Medical Sciences Commons^™

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.

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

Journal Articles

No abstract provided.

Limited Reliability Of The Spot Urine Protein/Creatinine Ratio In The Longitudinal Evaluation Of Patients With Lupus Nephritis, G. Shidham, I. Ayoub, D. Birmingham, P. Hebert, B. Rovin, B. Diamond, D. Wofsy, L. Hebert

Journal Articles

© 2018 International Society of Nephrology Introduction: Cross-sectional studies document that the spot protein/creatinine ratio (PCR) is often an inaccurate estimate of proteinuria magnitude compared with the 24-hour PCR, which is the gold standard. However, the extent to which the inaccuracy of the spot PCR varies over time and between individuals has not previously been reported. We address these crucial questions using a unique database, an National Institutes of Health trial in which lupus nephritis (LN) patients (N = 103) provided spot PCR testing each month and 24-hour PCR testing every 3 months for up to 15 months after induction …

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 …

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 …

Correction: The Cop9 Signalosome Interacts With And Regulates Interferon Regulatory Factor 5 Protein Stability [Mol Cell Biol, 38, (2013) (E00493-17)] Doi: 10.1128/Mcb.00493-17, 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 …

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 …

Characterization, Regulation, And Targeting Of Erythroid Progenitors In Normal And Disordered Human Erythropoiesis, B. M. Dulmovits, J. Hom, A. Narla, N. Mohandas, L. Blanc

Journal Articles

No abstract provided.

Unraveling Macrophage Heterogeneity In Erythroblastic Islands, K. G. Seu, J. Papoin, R. Fessler, J. Hom, G. Huang, N. Mohandas, L. Blanc, T. A. Kalfa

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No abstract provided.

Levodopa-Induced Abnormal Involuntary Movements Correlate With Altered Permeability Of The Blood-Brain-Barrier In The Basal Ganglia, R. P. Lerner, V. Francardo, K. Fujita, Z. Bimpisidis, V. A. Jourdain, C. C. Tang, S. L. Dewey, T. Chaly, M. A. Cenci, D. Eidelberg

Journal Articles

© 2017 The Author(s). Chronic levodopa treatment leads to the appearance of dyskinesia in the majority of Parkinson's disease patients. Neurovascular dysregulation in putaminal and pallidal regions is thought to be an underlying feature of this complication of treatment. We used microPET to study unilaterally lesioned 6-hydroxydopamine rats that developed levodopa-induced abnormal involuntary movements (AIMs) after three weeks of drug treatment. Animals were scanned with [15O]-labeled water and [18F]-fluorodeoxyglucose, to map regional cerebral blood flow and glucose metabolism, and with [11C]-isoaminobutyric acid (AIB), to assess blood-brain-barrier (BBB) permeability, following separate injections of levodopa or saline. Multitracer scan data were acquired …

Nicotinic Acetylcholine Receptor-Mediated Protection Of The Rat Heart Exposed To Ischemia Reperfusion, S. A. Mavropoulos, N. S. Khan, A. C. J. Levy, B. T. Faliks, C. P. Sison, V. A. Pavlov, Y. Zhang, K. Ojamaa

Journal Articles

No abstract provided.

The Frequency And Outcome Of Lupus Nephritis: Results From An International Inception Cohort Study, J. G. Hanly, A. G. O'Keeffe, L. Su, M. B. Urowitz, J. Romero-Diaz, C. Gordon, S. C. Bae, E. M. Ginzler, C. Aranow, V. Farewell, +35 Additional Authors

Journal Articles

OBJECTIVE: To determine nephritis outcomes in a prospective multi-ethnic/racial SLE inception cohort. METHODS: Patients in the Systemic Lupus International Collaborating Clinics inception cohort (

Analysis Of Igm Antibody Production And Repertoire In A Mouse Model Of Sjogren's Syndrome, J. M. Kramer, N. E. Holodick, T. C. Vizconde, I. Raman, M. Yan, Q. Z. Li, D. P. Gaile, T. L. Rothstein

Journal Articles

This study tested the hypothesis that B cells from salivary tissue are distinct in terms of proliferative capacity, immunoglobulin M secretion, repertoire, and autoantibody enrichment in Sjogren's syndrome. We sorted purified B cells from the spleen, cervical lymph nodes, and submandibular glands of a primary Sjogren's syndrome mouse model (Id3-/-). Enzyme-linked immunospot and proliferation assays were performed with stimulated B cells. We single-cell sorted B cells from the spleen, cervical lymph nodes, and submandibular gland tissue from Sjogren's syndrome mice and sequenced immunoglobulin M heavy-chain variable regions. Finally, autoantigen arrays were performed using immunoglobulin M derived from sera, cervical lymph …

Btk Inhibition Results In Impaired Cxcr4 Chemokine Receptor Surface Expression, Signaling And Function In Chronic Lymphocytic Leukemia, S. S. Chen, B. Y. Chang, S. Chang, T. Tong, S. Ham, B. Sherry, J. A. Burger, K. R. Rai, N. Chiorazzi

Journal Articles

Bruton's tyrosine kinase (BTK) is involved in the regulation of B-cell growth, migration and adhesion. The importance of BTK in cell trafficking is emphasized by the clonal contraction proceeded by lymphocytosis typical for the enzyme inhibitor, ibrutinib, in B-cell malignancies, including chronic lymphocytic leukemia (CLL). Here, we investigated BTK regulation of leukemic B-cell trafficking in a mouse model of aggressive TCL1 CLL-like disease. Inhibiting BTK by ibrutinib reduced surface membrane (sm) levels of CXCR4 but not CXCR5, CD49d and other adhesion/homing receptors. Decreased smCXCR4 levels resulted from blocking receptor signal transduction, which in turn aborted cycling from and to the …

Cytoplasmic Myosin-Exposed Apoptotic Cells Appear With Caspase-3 Activation And Enhance Cll Cell Viability, X. Cui, L. Zhang, A. R. Magli, R. Catera, X. J. Yan, D. O. Griffin, T. L. Rothstein, J. Barrientos, J. E. Kolitz, S. L. Allen, K. R. Rai, N. Chiorazzi, C. C. Chu

Journal Articles

The degree of chronic lymphocytic leukemia (CLL) B-cell antigen receptor (BCR) binding to myosin-exposed apoptotic cells (MEACs) correlates with worse patient outcomes, suggesting a link to disease activity. Therefore, we studied MEAC formation and the effects of MEAC binding on CLL cells. In cell line studies, both intrinsic (spontaneous or camptothecin-induced) and extrinsic (FasL- or anti-Fas-induced) apoptosis created a high percent of MEACs over time in a process associated with caspase-3 activation, leading to cytoplasmic myosin cleavage and trafficking to cell membranes. The involvement of common apoptosis pathways suggests that most cells can produce MEACs and indeed CLL cells themselves …

Elevated 1-Hour Plasma Glucose Levels Are Associated With Dysglycemia, Impaired Beta-Cell Function, And Insulin Sensitivity: A Pilot Study From A Real World Health Care Setting, R. Jagannathan, M. A. Sevick, H. Li, D. Fink, R. Dankner, A. Chetrit, J. Roth, M. Bergman

Journal Articles

No abstract provided.

Increased Pretreatment Serum Ifn-Beta/Alpha Ratio Predicts Non-Response To Tumour Necrosis Factor Alpha Inhibition In Rheumatoid Arthritis, T. Wampler Muskardin, P. Vashisht, J. M. Dorschner, M. A. Jensen, B. S. Chrabot, M. Kern, J. R. Curtis, R. Furie, P. K. Gregersen, T. B. Niewold, +14 Additional Authors

Journal Articles

OBJECTIVE: Studies suggest that circulating type I interferon (IFN) may predict response to biological agents in rheumatoid arthritis (RA). Prediction of response prior to initiating therapy would represent a major advancement. METHODS: We studied sera from a test set of 32 patients with RA from the Auto-immune Biomarkers Collaborative Network Consortium and a validation set of 92 patients with RA from the Treatment Efficacy and Toxicity in Rheumatoid Arthritis Database and Repository registry. The test set included those with good response or no response to tumour necrosis factor (TNF) inhibitors at 14 weeks by European League Against Rheumatism criteria. The …

Cytokine-Specific Neurograms In The Sensory Vagus Nerve., B. E. Steinberg, H. A. Silverman, M. K. Gunasekaran, T. Tsaava, E. Battinelli, A. Stiegler, C. E. Bouton, S. S. Chavan, J. J. Tracey, P. T. Huerta, +1 Additional Author

Journal Articles

The axons of the sensory, or afferent, vagus nerve transmit action potentials to the central nervous system in response to changes in the body's metabolic and physiological status. Recent advances in identifying neural circuits that regulate immune responses to infection, inflammation and injury have revealed that vagus nerve signals regulate the release of cytokines and other factors produced by macrophages. Here we record compound action potentials in the cervical vagus nerve of adult mice and reveal the specific activity that occurs following administration of the proinflammatory cytokines tumor necrosis factor (TNF) and interleukin 1β (IL-1β). Importantly, the afferent vagus neurograms …

Identification Of Iguratimod As An Inhibitor Of Macrophage Migration Inhibitory Factor (Mif) With Steroid-Sparing Potential, J. Bloom, C. Metz, S. Nalawade, J. Casabar, K. Fan Cheng, M. He, B. Sherry, T. Coleman, T. Forsthuber, Y. Al-Abed

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No abstract provided.

Dissociation Of Metabolic And Hemodynamic Levodopa Responses In The 6-Hydroxydopamine Rat Model, R. P. Lerner, Z. Bimpisidis, S. Agorastos, S. Scherrer, S. L. Dewey, M. A. Cenci, D. Eidelberg

Journal Articles

No abstract provided.

Association Analysis Of Copy Numbers Of Fc-Gamma Receptor Genes For Rheumatoid Arthritis And Other Immune-Mediated Phenotypes, L. Franke, H. El Bannoudi, D. T. Jansen, K. Kok, G. Trynka, D. Diogo, M. Swertz, K. Fransen, P. K. Gregersen, A. Zhernakova, +16 Additional Authors

Journal Articles

Segmental duplications (SDs) comprise about 5% of the human genome and are enriched for immune genes. SD loci often show copy numbers variations (CNV), which are difficult to tag with genotyping methods. CNV in the Fcgamma receptor region (FCGR) has been suggested to be associated with rheumatic diseases. The objective of this study was to delineate association of FCGR-CNV with rheumatoid arthritis (RA), coeliac disease and Inflammatory bowel disease incidence. We developed a method to accurately quantify CNV in SD loci based on the intensity values from the Immunochip platform and applied it to the FCGR locus. We determined the …

Dense Genotyping Of Immune-Related Loci In Idiopathic Inflammatory Myopathies Confirms Hla Alleles As The Strongest Genetic Risk Factor And Suggests Different Genetic Background For Major Clinical Subgroups, S. Rothwell, R. G. Cooper, I. E. Lundberg, F. W. Miller, P. K. Gregersen, J. Bowes, J. Vencovsky, K. Danko, V. Limaye, J. A. Lamb, +26 Additional Authors

Journal Articles

OBJECTIVES: The idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of rare autoimmune diseases characterised by muscle weakness and extramuscular manifestations such as skin rashes and interstitial lung disease. We genotyped 2566 IIM cases of Caucasian descent using the Immunochip; a custom array covering 186 established autoimmune susceptibility loci. The cohort was predominantly comprised of patients with dermatomyositis (DM, n=879), juvenile DM (JDM, n=481), polymyositis (PM, n=931) and inclusion body myositis (n=252) collected from 14 countries through the Myositis Genetics Consortium. RESULTS: The human leucocyte antigen (HLA) and PTPN22 regions reached genome-wide significance (p

Loci Associated With N-Glycosylation Of Human Igg Are Not Associated With Rheumatoid Arthritis: A Mendelian Randomisation Study, A. Yarwood, S. Viatte, Y. Okada, R. Plenge, K. Yamamoto, A. Barton, D. Symmons, S. Raychaudhuri, P. Gregersen, S. Eyre, +2 Additional Authors

Journal Articles

OBJECTIVES: A recent study identified 16 genetic variants associated with N-glycosylation of human IgG. Several of the genomic regions where these single nucleotide polymorphisms (SNPs) reside have also been associated with autoimmune disease (AID) susceptibility, suggesting there may be pleiotropy (genetic sharing) between loci controlling both N-glycosylation and AIDs. We investigated this by testing variants associated with levels of IgG N-glycosylation for association with rheumatoid arthritis (RA) susceptibility using a Mendelian randomisation study, and testing a subset of these variants in a less well-powered study of treatment response and severity. METHODS: SNPs showing association with IgG N-glycosylation were analysed for …

Lower Omega-3 Fatty Acids Are Associated With The Presence Of Anti-Cyclic Citrullinated Peptide Autoantibodies In A Population At Risk For Future Rheumatoid Arthritis: A Nested Case-Control Study, R. W. Gan, K. A. Young, G. O. Zerbe, M. K. Demoruelle, M. H. Weisman, J. H. Buckner, P. K. Gregersen, T. R. Mikuls, J. R. O'Dell, J. M. Norris, +4 Additional Authors

Journal Articles

OBJECTIVE: The aim of this study was to investigate omega-3 fatty acid (FA) supplement use and omega-3 FAs in erythrocyte membranes [omega-3 FA % in erythrocyte membranes (RBC)] and their association with anti-CCP autoantibodies in a population without RA, but who are at genetic risk for RA. METHODS: The multicentre Studies of the Etiology of RA (SERA) cohort includes RA-free subjects who are first-degree relatives of RA probands or are enriched with the HLA-DR4 allele. In a nested case-control study, 30 SERA cases were identified who were anti-CCP2 antibody positive. We further identified 47 autoantibody negative controls, frequency matched to …

What Is Damaging The Kidney In Lupus Nephritis?, A. Davidson

Journal Articles

Despite marked improvements in the survival of patients with severe lupus nephritis over the past 50 years, the rate of complete clinical remission after immune suppression therapy is

Whole-Exome Sequencing In Relapsing Chronic Lymphocytic Leukemia: Clinical Impact Of Recurrent Rps15 Mutations, V. Ljungstrom, D. Cortese, E. Young, T. Pandzic, L. Mansouri, K. Plevova, S. Ntoufa, P. Baliakas, N. Chiorazzi, R. Rosenquist, +24 Additional Authors

Journal Articles

Fludarabine, cyclophosphamide and rituximab (FCR) is first-line treatment for medically fit chronic lymphocytic leukemia (CLL) patients, however despite good response rates many patients eventually relapse. Whilst recent high-throughput studies have identified novel recurrent genetic lesions in adverse-prognostic CLL, the mechanisms leading to relapse after FCR therapy are not completely understood. To gain insight into this issue, we performed whole-exome sequencing of sequential samples from 41 CLL patients who were uniformly treated with FCR but relapsed after a median of 2 years. In addition to mutations with known adverse-prognostic impact (TP53, NOTCH1, ATM, SF3B1, NFKBIE, BIRC3) a large proportion of cases …