Hmgb1-Driven Inflammation And Intimal Hyperplasia After Arterial Injury Involves Cell-Specific Actions Mediated By Tlr4,
2015
Northwell Health
Hmgb1-Driven Inflammation And Intimal Hyperplasia After Arterial Injury Involves Cell-Specific Actions Mediated By Tlr4, J. Cai, H. Yuan, Q. Wang, H. Yang, Yousef Al-Abed, Z. Hua, J. Wang, D. Chen, Kevin J. Tracey, A. F. Chen, +7 Additional Authors
Journal Articles
No abstract provided.
Integrative Neuroscience Approach To Neuropsychiatric Lupus,
2015
Zucker School of Medicine at Hofstra/Northwell
Integrative Neuroscience Approach To Neuropsychiatric Lupus, P. T. Huerta, E. L. Gibson, C. Rey, T. S. Huerta
Journal Articles
We present a succinct review of our approach to study the interactions between the DNA-reactive antibodies that cross-react with the GluN2A and GluN2B subunits of the N-methyl-D-aspartate receptor, denoted DNRABs, and their brain targets in subjects with neuropsychiatric systemic lupus erythematosus (NPSLE). We have analyzed the DNRAB-based brain symptomatology in mouse models of NPSLE by using an integrative neuroscience approach, which includes behavioral assessment coupled with electrophysiological studies of neural networks and synaptic connections in target brain regions, such as the CA1 region of the hippocampus. Our results suggest a framework for understanding the interactions between immune factors and neural …
Effects Of Levodopa On Regional Cerebral Metabolism And Blood Flow,
2015
Northwell Health
Effects Of Levodopa On Regional Cerebral Metabolism And Blood Flow, J. H. Ko, R. P. Lerner, D. Eidelberg
Journal Articles
Levodopa (l-dopa) has been at the forefront of antiparkinsonian therapy for a half century. Recent advances in functional brain imaging have contributed substantially to the understanding of the effects of l-dopa and other dopaminergic treatment on the activity of abnormal motor and cognitive brain circuits in Parkinson's disease patients. Progress has also been made in understanding the functional pathology of dyskinesias, a common side effect of l-dopa treatment, at both regional and network levels. Here, we review these studies, focusing mainly on the new mechanistic insights provided by metabolic brain imaging and network analysis. (c) 2014 International Parkinson and Movement …
Reproducibility Of A Parkinsonism-Related Metabolic Brain Network In Non-Human Primates: A Descriptive Pilot Study With Fdg Pet,
2015
Northwell Heatlh
Reproducibility Of A Parkinsonism-Related Metabolic Brain Network In Non-Human Primates: A Descriptive Pilot Study With Fdg Pet, Y. L. Ma, T. H. Johnston, S. C. Peng, C. T. Zuo, J. B. Koprich, S. H. Fox, Y. H. Guan, D. Eidelberg, J. M. Brotchie
Journal Articles
Background: We have previously defined a parkinsonism-related metabolic brain network in rhesus macaques using a high-resolution research positron emission tomography camera. This brief article reports a descriptive pilot study to assess the reproducibility of network activity and regional glucose metabolism in independent parkinsonian macaques using a clinical positron emission tomography/CT camera. Methods: [F-18]fluorodeoxyglucose PET scans were acquired longitudinally over 3 months in three drug-naive parkinsonian and three healthy control cynomolgus macaques. Group difference and test-retest stability in network activity and regional glucose metabolism were evaluated graphically, using all brain images from these macaques. Results: Comparing the parkinsonian macaques with the …
Abnormal Metabolic Pattern Associated With Cognitive Impairment In Parkinson's Disease: A Validation Study,
2015
Northwell Health
Abnormal Metabolic Pattern Associated With Cognitive Impairment In Parkinson's Disease: A Validation Study, S. K. Meles, C. C. Tang, L. K. Teune, R. A. Dierckx, V. Dhawan, P. J. Mattis, K. L. Leenders, D. Eidelberg
Journal Articles
Cognitive deficits in Parkinson's disease (PD) have been associated with a specific metabolic covariance pattern. Although the expression of this PD cognition-related pattern (PDCP) correlates with neuropsychological performance, it is not known whether the PDCP topography is reproducible across PD populations. We therefore sought to identify a PDCP topography in a new sample comprised of 19 Dutch PD subjects. Network analysis of metabolic scans from these individuals revealed a significant PDCP that resembled the original network topography. Expression values for the new PDCP correlated (P = 0.001) with executive dysfunction on the Frontal Assessment Battery (FAB). Subject scores for the …
The Visual Perception Of Natural Motion: Abnormal Task-Related Neural Activity In Dyt1 Dystonia,
2015
Northwell Health
The Visual Perception Of Natural Motion: Abnormal Task-Related Neural Activity In Dyt1 Dystonia, W. Sako, K. Fujita, A. Vo, J. C. Rucker, J. R. Rizzo, M. Niethammer, M. Carbon, S. B. Bressman, A. M. Ulug, D. Eidelberg
Journal Articles
Although primary dystonia is defined by its characteristic motor manifestations, non-motor signs and symptoms have increasingly been recognized in this disorder. Recent neuroimaging studies have related the motor features of primary dystonia to connectivity changes in cerebello-thalamo-cortical pathways. It is not known, however, whether the non-motor manifestations of the disorder are associated with similar circuit abnormalities. To explore this possibility, we used functional magnetic resonance imaging to study primary dystonia and healthy volunteer subjects while they performed a motion perception task in which elliptical target trajectories were visually tracked on a computer screen. Prior functional magnetic resonance imaging studies of …
Maternal Antibodies And Developing Blood-Brain Barrier,
2015
Zucker School of Medicine at Hofstra/Northwell
Maternal Antibodies And Developing Blood-Brain Barrier, C. Kowal, A. Athanassiou, H. Chen, B. Diamond
Journal Articles
No abstract provided.
Md-2 Is Required For Disulfide Hmgb1-Dependent Tlr4 Signaling,
2015
Northwell Health
Md-2 Is Required For Disulfide Hmgb1-Dependent Tlr4 Signaling, H. Yang, H. Wang, Z. Ju, A. A. Ragab, W. Long, S. I. Valdes-Ferrer, M. He, J. Li, B. Lu, J. Roth, S. S. Chavan, K. J. Tracey, Y. Al-Abed, +10 Additional Authors
Journal Articles
Innate immune receptors for pathogen- and damage-associated molecular patterns (PAMPs and DAMPs) orchestrate inflammatory responses to infection and injury. Secreted by activated immune cells or passively released by damaged cells, HMGB1 is subjected to redox modification that distinctly influences its extracellular functions. Previously, it was unknown how the TLR4 signalosome distinguished between HMGB1 isoforms. Here we demonstrate that the extracellular TLR4 adaptor, myeloid differentiation factor 2 (MD-2), binds specifically to the cytokine-inducing disulfide isoform of HMGB1, to the exclusion of other isoforms. Using MD-2-deficient mice, as well as MD-2 silencing in macrophages, we show a requirement for HMGB1-dependent TLR4 signaling. …
Modular Analysis Of Peripheral Blood Gene Expression In Rheumatoid Arthritis Captures Reproducible Gene Expression Changes In Tumor Necrosis Factor Responders,
2015
Northwell Health
Modular Analysis Of Peripheral Blood Gene Expression In Rheumatoid Arthritis Captures Reproducible Gene Expression Changes In Tumor Necrosis Factor Responders, M. Oswald, M. E. Curran, S. L. Lamberth, R. M. Townsend, J. D. Hamilton, D. N. Chernoff, M. Kern, C. M. Pond, A. Lee, P. K. Gregersen, +3 Additional Authors
Journal Articles
Objective. To establish whether the analysis of whole-blood gene expression is useful in predicting or monitoring response to anti-tumor necrosis factor (anti-TNF) therapy in patients with rheumatoid arthritis (RA). Methods. Whole-blood RNA (using a PAXgene system to stabilize whole-blood RNA in the collection tube) was obtained at baseline and at 14 weeks from 3 independent cohorts, consisting of a combined total of 240 RA patients who were beginning therapy with anti-TNF. We used an approach to gene expression analysis that is based on modular patterns of gene expression, or modules. Results. Good and moderate responders according to the European League …
Mood Disorders In Systemic Lupus Erythematosus: Results From An International Inception Cohort Study,
2015
Zucker School of Medicine at Hofstra/Northwell
Mood Disorders In Systemic Lupus Erythematosus: Results From An International Inception Cohort Study, J. G. Hanly, L. Su, M. B. Urowitz, J. Romero-Diaz, C. Gordon, S. C. Bae, S. Bernatsky, A. E. Clarke, C. Aranow, V. Farewell, +32 Additional Authors
Journal Articles
ObjectiveTo examine the frequency, characteristics, and outcome of mood disorders, as well as clinical and autoantibody associations, in a multiethnic/racial, prospective inception cohort of patients with systemic lupus erythematosus (SLE). MethodsPatients were assessed annually for mood disorders (4 types, according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) and 18 other neuropsychiatric events. Global disease activity scores (SLE Disease Activity Index 2000 [SLEDAI-2K]), damage scores (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index [SDI]), and Short Form 36 subscales, mental and physical component summary scores were collected. Time to event, linear and ordinal regressions, and …
Not All Ighv3-21 Chronic Lymphocytic Leukemias Are Equal: Prognostic Considerations,
2015
Northwell Health
Not All Ighv3-21 Chronic Lymphocytic Leukemias Are Equal: Prognostic Considerations, P. Baliakas, A. Agathangelidis, A. Hadzidimitriou, L. A. Sutton, E. Minga, A. Tsanousa, X. J. Yan, C. C. Chu, N. Chiorazzi, K. Stamatopoulos, +38 Additional Authors
Journal Articles
An unresolved issue in chronic lymphocytic leukemia (CLL) is whether IGHV3-21 gene usage, in general, or the expression of stereotyped B-cell receptor immunoglobulin defining subset # 2 (IGHV3-21/IGLV3-21), in particular, determines outcome for IGHV3-21-utilizing cases. We reappraised this issue in 8593 CLL patients of whom 437 (5%) used the IGHV3-21 gene with 254/437 (58%) classified as subset # 2. Within subset # 2, immunoglobulin heavy variable (IGHV)-mutated cases predominated, whereas non-subset # 2/IGHV3-21 was enriched for IGHV-unmutated cases (P =.002). Subset # 2 exhibited significantly shorter time-to-first-treatment (TTFT) compared with non-subset # 2/IGHV3-21 (22 vs 60 months, P =.001). No …
The Osteopontin Transgenic Mouse Is A New Model For Sjogren's Syndrome,
2015
Northwell Health
The Osteopontin Transgenic Mouse Is A New Model For Sjogren's Syndrome, S. Husain-Krautter, J. M. Kramer, W. T. Li, B. C. Guo, T. L. Rothstein
Journal Articles
Osteopontin (Opn) is a cytokine involved in both physiological and pathological processes, and is elevated in many autoimmune diseases. Sjogren's syndrome (SS) is an autoimmune disease with a strong female predilection characterized by lymphocytic infiltration of exocrine glands. We hypothesized that Opn contributes to SS pathogenesis. We examined an established SS model and found increased Opn locally and systemically. Next, we examined Opn transgenic (Opn Tg) mice for evidence of SS. Opn Tg animals exhibited lymphocytic infiltration of salivary and lacrimal glands, and Opn co-localized with the infiltrates. Moreover, saliva production was reduced, and SS autoantibodies were observed in the …
Partitioning Heritability By Functional Annotation Using Genome-Wide Association Summary Statistics,
2015
Northwell Health
Partitioning Heritability By Functional Annotation Using Genome-Wide Association Summary Statistics, H. K. Finucane, B. Bulik-Sullivan, A. Gusev, G. Trynka, Y. Reshef, P. R. Loh, V. Anttila, S. Purcell, E. Stahl, A. L. Price, +12 Additional Authors
Journal Articles
Recent work has demonstrated that some functional categories of the genome contribute disproportionately to the heritability of complex diseases. Here we analyze a broad set of functional elements, including cell type-specific elements, to estimate their polygenic contributions to heritability in genome-wide association studies (GWAS) of 17 complex diseases and traits with an average sample size of 73,599. To enable this analysis, we introduce a new method, stratified LD score regression, for partitioning heritability from GWAS summary statistics while accounting for linked markers. This new method is computationally tractable at very large sample sizes and leverages genome-wide information. Our findings include …
Randomized, Double-Blind, Placebo-Controlled Trial Of The Effect Of Vitamin D3 On The Interferon Signature In Patients With Systemic Lupus Erythematosus,
2015
Zucker School of Medicine at Hofstra/Northwell
Randomized, Double-Blind, Placebo-Controlled Trial Of The Effect Of Vitamin D3 On The Interferon Signature In Patients With Systemic Lupus Erythematosus, C. Aranow, D. L. Kamen, M. Dall'era, E. M. Massarotti, M. C. Mackay, F. Koumpouras, A. Coca, W. W. Chatham, M. E. Clowse, L. G. Criscione-Schreiber, S. Callahan, E. A. Goldmuntz, L. Keyes-Elstein, M. Oswald, P. K. Gregersen, B. Diamond
Journal Articles
OBJECTIVE: Vitamin D modulates the immune response and blocks induction of an interferon (IFN) signature by systemic lupus erythematosus (SLE) sera. This study was undertaken to investigate the effects of vitamin D supplementation on the IFN signature in patients with SLE. METHODS: SLE patients (n = 57) with stable, inactive disease, a serum 25-hydroxyvitamin D (25[OH]D) level/=30 ng/ml) was not observed in any of the patients who were receiving placebo, while repletion was observed in 16 of 33 patients receiving vitamin D3 . The percentage of patients with an IFN signature response did not differ among the treatment groups. Moreover, …
Rewiring Of Sigm-Mediated Intracellular Signaling Through The Cd180 Toll-Like Receptor,
2015
Northwell Health
Rewiring Of Sigm-Mediated Intracellular Signaling Through The Cd180 Toll-Like Receptor, N. Porakishvili, K. Vispute, A. J. Steele, N. Rajakaruna, N. Kulikova, T. Tsertsvadze, R. N. Damle, K. R. Rai, N. Chiorazzi, P. M. Lydyard, +2 Additional Authors
Journal Articles
Chronic lymphocytic leukemia (CLL) development and progression are thought to be driven by unknown antigens/autoantigens through the B cell receptor (BCR) and environmental signals for survival and expansion including toll-like receptor (TLR) ligands. CD180/RP105, a membrane-associated orphan receptor of the TLR family, induces normal B cell activation and proliferation and is expressed by approximately 60% of CLL samples. Half of these respond to ligation with anti-CD180 antibody by increased activation/phosphorylation of protein kinases associated with BCR signaling. Hence CLL cells expressing both CD180 and the BCR could receive signals via both receptors. Here we investigated cross-talk between BCR and CD180-mediated …
Rodent Models Of Neuroinflammation For Alzheimer's Disease,
2015
Northwell Health
Rodent Models Of Neuroinflammation For Alzheimer's Disease, A. Nazem, R. Sankowski, M. Bacher, Y. Al-Abed
Journal Articles
Alzheimer's disease remains incurable, and the failures of current disease-modifying strategies for Alzheimer's disease could be attributed to a lack of in vivo models that recapitulate the underlying etiology of late-onset Alzheimer's disease. The etiology of late-onset Alzheimer's disease is not based on mutations related to amyloid-beta (A beta) or tau production which are currently the basis of in vivo models of Alzheimer's disease. It has recently been suggested that mechanisms like chronic neuroinflammation may occur prior to amyloid-beta and tau pathologies in late-onset Alzheimer's disease. The aim of this study is to analyze the characteristics of rodent models of …
A Selective Novel Peroxisome Proliferator-Activated Receptor ( Ppar)-Alpha Antagonist Induces Apoptosis And Inhibits Proliferation Of Cll Cells In Vitro And In Vivo,
2015
Zucker School of Medicine at Hofstra/Northwell
A Selective Novel Peroxisome Proliferator-Activated Receptor ( Ppar)-Alpha Antagonist Induces Apoptosis And Inhibits Proliferation Of Cll Cells In Vitro And In Vivo, D. Messmer, K. Lorrain, K. Stebbins, Y. Bravo, N. Stock, G. Cabrera, L. Correa, N. Chiorazzi, X. J. Yan, D. Lorrain, +4 Additional Authors
Journal Articles
Tumor-specific metabolic changes can reveal new therapeutic targets. Our findings implicate a supporting role for fatty acid metabolism in chronic lymphocytic leukemia (CLL) cell survival. Peroxisome proliferator-activated receptor (PPAR)-alpha, a major transcriptional regulator of fatty acid oxidation, was recently shown to be upregulated in CLL. To evaluate PPAR alpha as a potential therapeutic target, we developed a highly selective, potent small molecule antagonist of PPAR alpha, NXT629. NXT629 inhibited agonist-induced transcription of PPAR alpha-regulated genes, demonstrating target engagement in CLL cells. Furthermore, NXT629 induced apoptosis of CLL cells even in the presence of a protective microenvironment. To mimic the proliferative …
Tlr-9 And Il-15 Synergy Promotes The In Vitro Clonal Expansion Of Chronic Lymphocytic Leukemia B Cells,
2015
Zucker School of Medicine at Hofstra/Northwell
Tlr-9 And Il-15 Synergy Promotes The In Vitro Clonal Expansion Of Chronic Lymphocytic Leukemia B Cells, P. K. A. Mongini, R. Gupta, E. Boyle, J. Nieto, H. Lee, J. Stein, J. Bandovic, T. Stankovic, J. Barrientos, J. E. Kolitz, S. L. Allen, K. Rai, C. C. Chu, N. Chiorazzi
Journal Articles
Clinical progression of B cell chronic lymphocytic leukemia (B-CLL) reflects the clone's Ag receptor (BCR) and involves stroma-dependent B-CLL growth within lymphoid tissue. Uniformly elevated expression of TLR-9, occasional MYD88 mutations, and BCR specificity for DNA or Ags physically linked to DNA together suggest that TLR-9 signaling is important in driving B-CLL growth in patients. Nevertheless, reports of apoptosis after B-CLL exposure to CpG oligodeoxynucleotide (ODN) raised questions about a central role for TLR-9. Because normal memory B cells proliferate vigorously to ODN+IL-15, a cytokine found in stromal cells of bone marrow, lymph nodes, and spleen, we examined whether this …
Immune Dysregulation In Patients Persistently Infected With Human Papillomaviruses 6 And 11,
2015
Northwell Researcher
Immune Dysregulation In Patients Persistently Infected With Human Papillomaviruses 6 And 11, A. V. Lucs, J. A. Devoti, L. Hatam, A. Afzal, A. L. Abramson, B. M. Steinberg, V. R. Bonagura
Journal Articles
Human Papillomaviruses (HPVs) 6 and 11 are part of a large family of small DNA viruses, some of which are commensal. Although much of the population can contain or clear infection with these viruses, there is a subset of individuals who develop persistent infection that can cause significant morbidity and on occasion mortality. Depending on the site of infection, patients chronically infected with these viruses develop either recurrent, and on occasion, severe genital warts or recurrent respiratory papillomas that can obstruct the upper airway. The HPV-induced diseases described are likely the result of a complex and localized immune suppressive milieu …
N-Acetylcysteine Attenuates Tumor Necrosis Factor Alpha Levels In Autoimmune Inner Ear Disease Patients,
2015
Hofstra Northwell School of Medicine
N-Acetylcysteine Attenuates Tumor Necrosis Factor Alpha Levels In Autoimmune Inner Ear Disease Patients, S. Pathak, C. Stern, A. Vambutas
Journal Articles
Autoimmune inner ear disease (AIED) is a poorly understood disease marked by bilateral, rapidly progressive hearing loss triggered by unknown stimuli, which is corticosteroid responsive in 60 % of patients. Although the mechanism of the disease is not precisely understood, a complex interaction of cytokines is believed to contribute toward the inflammatory disease process and hearing loss. Previously, we showed the role of TNF-alpha in steroid-sensitive and IL-1beta in steroid-resistant immune-mediated hearing loss. N-Acetylcysteine (NAC), a broad spectrum antioxidant, has been effective in other autoimmune disorders. Other studies have shown NAC to have a protective adjunct role in human idiopathic …
