Medicine and Health Sciences Commons^™

Gene-Level Association Analysis Of Systemic Sclerosis: A Comparison Of African-Americans And White Populations, O. Y. Gorlova, Y. Li, I. Gorlov, J. Ying, W. V. Chen, S. Assassi, J. D. Reveille, P. K. Gregersen, A. T. Lee, D. Khanna, M. D. Mayes, +22 Additional Authors

Journal Articles

© 2018 Gorlova et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Gene-level analysis of ImmunoChip or genome-wide association studies (GWAS) data has not been previously reported for systemic sclerosis (SSc, scleroderma). The objective of this study was to analyze genetic susceptibility loci in SSc at the gene level and to determine if the detected associations were shared in African-American and White populations, using data from ImmunoChip and GWAS genotyping studies. The White …

Lifelong Behavioral And Neuropathological Consequences Of Repetitive Mild Traumatic Brain Injury, B. C. Mouzon, C. Bachmeier, J. O. Ojo, C. M. Acker, S. Ferguson, D. Paris, G. Ait-Ghezala, G. Crynen, P. Davies, F. Crawford, +2 Additional Authors

Journal Articles

© 2017 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association. Objective: Exposure to repetitive concussion, or mild traumatic brain injury (mTBI), has been linked with increased risk of long-term neurodegenerative changes, specifically chronic traumatic encephalopathy (CTE). To date, preclinical studies largely have focused on the immediate aftermath of mTBI, with no literature on the lifelong consequences of mTBI in these models. This study provides the first account of lifelong neurobehavioral and histological consequences of repetitive mTBI providing unique insight into the constellation of evolving and ongoing pathologies with late …

Neuro-Immune Interactions In Inflammation And Host Defense: Implications For Transplantation, S. S. Chavan, P. Ma, I. M. Chiu

Journal Articles

© 2017 The American Society of Transplantation and the American Society of Transplant Surgeons Sensory and autonomic neurons of the peripheral nervous system (PNS) play a critical role in regulating the immune system during tissue inflammation and host defense. Recent studies have identified the molecular mechanisms underlying the bidirectional communication between the nervous system and the immune system. Here, we highlight the studies that demonstrate the importance of the neuro-immune interactions in health and disease. Nociceptor sensory neurons detect immune mediators to produce pain, and release neuropeptides that act on the immune system to regulate inflammation. In parallel, neural reflex …

Dynamic Hydrostatic Pressure Regulates Nucleus Pulposus Phenotypic Expression And Metabolism In A Cell Density-Dependent Manner, B. S. Shah, N. O. Chahine

Journal Articles

© 2018 by ASME. Dynamic hydrostatic pressure (HP) loading can modulate nucleus pulposus (NP) cell metabolism, extracellular matrix (ECM) composition, and induce transformation of notochordal NP cells into mature phenotype. However, the effects of varying cell density and dynamic HP magnitude on NP phenotype and metabolism are unknown. This study examined the effects of physiological magnitudes of HP loading applied to bovine NP cells encapsulated within three-dimensional (3D) alginate beads. Study 1: seeding density (1 M/mL versus 4 M/mL) was evaluated in unloaded and loaded (0.1 MPa, 0.1 Hz) conditions. Study 2: loading magnitude (0, 0.1, and 0.6 MPa) applied …

Smoking Is The Most Significant Modifiable Lung Cancer Risk Factor In Systemic Lupus Erythematosus, S. Bernatsky, R. Ramsey-Goldman, M. Petri, M. B. Urowitz, D. D. Gladman, P. R. Fortin, E. H. Yelin, E. Ginzler, C. Aranow, A. E. Clarke, +9 Additional Authors

Journal Articles

Copyright © 2018 The Journal of Rheumatology. All rights reserved. Objective. To assess lung cancer risk in systemic lupus erythematosus (SLE), relative to demographics, drug exposures, smoking, and disease activity. Methods.We analyzed data from 14 SLE cohorts. We calculated adjusted HR estimates for lung cancer in SLE, relative to demographics, smoking, time-dependent medication exposures, and cumulative disease activity [mean adjusted SLE Disease Activity Index (SLEDAI) scores]. This project was approved by the ethics boards of all participating institutions, including the Institutional Review Board of the McGill University Health Centre. The ethics approval number for the Cancer Risk study is GEN-06-031. …

Glucocorticoid Use And Factors Associated With Variability In This Use In The Systemic Lupus International Collaborating Clinics Inception Cohort, J. Little, B. Parker, M. Lunt, J. G. Hanly, M. B. Urowitz, A. E. Clarke, J. Romero-Diaz, C. Aranow, M. Mackay, I. N. Bruce, +32 Additional Authors

Journal Articles

© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. Objectives. To describe glucocorticoid (GC) use in the SLICC inception cohort and to explore factors associated with GC use. In particular we aimed to assess temporal trends in GC use and to what extent physician-related factors may influence use. Methods. Patients were recruited within 15 months of diagnosis of SLE from 33 centres between 1999 and 2011 and continue to be reviewed annually. Descriptive statistics were used to detail oral and parenteral GC use. Cross sectional and longitudinal analyses were …

Global And Multi-Focal Changes In Cerebral Blood Flow During Subthalamic Nucleus Stimulation In Parkinson’S Disease, A. M. Mubeen, B. Ardekani, M. Tagliati, R. Alterman, V. Dhawan, D. Eidelberg, J. J. Sidtis

Journal Articles

© 2017, © The Author(s) 2017. Electrical stimulation of subthalamic nuclei (STN) is a widely used therapy in Parkinson’s disease (PD). While deep brain stimulation (DBS) of the STN alters the neurophysiological activity in basal ganglia, the therapeutic mechanism has not been established. A positron emission tomography (PET) study of cerebral blood flow (CBF) during speech production in PD subjects treated with STN-DBS found significant increases in global (whole-brain) CBF.1That study utilized a series of whole-slice regions of interest to obtain global CBF values. The present study examined this effect using a voxel-based principal component analysis (PCA) combined with Fisher’s …

New Insights Into The Function Of Rab Gtpases In The Context Of Exosomal Secretion, L. Blanc, M. Vidal

Journal Articles

© 2017 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group © 2017, © Lionel Blanc and Michel Vidal. In the last two decades, extracellular vesicle-mediated communication between cells has become a major field in cell biology. However, the function of extracellular vesicles is far from clear, especially due to the disparity of released vesicles by cells. Basically, one must consider vesicles budding from the cell plasma membrane (ectosomes) and vesicles released upon fusion of an endosomal multivesicular compartment (exosomes). Moreover, even for exosomes, we report and discuss here the possibility that different routes regulated by …

No Improvement In Long-Term Survival Over Time For Chronic Lymphocytic Leukemia Patients In Stereotyped Subsets #1 And #2 Treated With Chemo(Immuno)Therapy, P. Baliakas, M. Mattsson, A. Hadzidimitriou, E. Minga, A. Agathangelidis, L. A. Sutton, L. Scarfo, Z. Davis, N. Chiorazzi, K. Stamatopoulos, +30 Additional Authors

Journal Articles

No abstract provided.

Editorial: Neuro-Immune Interactions In Inflammation And Autoimmunity, N. Terrando, V. A. Pavlov

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No abstract provided.

Somatic Cll Mutations Occur At Multiple Distinct Hematopoietic Maturation Stages: Documentation And Cautionary Note Regarding Cell Fraction Purity, S. Marsilio, H. Khiabanian, G. Fabbri, S. Vergani, C. Scuoppo, E. Montserrat, E. J. Shpall, M. Hadigol, K. R. Rai, N. Chiorazzi, +4 Additional Authors

Journal Articles

No abstract provided.

Genetic Background May Contribute To The Latitude-Dependent Prevalence Of Dermatomyositis And Anti-Tif1-Γ Autoantibodies In Adult Patients With Myositis, J. E. Parkes, S. Rothwell, A. Oldroyd, H. Chinoy, J. A. Lamb, I. E. Lundberg, F. W. Miller, P. K. Gregersen, G. Marder, Z. E. Betteridge, +25 Additional Authors

Journal Articles

© 2018 The Author(s). Background: The prevalence of dermatomyositis (DM) versus DM and polymyositis (PM) combined has been shown to be negatively associated with latitude. This observation has been attributed to increasing exposure to ultraviolet (UV) light towards the equator. In this study, we investigated whether differing genetic background in populations could contribute to this distribution of DM. Methods: Case data derived from the MYOGEN (Myositis Genetics Consortium) Immunochip study (n = 1769) were used to model the association of DM prevalence and DM-specific autoantibodies with latitude. Control data (n = 9911) were used to model the relationship of human …

Mutational Spectrum In A Worldwide Study Of 29,700 Families With Brca1 Or Brca2 Mutations, T. R. Rebbeck, T. M. Friebel, E. Friedman, U. Hamann, D. Huo, A. Kwong, E. Olah, O. I. Olopade, A. Lee, K. L. Nathanson, +231 Additional Authors

Journal Articles

No abstract provided.

Comparison Of Therapeutic Triiodothyronine Versus Metoprolol In The Treatment Of Myocardial Infarction In Rats, K. Zhang, Y. D. Tang, Y. Zhang, K. Ojamaa, Y. Li, A. S. Saini, M. A. Carrillo-Sepulveda, V. Rajagopalan, A. M. Gerdes

Journal Articles

© 2018 Mary Ann Liebert, Inc. Background: Beta blockers are standard therapy for myocardial infarction (MI). Preclinical studies have shown efficacy and safety of thyroid hormone (TH) treatment of cardiovascular disorders. Since THs interact with the sympathoadrenergic system, this study aimed to compare triiodothyronine (T3) and metoprolol (Met) in the treatment of rats with MI on pathophysiology and TH-adrenergic signaling. Methods: Female Sprague-Dawley rats aged 12 weeks underwent left anterior descending coronary artery ligation (MI) or sham surgeries. T3 (5 μg/kg/day) or Met (100 mg/kg/day) was given in drinking water immediately after surgery for eight weeks. At the terminal of …

Hydroxychloroquine Prescription Trends And Predictors For Excess Dosing Per Recent Ophthalmology Guidelines, A. M. Jorge, R. B. Melles, Y. Zhang, N. Lu, S. K. Rai, L. H. Young, K. H. Costenbader, R. Ramsey-Goldman, C. Aranow Md, H. Choi, +6 Additional Authors

Journal Articles

© 2018 The Author(s). Background: Hydroxychloroquine (HCQ) retinopathy may be more common than previously recognized; recent ophthalmology guidelines have revised recommendations from ideal body weight (IBW)-based dosing to actual body weight (ABW)-based dosing. However, contemporary HCQ prescribing trends in the UK remain unknown. Methods: We examined a UK general population database to investigate HCQ dosing between 2007 and 2016. We studied trends of excess HCQ dosing per ophthalmology guidelines (defined by exceeding 6.5 mg/kg of IBW and 5.0 mg/kg of ABW) and determined their independent predictors using multivariable logistic regression analyses. Results: Among 20,933 new HCQ users (78% female), the …

Molecular And Functional Neuroscience In Immunity, V. A. Pavlov, S. S. Chavan, K. J. Tracey

Journal Articles

No abstract provided.

Methods For High-Dimensonal Analysis Of Cells Dissociated From Cyropreserved Synovial Tissue, L. T. Donlin, D. A. Rao, K. Wei, K. Slowikowski, M. J. Mcgeachy, J. D. Turner, P. K. Gregersen, R. Furie, B. Diamond, M. Mcmahon, +81 Additional Authors

Journal Articles

© 2018 The Author(s). Background: Detailed molecular analyses of cells from rheumatoid arthritis (RA) synovium hold promise in identifying cellular phenotypes that drive tissue pathology and joint damage. The Accelerating Medicines Partnership RA/SLE Network aims to deconstruct autoimmune pathology by examining cells within target tissues through multiple high-dimensional assays. Robust standardized protocols need to be developed before cellular phenotypes at a single cell level can be effectively compared across patient samples. Methods: Multiple clinical sites collected cryopreserved synovial tissue fragments from arthroplasty and synovial biopsy in a 10% DMSO solution. Mechanical and enzymatic dissociation parameters were optimized for viable cell …

Sputum Detection Of Predisposing Genetic Mutations In Women With Pulmonary Nontuberculous Mycobacterial Disease, J. V. Philley, K. L. Hertweck, A. Kannan, B. A. Brown-Elliott, R. J. Wallace, A. Kurdowska, H. Ndetan, K. P. Singh, E. J. Miller, S. Dasgupta, +1 Additional Author

Journal Articles

© 2018, The Author(s). Nontuberculous mycobacterial lung disease (NTM), including Mycobacterium avium complex (MAC), is a growing health problem in North America and worldwide. Little is known about the molecular alterations occurring in the tissue microenvironment during NTM pathogenesis. Utilizing next generation sequencing, we sequenced sputum and matched lymphocyte DNA in 15 MAC patients for a panel of 19 genes known to harbor cancer susceptibility associated mutations. Thirteen of 15 NTM subjects had a diagnosis of breast cancer (BCa) before or after NTM infection. Thirty three percent (4/12) of these NTM-BCa cases exhibited at least 3 somatic mutations in sputa …

Altered Leukocyte Gene Expression After Traumatic Spinal Cord Injury: Clinical Implications, P. E. Herman, O. Bloom

Journal Articles

No abstract provided.

Fine-Mapping And Functional Studies Highlight Potential Causal Variants For Rheumatoid Arthritis And Type 1 Diabetes, H. J. Westra, M. Martínez-Bonet, S. Onengut-Gumuscu, A. Lee, Y. Luo, N. Teslovich, J. Worthington, J. Martin, P. K. Gregersen, S. Raychaudhuri, +9 Additional Authors

Journal Articles

© 2018, The Author(s), under exclusive licence to Springer Nature America, Inc. To define potentially causal variants for autoimmune disease, we fine-mapped1,276 rheumatoid arthritis (11,475 cases, 15,870 controls)3and type 1 diabetes loci (9,334 cases, 11,111 controls)4. After sequencing 799 1-kilobase regulatory (H3K4me3) regions within these loci in 568 individuals, we observed accurate imputation for 89% of common variants. We defined credible sets of ≤5 causal variants at 5 rheumatoid arthritis and 10 type 1 diabetes loci. We identified potentially causal missense variants at DNASE1L3, PTPN22, SH2B3, and TYK2, and noncoding variants at MEG3, CD28–CTLA4, and IL2RA. We also identified potential …

Anticancer And Differentiation Properties Of The Nitric Oxide Derivative Of Lopinavir In Human Glioblastoma Cells, M. S. Basile, E. Mazzon, T. Krajnovic, D. Draca, E. Cavalli, Y. Al-Abed, P. Bramanti, F. Nicoletti, S. Mijatovic, D. Maksimovic-Ivanic

Journal Articles

© 2018 by the authors. Glioblastoma (GBM) is the most frequent and deadly form of primary malignant brain tumor among adults. A promising emerging approach for GBM treatment may be offered from HIV protease inhibitors (HIV-PIs). In fact, in addition to their primary pharmacological activity in the treatment of HIV infection, they possess important anti-neoplastic effects. According to previous studies, the addition of a nitric oxide (NO) donating group to parental compounds can reduce their toxicity and enhance the anticancer action of various compounds, including HIV-PIs. In this study we compared the effects of the HIV-PI Lopinavir (Lopi) and of …

Economic Evaluation Of Lupus Nephritis In The Systemic Lupus International Collaborating Clinics Inception Cohort Using A Multistate Model Approach., M. R.W. Barber, J. G. Hanly, L. Su, M. B. Urowitz, Y. St Pierre, J. Romero-Diaz, C. Gordon, C. Aranow, M. Mackay, A. E. Clarke, +30 Additional Authors

Journal Articles

OBJECTIVE: Little is known about the long-term costs of lupus nephritis (LN). The costs were compared between patients with and without LN using multistate modeling.

METHODS: Patients from 32 centers in 11 countries were enrolled in the Systemic Lupus International Collaborating Clinics inception cohort within 15 months of diagnosis and provided annual data on renal function, hospitalizations, medications, dialysis, and selected procedures. LN was diagnosed by renal biopsy or the American College of Rheumatology classification criteria. Renal function was assessed annually using the estimated glomerular filtration rate (GFR) or estimated proteinuria. A multistate model was used to predict 10-year cumulative …

Corrected And Republished From: The Cop9 Signalosome Interacts With And Regulates Interferon Regulatory Factor 5 Protein Stability., J. Korczeniewska, B. J. Barnes

Journal Articles

© 2018 American Society for Microbiology. The transcription factor interferon regulatory factor 5 (IRF5) exerts crucial functions in the regulation of host immunity against extracellular pathogens, DNA damage-induced apoptosis, death receptor signaling, and macrophage polarization. Tight regulation of IRF5 is thus warranted for an efficient response to extracellular stressors and for limiting autoimmune and inflammatory responses. Here we report that the COP9 signalosome (CSN), a general modulator of diverse cellular and developmental processes, associates constitutively with IRF5 and promotes its protein stability. The constitutive CSN/IRF5 interaction was identified using proteomics and confirmed by endogenous immunoprecipitations. The CSN/IRF5 interaction occurred on …

Lupus Community Panel Proposals For Optimising Clinical Trials: 2018, J. T. Merrill, S. Manzi, C. Aranow, A. Askenase, I. Bruce, E. Chakravarty, B. Chong, K. Costenbader, M. Dall'era, V. P. Werth, +7 Additional Authors

Journal Articles

© 2018 Article author(s). Formidable impediments stand in the way of treatment development for lupus. These include the unwieldy size of current trials, international competition for scarce patients, complex outcome measures and a poor understanding of these outcomes in the world at large. The heterogeneity of the disease itself coupled to superimposition of variegated background polypharmacy has created enough immunological noise to virtually ensure the failure of lupus treatment trials, leaving an understandable suspicion that at least some of the results in testing failed drugs over the years may not have been negative, but merely uninterpretable. The authors have consulted …

Study Of Flare Assessment In Systemic Lupus Erythematosus Based On Paper Patients, D. Isenberg, J. Sturgess, E. Allen, C. Aranow, A. Askanase, B. Sang-Cheol, S. Bernatsky, I. Bruce, J. Buyon, C. Gordon, +29 Additional Authors

Journal Articles

© 2017, The Authors. Arthritis Care & Research published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology. Objective: To determine the level of agreement of disease flare severity (distinguishing severe, moderate, and mild flare and persistent disease activity) in a large paper-patient exercise involving 988 individual cases of systemic lupus erythematosus. Methods: A total of 988 individual lupus case histories were assessed by 3 individual physicians. Complete agreement about the degree of flare (or persistent disease activity) was obtained in 451 cases (46%), and these provided the reference standard for the second part of the study. This …

On Statistical Modeling Of Sequencing Noise In High Depth Data To Assess Tumor Evolution, R. Rabadan, G. Bhanot, S. Marsilio, N. Chiorazzi, L. Pasqualucci, H. Khiabanian

Journal Articles

© 2017, Springer Science+Business Media, LLC, part of Springer Nature. One cause of cancer mortality is tumor evolution to therapy-resistant disease. First line therapy often targets the dominant clone, and drug resistance can emerge from preexisting clones that gain fitness through therapy-induced natural selection. Such mutations may be identified using targeted sequencing assays by analysis of noise in high-depth data. Here, we develop a comprehensive, unbiased model for sequencing error background. We find that noise in sufficiently deep DNA sequencing data can be approximated by aggregating negative binomial distributions. Mutations with frequencies above noise may have prognostic value. We evaluate …

High Mobility Group Box 1 Orchestrates Tissue Regeneration Via Cxcr4, M. Tirone, N. L. Tran, C. Ceriotti, A. Gorzanelli, M. Canepari, R. Bottinelli, A. Raucci, M. He, Y. Al-Abed, E. Vénéreau, +17 Additional Authors

Journal Articles

© 2018 Tirone et al. Inflammation and tissue regeneration follow tissue damage, but little is known about how these processes are coordinated. High Mobility Group Box 1 (HMGB1) is a nuclear protein that, when released on injury, triggers inflammation. We previously showed that HMGB1 with reduced cysteines is a chemoattractant, whereas a disulfide bond makes it a proinflammatory cytokine. Here we report that fully reduced HMGB1 orchestrates muscle and liver regeneration via CXCR4, whereas disulfide HMGB1 and its receptors TLR4/MD-2 and RAGE (receptor for advanced glycation end products) are not involved. Injection of HMGB1 accelerates tissue repair by acting on …

B Cell-Intrinsic Role For Irf5 In Tlr9/Bcr-Induced Human B Cell Activation, Proliferation, And Plasmablast Differentiation, S. De, B. Zhang, T. Shih, S. Singh, A. Winkler, R. Donnelly, B. J. Barnes

Journal Articles

© 2018 De, Zhang, Shih, Singh, Winkler, Donnelly and Barnes. Upon recognition of antigen, B cells undergo rapid proliferation followed by differentiation to specialized antibody secreting cells (ASCs). During this transition, B cells are reliant upon a multilayer transcription factor network to achieve a dramatic remodeling of the B cell transcriptional landscape. Increased levels of ASCs are often seen in autoimmune diseases and it is believed that altered expression of regulatory transcription factors play a role in this imbalance. The transcription factor interferon regulatory factor 5 (IRF5) is one such candidate as polymorphisms in IRF5 associate with risk of numerous …

Disruption Of Network For Visual Perception Of Natural Motion In Primary Dystonia, K. Fujita, W. Sako, A. Vo, S. B. Bressman, D. Eidelberg

Journal Articles

© 2017 Wiley Periodicals, Inc. In healthy subjects, brain activation in motor regions is greater during the visual perception of “natural” target motion, which complies with the two-thirds power law, than of “unnatural” motion, which does not. It is unknown whether motion perception is normally mediated by a specific network that can be altered in the setting of disease. We used block-design functional magnetic resonance imaging and covariance analysis to identify normal network topographies activated in response to “natural” versus “unnatural” motion. A visual motion perception-related pattern (VPRP) was identified in 12 healthy subjects, characterized by covarying activation responses in …

Folic Acid Derived-P5779 Mimetics Regulate Damp-Mediated Inflammation Through Disruption Of Hmgb1:Tlr4:Md-2 Axes, S. Sun, M. He, Y. Wang, H. Yang, Y. Al-Abed

Journal Articles

© 2018 Sun et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. High mobility group box 1 (HMGB1) is a damage-associated molecular pattern (DAMP) protein that mediates inflammatory responses after infection or injury. Previously, we reported a peptide inhibitor of HMGB1 (P5779) that acts by directly interrupting HMGB1/MD-2 binding. Here, fingerprint similarity search and docking studies suggest folic acid derived-drugs function as P5779 mimetopes. Molecular dynamic (MD) simulation studies demonstrate that folic acid …