to understand how sensors distributed within a compliant robotic fin can be used to estimate and predict the fin's propulsive force.

Spongiform encephalopathy in transgenic mice expressing a point mutation in the β2-α2 loop of the prion protein.

Transmissible spongiform encephalopathies are fatal neurodegenerative diseases attributed to misfolding of the cellular prion protein, PrP(C), into a β-sheet-rich, aggregated isoform, PrP(Sc). We previously found that expression of mouse PrP with the two amino acid substitutions S170N and N174T, which result in high structural order of the β2-α2 loop in the NMR structure at pH 4.5 and 20°C, caused transmissible de novo prion disease in transgenic mice.

A universal method for detection of amyloidogenic misfolded proteins.

Diseases associated with the misfolding of endogenous proteins, such as Alzheimer's disease and type II diabetes, are becoming increasingly prevalent. The pathophysiology of these diseases is not totally understood, but mounting evidence suggests that the misfolded protein aggregates themselves may be toxic to cells and serve as key mediators of cell death. As such, an assay that can detect aggregates in a sensitive and selective fashion could provide the basis for early detection of disease, before cellular damage occurs.

Aβ40 oligomers identified as a potential biomarker for the diagnosis of Alzheimer's disease.

Alzheimer's Disease (AD) is the most prevalent form of dementia worldwide, yet the development of therapeutics has been hampered by the absence of suitable biomarkers to diagnose the disease in its early stages prior to the formation of amyloid plaques and the occurrence of irreversible neuronal damage. Since oligomeric Aβ species have been implicated in the pathophysiology of AD, we reasoned that they may correlate with the onset of disease. As such, we have developed a novel misfolded protein assay for the detection of soluble oligomers composed of Aβ x-40 and x-42 peptide (hereafter Aβ40 and Aβ42) from cerebrospinal fluid (CSF).

Atypical prion protein conformation in familial prion disease with PRNP P105T mutation.

Protease-resistant prion protein (PrP(Sc) ) is diagnostic of prion disease, yet its detection is frequently difficult. Here, we describe a patient with a PRNP P105T mutation and typical familial prion disease. Brain PrP(Sc) was undetectable by conventional Western blotting and barely detectable after phosphotungstate precipitation, where it displayed an atypical pattern suggestive of noncanonical conformation.

The octarepeat region of the prion protein is conformationally altered in PrP(Sc).

Background: Prion diseases are fatal neurodegenerative disorders characterized by misfolding and aggregation of the normal prion protein PrP(C). Little is known about the details of the structural rearrangement of physiological PrP(C) into a still-elusive disease-associated conformation termed PrP(Sc). Increasing evidence suggests that the amino-terminal octapeptide sequences of PrP (huPrP, residues 59-89), though not essential, play a role in modulating prion replication and disease presentation.

Resistance of bovine spongiform encephalopathy (BSE) prions to inactivation.

Distinct prion strains often exhibit different incubation periods and patterns of neuropathological lesions. Strain characteristics are generally retained upon intraspecies transmission, but may change on transmission to another species. We investigated the inactivation of two related prions strains: BSE prions from cattle and mouse-passaged BSE prions, termed 301V.

Factors associated with time to laparoscopic cholecystectomy for acute cholecystitis.

Aim: To determine patient and process of care factors associated with performance of timely laparoscopic cholecystectomy for acute cholecystitis.

Methods: A retrospective medical record review of 88 consecutive patients with acute cholecystitis was conducted. Data collected included demographic data, co-morbidities, symptoms and physical findings at presentation, laboratory and radiological investigations, length of stay, complications, and admission service (medical or surgical).

Characterization of prion protein (PrP)-derived peptides that discriminate full-length PrPSc from PrPC.

On our initial discovery that prion protein (PrP)-derived peptides were capable of capturing the pathogenic prion protein (PrP(Sc)), we have been interested in how these peptides interact with PrP(Sc). After screening peptides from the entire human PrP sequence, we found two peptides (PrP(19-30) and PrP(100-111)) capable of binding full-length PrP(Sc) in plasma, a medium containing a complex mixture of other proteins including a vast excess of the normal prion protein (PrP(C)). The limit of detection for captured PrP(Sc) was calculated to be 8 amol from a approximately 10(5)-fold dilution of 10% (wt/vol) human variant Creutzfeldt-Jakob disease brain homogenate, with >3,800-fold binding specificity to PrP(Sc) over PrP(C).

Phosphorothioate oligonucleotides reduce PrP levels and prion infectivity in cultured cells.

Prions are composed solely of the disease-causing prion protein (PrPSc) that is formed from the cellular isoform PrPC by a posttranslational process. Here we report that short phosphorothioate DNA (PS-DNA) oligonucleotides diminished the levels of both PrPC and PrPSc in prion-infected neuroblastoma (ScN2a) cells. The effect of PS-DNA on PrP levels was independent of the nucleotide sequence.

Continuum of prion protein structures enciphers a multitude of prion isolate-specified phenotypes.

On passaging synthetic prions, two isolates emerged with incubation times differing by nearly 100 days. Using conformational-stability assays, we determined the guanidine hydrochloride (Gdn.HCl) concentration required to denature 50% of disease-causing prion protein (PrP(Sc)) molecules, denoted as the [Gdn.

Inactivation of prions by acidic sodium dodecyl sulfate.

Prompted by the discovery that prions become protease-sensitive after exposure to branched polyamine dendrimers in acetic acid (AcOH) (S. Supattapone, H. Wille, L.

Transmission barriers for bovine, ovine, and human prions in transgenic mice.

Transgenic (Tg) mice expressing full-length bovine prion protein (BoPrP) serially propagate bovine spongiform encephalopathy (BSE) prions without posing a transmission barrier. These mice also posed no transmission barrier for Suffolk sheep scrapie prions, suggesting that cattle may be highly susceptible to some sheep scrapie strains. Tg(BoPrP) mice were also found to be susceptible to prions from humans with variant Creutzfeldt-Jakob disease (CJD); on second passage in Tg(BoPrP) mice, the incubation times shortened by 30 to 40 days.

Trafficking of prion proteins through a caveolae-mediated endosomal pathway.

To understand the posttranslational conversion of the cellular prion protein (PrPC) to its pathologic conformation, it is important to define the intracellular trafficking pathway of PrPC within the endomembrane system. We studied the localization and internalization of PrPC in CHO cells using cryoimmunogold electron microscopy. At steady state, PrPC was enriched in caveolae both at the TGN and plasma membrane and in interconnecting chains of endocytic caveolae.

Differential inhibition of prion propagation by enantiomers of quinacrine.

Prion diseases are fatal neurologic disorders caused by accumulation of a pathogenic isoform (PrP(Sc)) of the prion protein (PrP). The recent discovery of the inhibitory action of quinacrine on PrP(Sc) formation in scrapie-infected neuroblastoma (ScN2a) cells raised the possibility of a treatment for patients with prion disease. To investigate the efficacy of quinacrine enantiomers, we measured the inhibitory effect of these isomers on PrP(Sc) formation in ScN2a cells.