Xenotropic Murine Leukemia Virus-Related Virus as a Case Study: Using a Precautionary Risk Management Approach for Emerging Blood-Borne Pathogens in Canada

In October 2009 it was reported that 68 of 101 patients with chronic fatigue syndrome (CFS) in the United States, when tested, were infected with a novel gamma retrovirus, xenotropic murine leukemia virus-related virus (XMRV) (Lombardi et al., 2009). XMRV is a recently discovered human gammaretrovirus first described in prostate cancers that shares significant homology with murine leukemia virus (MLV) (Ursiman et al., 2006). It is known that XMRV can cause leukemias and sarcomas in several rodent, feline, and primate species but has not been shown to cause disease in humans. XMRV was detectable in the peripheral blood mononuclear cells (PBMCs) and plasma of individuals diagnosed with CFS (Lombardi et al., 2009). After this report was published there was a great deal of uncertainty surrounding this emergent virus and its involvement in the etiology of CFS. The uncertainty was, in part, due to CFS being a complex, poorly understood multi-system disorder with different disease criteria used for its diagnosis. CFS, also known as Myalgic Encephalomyelitis (ME), is a debilitating disease of unknown origin that is estimated to affect 17 million people worldwide. The initial report connecting XMRV to prostate cancers and CFS garnered significant media and scientific interest since it provided a potential Susie ElSaadany2**, Tamer Oraby1 * Daniel Krewski1, 4 and Peter R. Ganz5 1McLaughlin Centre for Population Health Risk Assessment, Institute of Population Health, University of Ottawa, Ontario, Canada 2Blood Safety Surveillance and Health Care Acquired Infections Division, Centre for Communicable Diseases and Infection Control, Public Health Agency of Canada, Ottawa, Ontario, Canada 3Aspinall and Associates, Cleveland House, High Street, and Earth Sciences, Bristol University, Bristol, United Kingdom 4Department of Epidemiology and Community Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada 5Health Canada, Director’s Office, Ottawa, Ontario, Canada ** Corresponding Author , Marian Laderoute2 , Jun Wu2 , Willy Aspinall3 , www.intechopen.com 32 The Continuum of Health Risk Assessments explanation for the disease but also an avenue for possible therapeutic treatments since XMRV is known to be susceptible to some anti-retroviral drugs (Cohen, 2011)

Functional and biochemical parameters of peptide antigen presentation

To understand the mechanism by which peptide antigens are processed and presented to T cells, we examined the T-cell response to the 13-amino-acid peptide [alpha]-melanocyte-stimulating hormone ([alpha]-MSH). To determine the fine specificity of T-cell recognition, T cells specific for [alpha]-MSH, and genetically restricted by I-Ab/d, were challenged with different [alpha]-MSH analogs and homologs. It was found that intact [alpha]-MSH, including the blocked amino and carboxy termini of the native molecule, was required for T-cell responsiveness. Antigen-presenting cells (APC) could be briefly pulsed with [alpha]-MSH and then present the [alpha]-MSH antigenic determinant to T cells, indicating that the relevant antigen was retained by the APC. APC stimulatory capacity was dramatically reduced by aldehyde treatment of the APC, or by pulsing the APC with [alpha]-MSH at low temperature. Efficient [alpha]-MSH pulsing was also impaired by treatment of the APC with the carboxylic ionophore, monensin, but not by the lysosomotropic agents chloroquine and methylamine. In addition, isolated APC plasma membranes added to the T cells in the presence of soluble [alpha]-MSH were not stimulatory. However, plasma membranes isolated from APC that had been previously pulsed with [alpha]-MSH retained stimulatory activity for T-cell responses. The only detectable [alpha]-MSH contained in these pulsed APC membranes was in an acid-stable complex of higher molecular weight than native peptide. The amount of [alpha]-MSH detected in the cellular membrane fraction isolated by density gradient sedimentation was also reduced by treatments that reduced the APC stimulatory capacity, such as pulsing at low temperature or in the presence of monensin. Taken together, these results suggest that processing of [alpha]-MSH is unlike that heretofore described for other peptide antigens and seems to involve APC handling to form the stimulatory moiety presented on the APC surface.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/27319/1/0000341.pd

The Translational Medicine Ontology and Knowledge Base: driving personalized medicine by bridging the gap between bench and bedside

Background: Translational medicine requires the integration of knowledge using heterogeneous data from health care to the life sciences. Here, we describe a collaborative effort to produce a prototype Translational Medicine Knowledge Base (TMKB) capable of answering questions relating to clinical practice and pharmaceutical drug discovery. Results: We developed the Translational Medicine Ontology (TMO) as a unifying ontology to integrate chemical, genomic and proteomic data with disease, treatment, and electronic health records. We demonstrate the use of Semantic Web technologies in the integration of patient and biomedical data, and reveal how such a knowledge base can aid physicians in providing tailored patient care and facilitate the recruitment of patients into active clinical trials. Thus, patients, physicians and researchers may explore the knowledge base to better understand therapeutic options, efficacy, and mechanisms of action. Conclusions: This work takes an important step in using Semantic Web technologies to facilitate integration of relevant, distributed, external sources and progress towards a computational platform to support personalized medicine. Availability: TMO can be downloaded from http://code.google.com/p/translationalmedicineontology and TMKB can be accessed at http://tm.semanticscience.org/sparql

GWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder affecting 0.5–2% of pregnancies. The majority of cases present in the third trimester with pruritus, elevated serum bile acids and abnormal serum liver tests. ICP is associated with an increased risk of adverse outcomes, including spontaneous preterm birth and stillbirth. Whilst rare mutations affecting hepatobiliary transporters contribute to the aetiology of ICP, the role of common genetic variation in ICP has not been systematically characterised to date. Here, we perform genome-wide association studies (GWAS) and meta-analyses for ICP across three studies including 1138 cases and 153,642 controls. Eleven loci achieve genome-wide significance and have been further investigated and fine-mapped using functional genomics approaches. Our results pinpoint common sequence variation in liver-enriched genes and liver-specific cis-regulatory elements as contributing mechanisms to ICP susceptibility

The use of rituximab and bendamustine in treating chronic lymphocytic leukaemia (CLL) in end-stage renal disease (ESRD)

A patient with a history of type 2 diabetes mellitus and chronic lymphocytic leukaemia has renal failure with large kidneys. The patient refused kidney biopsy to determine the aetiology of her renal failure. She uses peritoneal dialysis to treat renal failure. She received rituximab and bendamustine to treat chronic lymphocytic leukaemia. Adenopathy resolves with treatment and she does not experience any electrolyte disturbances or decrease in urine output as a result of chemotherapy in the setting of renal failure. Renal function did not recover with chemotherapy

Boundary Treatments For Multilevel Methods On Unstructured Meshes

. In applying multilevel iterative methods on unstructured meshes, the grid hierarchy can allow general coarse grids whose boundaries may be non-matching to the boundary of the fine grid, so special care is needed to correctly handle different types of boundary conditions. Standard coarse-to-fine grid transfer operators with linear interpolants result in a zero boundary condition for fine grid nodes which are not in the coarse grid domain, and are not accurate enough at Neumann boundaries. We propose two effective ways to adapt the standard coarse-to-fine interpolations to correctly implement boundary conditions in such cases: (1) modified coarse grid boundaries and (2) modified interpolations. We prove that all the proposed interpolants possess the local optimal L 2 -approximation and H 1 -stability, which are essential in the convergence analysis of the multilevel methods for second order elliptic and parabolic problems on unstructured meshes, and provide some numerical examples ..

Automatic identification of posteroanterior cephalometric landmarks using a novel deep learning algorithm: a comparative study with human experts

Abstract This study aimed to propose a fully automatic posteroanterior (PA) cephalometric landmark identification model using deep learning algorithms and compare its accuracy and reliability with those of expert human examiners. In total, 1032 PA cephalometric images were used for model training and validation. Two human expert examiners independently and manually identified 19 landmarks on 82 test set images. Similarly, the constructed artificial intelligence (AI) algorithm automatically identified the landmarks on the images. The mean radial error (MRE) and successful detection rate (SDR) were calculated to evaluate the performance of the model. The performance of the model was comparable with that of the examiners. The MRE of the model was 1.87 ± 1.53 mm, and the SDR was 34.7%, 67.5%, and 91.5% within error ranges of < 1.0, < 2.0, and < 4.0 mm, respectively. The sphenoid points and mastoid processes had the lowest MRE and highest SDR in auto-identification; the condyle points had the highest MRE and lowest SDR. Comparable with human examiners, the fully automatic PA cephalometric landmark identification model showed promising accuracy and reliability and can help clinicians perform cephalometric analysis more efficiently while saving time and effort. Future advancements in AI could further improve the model accuracy and efficiency