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Markle J.G.,Rockefeller University | Fish E.N.,Toronto General Research Institute | Fish E.N.,University of Toronto
Trends in Immunology | Year: 2014

The significant contributions of sex to an immune response, specifically in the context of the sex bias observed in susceptibility to infectious and autoimmune diseases and their pathogenesis, have until recently, largely been ignored and understudied. This review highlights recent findings related to sex-specific factors that provide new insights into how sex determines the transcriptome, the microbiome, and the consequent immune cell functional profile to define an immune response. Unquestionably, accumulating data confirm that sex matters and must be a consideration when decisions around therapeutic intervention strategies are developed. © 2013 Elsevier Ltd.


Branch D.R.,Toronto General Research Institute
Current Opinion in Hematology | Year: 2010

Purpose of Review: Histo-blood group antigens belonging to the P1PK and GLOB blood group systems are involved in bacterial infections, but a substantial body of evidence is emerging that some of these glycosphingolipids play a role in HIV infection. These recent findings have raised additional questions regarding the possible role of the Pk/Gb3 histo-blood group antigen in HIV-1 infection. Recent Findings: Early studies implicated a number of glycosphingolipids able to interact with HIV envelope glycoprotein 120. It has been recently reported that cellular or soluble P k/Gb3 histo-blood group antigen provides protection from HIV-1 infection. This resistance mechanism appears to be mediated through inhibition of fusion of the HIV-1 envelope to the cell target membrane. Protection has been shown to be provided to both HIV-1 X4 and R5 tropic strains. Indeed, an inverse correlation has been documented between the expression of Pk/Gb3 on the cellular membrane and susceptibility to HIV infection. Moreover, soluble Pk/Gb3 analogues have been shown to inhibit HIV infection. Summary: The Pk/Gb3 histo-blood group antigen is the first described cell surface expressed natural resistance factor for prevention of HIV infection. Increased expression of Pk/Gb3 correlates to decreased HIV infection, whereas decreased or absent Pk/Gb3 increases HIV susceptibility. Soluble Pk/Gb3 analogues can inhibit HIV by two mechanisms: direct inhibition of the free virus and inhibition of viral entry. Future development of soluble Pk/Gb3 analogues, pharmacologic means of increasing cell surface expression of P k/Gb3 on HIV susceptible target cells or both may result in novel therapeutic modalities for the prevention and eradication of HIV/AIDS. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Galligan C.L.,Toronto General Research Institute | Fish E.N.,Toronto General Research Institute
Arthritis and Rheumatism | Year: 2012

Objective Rheumatoid arthritis (RA) is a systemic autoimmune disease resulting in joint inflammation. Fibroblast-like synoviocytes in affected joints are responsible for pannus formation and cytokine/chemokine production, resulting in leukocyte recruitment and bone/cartilage destruction. Previously, we identified a multipotent stem cell population of activated fibrocytes in the blood of patients with RA that may have a role in disease pathogenesis, perhaps as fibroblast-like synoviocyte precursors. The aim of this study was to further characterize the contribution of circulating fibrocytes to the pathogenesis of RA. Methods Circulating fibrocytes were isolated from mice with collagen-induced arthritis and transferred intravenously into recipient mice with collagen antibody-induced arthritis (CAIA). The activation status of circulating fibrocytes was determined using multidimensional phosphoflow cytometric analysis of the signaling effectors STAT-5, STAT-1, AKT, and JNK. Circulating fibrocyte trafficking and matrix metalloproteinase (MMP) activity were assessed in real time using fluorescence molecular tomography, specifically labeling circulating fibrocytes with CellVue Maroon and measuring MMP activity using MMPSense 680. Results The numbers of circulating fibrocytes were increased early during the onset of CAIA, concomitant with their activation, as measured by phosphorylation of STAT-5. Adoptive transfer of circulating fibrocytes augmented disease scores and increased class II major histocompatibility complex expression and peripheral blood phosphoactivation profiles in recipient mice with CAIA. Notably, adoptively transferred fluorescence-labeled circulating fibrocytes rapidly migrated into the affected joints of recipient mice with CAIA, and this was associated with augmented neutrophil recruitment into affected joints and MMP activation. Conclusion Circulating fibrocytes migrate to joints and influence the onset of disease processes in arthritis. Copyright © 2012 by the American College of Rheumatology.


Galligan C.L.,Toronto General Research Institute
Rheumatology (Oxford, England) | Year: 2010

RA is a common, relapsing autoimmune disease primarily affecting the joints. Fibroblast-like synovial (FLS) cells are thought to be responsible for pannus formation and secretion of factors that recruit leucocytes to affected joints, thereby promoting bone and cartilage destruction. Fibrocytes are multipotent circulating stem cells that may have a role in RA pathogenesis, perhaps as the precursors of the FLS cells, or by regulating FLS cell function. We utilized multidimensional phospho-specific flow cytometry to characterize the activation status of peripheral blood (PB) fibrocytes derived from human RA patients at different stages of disease and from mice with CIA. Human PB fibrocytes from RA patients exhibited phosporylation activation of the p44/42 and p38 MAP kinases (MAPKs), and STAT3 (signal transducer and activator of transcription) and STAT-5 early in disease, within the first year of diagnosis. Similarly, in murine CIA, an increase in the total number of PB phosphoSTAT5-positive fibrocytes was observed at early time points in disease. Notably, in the affected paws of mice with CIA, we identified an increased number of fibrocytes, in contrast to the paws of control mice. These data suggest that activated fibrocytes may influence the disease process in RA and may serve as surrogate markers for disease in the PB of affected patients.


Gagliardi A.R.,Toronto General Research Institute | Alhabib S.,King Abdullah University of Science and Technology
Implementation Science | Year: 2015

Background: There is currently no reliable way to choose strategies that are appropriate for implementing guidelines facing different barriers. This study examined trends in guideline implementation by topic over a 10-year period to explore whether and how strategies may be suitable for addressing differing barriers. Methods: A scoping systematic review was performed. MEDLINE and EMBASE were searched from 2004 to 2013 for studies that evaluated the implementation of guidelines on arthritis, diabetes, colorectal cancer and heart failure. Data on study characteristics, reason for implementation (new guideline or quality improvement), implementation strategy used, rationale for selecting that strategy and reported impact were extracted and summarized. Interventions were mapped against a published taxonomy of guideline implementation strategies. Results: The search resulted in 1,709 articles; 156 were retrieved and 127 were excluded largely because they did not evaluate guideline implementation, leaving 32 eligible for review (4 arthritis, 3 colorectal cancer, 21 diabetes, 4 heart failure). Six of 7 randomized trials and 8 of 25 observational studies had a low risk of bias. Most studies promoted guideline use for quality improvement (78.0%). Few studies rationalized strategy choice (18.8%). Most employed multiple approaches and strategies, most often educational meetings and print material for professionals or patients. Few studies employed organizational, financial or regulatory approaches. Strategies employed that were unique to the published taxonomy included professional (print material, tailoring guidelines, self-audit training or material) and patient strategies (education, counselling, group interaction, print material, reminders). Most studies achieved positive impact (87.5%). This did not appear to be associated with guideline topic, use of theory or barrier assessment, or number or type of implementation approaches and strategies. Conclusions: While few studies were eligible, limiting insight on how to choose implementation strategies that address guideline-specific barriers, this review identified other important findings. Education for professionals or patients and print material were the most commonly employed strategies for translating guidelines to practice. Mapping of strategies onto the published taxonomy identified gaps in guideline implementation that represent opportunities for future research and expanded the taxonomy. © 2015 Gagliardi and Alhabib; licensee BioMed Central.


Radhakrishnan J.,Columbia University | Cattran D.C.,Toronto General Research Institute
Kidney International | Year: 2012

The KDIGO guideline for glomerulonephritis is designed to assist health-care providers in treating patients with glomerular diseases. A guideline is not a set of rules but is intended to allow the practitioner to make an informed decision based on the available evidence. Due to its general nature and the variability of strength of the available studies, it is often difficult to directly apply a guideline to the care of an individual patient. This commonly relates to the limited generalizability of the evidence, i.e., does not cover every clinical scenario. To underscore this point, we have introduced within the context of the glomerulonephritis guideline cases with specific features to illustrate the constant need for clinical judgment. These vignettes are intended to demonstrate how the best treatment plans should be individualized and take into account patient preference and clinical acumen, as well as the best available evidence. © 2012 International Society of Nephrology.


Stewart D.E.,Toronto General Research Institute
New England Journal of Medicine | Year: 2011

A 24-year-old married woman presents with a 1-month history of diminished concentration and interest, insomnia, fatigue, tearfulness, and depressed mood. She is 10 weeks pregnant, stopped working 3 weeks ago, and mostly stays in bed. Two years ago, she was successfully treated briefly with sertraline at a daily dose of 50 mg for depression after a suicide attempt. She reports that she wants to continue the pregnancy and says that she does not feel suicidal. What would you advise? Copyright © 2011 Massachusetts Medical Society.


Galligan C.L.,Toronto General Research Institute | Fish E.N.,Toronto General Research Institute
Journal of Leukocyte Biology | Year: 2013

Autoimmunity is a chronic process resulting in inflammation, tissue damage, and subsequent tissue remodeling. Circulating fibrocytes are bone marrow-derived cells with characteristics of hematopoietic and mesenchymal cells. These cells have been implicated in many inflammatory and fibrotic conditions as well as in wound healing. Fibrocytes can amplify the inflammatory/immune response through multiple mechanisms, including antigen presentation, cytokine and chemokine secretion, and production of MMPs. Increased numbers of circulating fibrocytes are observed in RA, systemic scleroderma, and Graves' disease. Here, we review the current literature and potential involvement of fibrocytes in inflammation and autoimmunity. © Society for Leukocyte Biology.


Swirski F.K.,Harvard University | Robbins C.S.,Toronto General Research Institute | Nahrendorf M.,Harvard University
Trends in Immunology | Year: 2016

Macrophages inhabit all major organs, and are capable of adapting their functions to meet the needs of their home tissues. The recent recognition that tissue macrophages derive from different sources, coupled with the notion that environmental cues and inflammatory stimuli can sculpt and agitate homeostasis, provides a frame of reference from which we can decipher the breadth and depth of macrophage activity. Here we discuss macrophages residing in the cardiovascular system, focusing particularly on their development and function in steady state and disease. Central to our discussion is the tension between macrophage ontogeny as a determinant of macrophage function, and the idea that tissues condition macrophage activities and supplant the influence of macrophage origins in favor of environmental demands. © 2015 Elsevier Ltd.


Jin T.,Toronto General Research Institute
Endocrine Reviews | Year: 2016

The role of the Wnt signaling pathway in metabolic homeostasis has drawn our intensive attention, especially after the genome-wide association study discovery that certain polymorphisms of its key effector TCF7L2 are strongly associated with the susceptibility to type 2 diabetes. For a decade, great efforts have been made in determining the function of TCF7L2 in various metabolic organs, which have generated both considerable achievements and disputes. In this review, I will briefly introduce the canonical Wnt signaling pathway, focusing on its effector -catenin/TCF, including emphasizing the bidirectional feature of TCFs and -catenin posttranslational modifications. I will then summarize the observations on the association between TCF7L2 polymorphisms and type 2 diabetes risk. The main content, however, is on the intensive functional exploration of the metabolic role of TCF7L2, including the disputes generated on determining its role in the pancreas and liver with various transgenicmouselines. Finally, I will discuss those achievements and disputes and presentmyfuture perspectives. © 2016 by the Endocrine Society.

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