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The antiphospholipid syndrome: still an enigma.
Chaturvedi S, McCrae KR
(2015) Hematology Am Soc Hematol Educ Program 2015: 53-60
MeSH Terms: Administration, Oral, Antibodies, Antiphospholipid, Anticoagulants, Antiphospholipid Syndrome, Female, Heparin, Low-Molecular-Weight, Humans, Hydroxychloroquine, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Immune System, Inflammation, Lupus Coagulation Inhibitor, Pregnancy, Pregnancy Complications, Cardiovascular, Protein Binding, Protein Structure, Tertiary, Risk, Thrombosis, Treatment Outcome, beta 2-Glycoprotein I
Show Abstract · Added December 16, 2015
Antiphospholipid syndrome (APS) is defined by clinical manifestations that include thrombosis and/or fetal loss or pregnancy morbidity in patients with antiphospholipid antibodies (aPL). Antiphospholipid antibodies are among the most common causes of acquired thrombophilia, but unlike most of the genetic thrombophilias are associated with both venous and arterial thrombosis. Despite an abundance of clinical and basic research on aPL, a unified mechanism that explains their prothrombotic activity has not been defined; this may reflect the heterogeneity of aPL and/or the fact that they may influence multiple pro- and/or antithrombotic pathways. Antiphospholipid antibodies are directed primarily toward phospholipid binding proteins rather than phospholipid per se, with the most common antigenic target being β2-glycoprotein 1 (β2GPI) although antibodies against other targets such as prothrombin are well described. Laboratory diagnosis of aPL depends upon the detection of a lupus anticoagulant (LA), which prolongs phospholipid-dependent anticoagulation tests, and/or anticardiolipin and anti-β2-glycoprotein 1 antibodies. Indefinite anticoagulation remains the mainstay of therapy for thrombotic APS, although new strategies that may improve outcomes are emerging. Preliminary reports suggest caution in the use of direct oral anticoagulants in patients with APS-associated thrombosis. Based on somewhat limited evidence, aspirin and low molecular weight heparin are recommended for obstetrical APS. There remains a pressing need for better understanding of the pathogenesis of APS in humans, for identification of clinical and laboratory parameters that define patients at greatest risk for APS-related events, and for targeted treatment of this common yet enigmatic disorder.
© 2015 by The American Society of Hematology. All rights reserved.
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20 MeSH Terms
Fatal antimalarial-induced cardiomyopathy: report of 2 cases.
Azimian M, Gultekin SH, Hata JL, Atkinson JB, Ely KA, Fuchs HA, Mobley BC
(2012) J Clin Rheumatol 18: 363-6
MeSH Terms: Adult, Antimalarials, Arthritis, Rheumatoid, Cardiomyopathies, Chloroquine, Fatal Outcome, Female, Humans, Hydroxychloroquine, Lupus Erythematosus, Systemic, Middle Aged
Show Abstract · Added August 14, 2014
Chloroquine and hydroxychloroquine are used to chronically treat certain rheumatologic diseases and are generally considered safe. We describe 2 patients with skeletal myopathy and fatal cardiomyopathy-uncommon and underrecognized adverse effects of these agents. Both patients developed arrhythmias and heart failure, and 1 patient had documented diaphragmatic involvement. Muscle specimens showed typical vacuolar myopathy (indicative of impaired autophagy) with myeloid bodies in both patients and curvilinear bodies in 1 patient. Antimalarial-induced cardiomyopathy should be considered in patients receiving these medications with otherwise unexplained muscle weakness or cardiac symptoms. Whether autophagy enhancers can be used to manage such myopathies merits investigation.
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11 MeSH Terms
Changes in cotherapies after initiation of disease-modifying antirheumatic drug therapy in patients with rheumatoid arthritis.
Kawai VK, Grijalva CG, Arbogast PG, Curtis JR, Solomon DH, Delzell E, Chen L, Ouellet-Hellstrom R, Herrinton L, Liu L, Mitchel EF, Stein CM, Griffin MR
(2011) Arthritis Care Res (Hoboken) 63: 1415-24
MeSH Terms: Adrenal Cortex Hormones, Adult, Aged, Anti-Inflammatory Agents, Non-Steroidal, Antirheumatic Agents, Arthritis, Rheumatoid, Cohort Studies, Drug Administration Schedule, Drug Therapy, Combination, Female, Humans, Hydroxychloroquine, Isoxazoles, Leflunomide, Male, Methotrexate, Middle Aged, Narcotics, Retrospective Studies, Sulfasalazine, Time Factors, Treatment Outcome, Tumor Necrosis Factor-alpha
Show Abstract · Added December 10, 2013
Objective. We hypothesized that initiation of a new disease-modifying antirheumatic drug (DMARD) for treatment of rheumatoid arthritis (RA) would decrease the use of corticosteroids, nonsteroidal antiinflammatory drugs (NSAIDs), and narcotics.Methods. Using administrative databases, we assembled 4 retrospective cohorts of RA patients (1998-2005) and identified 5 groups initiating DMARD regimens: methotrexate (MTX) with (new MTX) or without (first MTX) use of other nonbiologic DMARDs in the previous year; new hydroxychloroquine (HCQ) and/or sulfasalazine (SSZ; new HCQ/SSZ)and new leflunomide (new LEF), both with previous use of MTX; and new tumor necrosis factor α (TNFα) antagonists(new anti-TNF). We compared within-person differences in any use of cotherapies (≥ prescription) between the 6 months before and the 6-12 months after DMARD initiation.Results. Among 32,476 DMARD initiators, the prevalence of corticosteroid, NSAID, and narcotic use increased by 15%, 5%,and 6%, respectively, in the 6 months before initiation compared to the previous 6 months, suggesting worsening of the disease. In the 6-12 months after initiation for most initiator groups, more patients stopped using corticosteroids and NSAIDs than started, with overall decreases of 8.9% (95% confidence interval [95% CI] 8.4-9.4%) for corticosteroids and 12.9% (95%CI 12.3-13.4%) for NSAIDs. The proportion of narcotic users changed little (overall decrease of 2.5%; 95% CI 1.9-3.0%).Conclusion. Use of all 3 cotherapies increased in the 6 months before initiation of new DMARD regimens for RA. Use of corticosteroids and NSAIDs decreased modestly 6-12 months after initiation, but there was only a very small decrease in narcotic use. These differential changes require further study.
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23 MeSH Terms
Chloroquine is effective against influenza A virus in vitro but not in vivo.
Vigerust DJ, McCullers JA
(2007) Influenza Other Respir Viruses 1: 189-92
MeSH Terms: Animals, Antiviral Agents, Body Weight, Chloroquine, Female, Ferrets, Influenza A virus, Mice, Mice, Inbred BALB C, Microbial Sensitivity Tests, Nasal Cavity, Orthomyxoviridae Infections
Show Abstract · Added March 22, 2016
BACKGROUND - Chloroquine is an inexpensive and widely available 9-aminoquinolone used in the management of malaria. Recently, in vitro assays suggest that chloroquine may have utility in the treatment of several viral infections including influenza.
OBJECTIVES - We sought to test whether chloroquine is effective against influenza in vivo in relevant animal models.
METHODS - The effectiveness of chloroquine at preventing or ameliorating influenza following viral challenge was assessed in established mouse and ferret disease models.
RESULTS - Although active against influenza viruses in vitro, chloroquine did not prevent the weight loss associated with influenza virus infection in mice after challenge with viruses expressing an H1 or H3 hemagglutinin protein. Similarly, clinical signs and viral replication in the nose of ferrets were not altered by treatment.
CONCLUSIONS - Although in vitro results were promising, chloroquine was not effective as preventive therapy in vivo in standard mouse and ferret models of influenza virus infection. This dampens enthusiasm for the potential utility of the drug for humans with influenza.
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12 MeSH Terms
Intracellular trafficking of recycling apolipoprotein E in Chinese hamster ovary cells.
Braun NA, Mohler PJ, Weisgraber KH, Hasty AH, Linton MF, Yancey PG, Su YR, Fazio S, Swift LL
(2006) J Lipid Res 47: 1176-86
MeSH Terms: ATP Binding Cassette Transporter 1, ATP-Binding Cassette Transporters, Animals, Apolipoprotein A-I, Apolipoproteins E, Brefeldin A, CHO Cells, Chloroquine, Cholesterol, Cricetinae, Cricetulus, Cyclodextrins, Female, Fluorescent Antibody Technique, Humans, Lipoproteins, VLDL, Microscopy, Confocal, Monensin, Protein Transport
Show Abstract · Added December 10, 2013
We have investigated apolipoprotein E (apoE) recycling in Chinese hamster ovary (CHO) cells, a peripheral cell that does not produce lipoproteins or express apoE. Using a pulse-chase protocol in which cells were pulsed with 125I-apoE-VLDL and chased for different periods, approximately 30% of the apoE internalized during the pulse was resecreted within a 4 h chase in a relatively lipid-free state. The addition of lysosomotropic agents or brefeldin A had no effect on apoE recycling. Unlike previous results with hepatocytes and macrophages, neither apoA-I nor upregulation of ABCA1 stimulated apoE recycling. However, cyclodextrin, which extracts cholesterol from plasma membrane lipid rafts, increased recycling. Confocal studies revealed that apoE, internalized during a 1 h pulse, colocalizes with early endosomal antigen-1, Rab5, Rab11a, and lysobisphosphatidic acid but not with lysosomal-associated membrane protein-1. Colocalization of apoE and Rab11a persisted even after cells had been chased for 1 h, suggesting a pool of apoE within the endosomal recycling compartment (ERC). Our data suggest that apoE recycling in CHO cells is linked to cellular cholesterol removal via the ERC and phospholipid-containing acceptors in a pathway alternative to the ABCA1-apoA-I axis.
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4 Members
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19 MeSH Terms
Activation of protein kinase A modulates trafficking of the human cardiac sodium channel in Xenopus oocytes.
Zhou J, Yi J, Hu N, George AL, Murray KT
(2000) Circ Res 87: 33-8
MeSH Terms: Animals, Chloroquine, Cyclic AMP-Dependent Protein Kinases, Enzyme Activation, Female, Humans, Ion Channel Gating, Monensin, Myocardium, Oocytes, Recombinant Proteins, Sodium Channels, Xenopus laevis
Show Abstract · Added January 20, 2015
Voltage-gated Na(+) channels are critical determinants of electrophysiological properties in the heart. Stimulation of beta-adrenergic receptors, which activate cAMP-dependent protein kinase (protein kinase A [PKA]), can alter impulse conduction in normal tissue and promote development of cardiac arrhythmias in pathological states. Recent studies demonstrate that PKA activation increases cardiac Na(+) currents, although the mechanism of this effect is unknown. To explore the molecular basis of Na(+) channel modulation by beta-adrenergic receptors, we have examined the effects of PKA activation on the recombinant human cardiac Na(+) channel, hH1. Both in the absence and the presence of hbeta(1) subunit coexpression, activation of PKA caused a slow increase in Na(+) current that did not saturate despite kinase stimulation for 1 hour. In addition, there was a small shift in the voltage dependence of channel activation and inactivation to more negative voltages. Chloroquine and monensin, compounds that disrupt plasma membrane recycling, reduced hH1 current, suggesting rapid turnover of channels at the cell surface. Preincubation with these agents also prevented the PKA-mediated rise in Na(+) current, indicating that this effect likely resulted from an increased number of Na(+) channels in the plasma membrane. Experiments using chimeric constructs of hH1 and the skeletal muscle Na(+) channel, hSKM1, identified the I-II interdomain loop of hH1 as the region responsible for the PKA effect. These results demonstrate that activation of PKA modulates both trafficking and function of the hH1 channel, with changes in Na(+) current that could either speed or slow conduction, depending on the physiological circumstances.
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13 MeSH Terms
Cholesteryl ester hydrolysis in J774 macrophages occurs in the cytoplasm and lysosomes.
Avart SJ, Bernard DW, Jerome WG, Glick JM
(1999) J Lipid Res 40: 405-14
MeSH Terms: Animals, Cell Line, Chloroquine, Cholesterol Esters, Cytoplasm, Foam Cells, Hydrolysis, Kinetics, Lysosomes, Macrophages, Mice, Microscopy, Electron, Microscopy, Polarization, Organophosphorus Compounds, Triglycerides, Umbelliferones
Show Abstract · Added December 10, 2013
The relationship of cholesteryl ester hydrolysis to the physical state of the cholesteryl ester in J774 murine macrophages was explored in cells induced to store cholesteryl esters either in anisotropic (ordered) inclusions or isotropic (liquid) inclusions. In contrast to other cell systems, the rate of cholesteryl ester hydrolysis was faster in cells containing anisotropic inclusions than in cells containing isotropic inclusions. Two contributing factors were identified. Kinetic analyses of the rates of hydrolysis are consistent with a substrate competition by co-deposited triglyceride in cells with isotropic inclusions. In addition, hydrolysis of cholesteryl esters in cells with anisotropic droplets is mediated by both cytoplasmic and lysosomal lipolytic enzymes, as shown by using the lysosomotropic agent, chloroquine, and an inhibitor of neutral cholesteryl ester hydrolase, umbelliferyl diethylphosphate. In cells containing anisotropic inclusions, hydrolysis was partially inhibited by incubation in media containing either chloroquine or umbelliferyl diethylphosphate. Together, chloroquine and umbelliferyl diethylphosphate completely inhibited hydrolysis. However, when cells containing isotropic inclusions were incubated with umbelliferyl diethylphosphate, cholesteryl ester hydrolysis was completely inhibited, but chloroquine had no effect. Transmission electron microscopy demonstrated a primarily lysosomal location for lipid droplets in cells with anisotropic droplets and both non-lysosomal and lysosomal populations of lipid droplets in cells with isotropic droplets. These results support the conclusion that there is a lysosomal component to the hydrolysis of stored cholesteryl esters in foam cells.
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16 MeSH Terms
TAP peptide transporter-independent presentation of heat-killed Sendai virus antigen on MHC class I molecules by splenic antigen-presenting cells.
Liu T, Chambers B, Diehl AD, Van Kaer L, Jondal M, Ljunggren HG
(1997) J Immunol 159: 5364-71
MeSH Terms: ATP Binding Cassette Transporter, Subfamily B, Member 2, ATP-Binding Cassette Transporters, Animals, Antigen-Presenting Cells, Antigens, Viral, CD8-Positive T-Lymphocytes, Chloroquine, Cytochalasin D, Epitopes, Histocompatibility Antigens Class I, Hot Temperature, Mice, Mice, Inbred C57BL, Respirovirus, Spleen, Tumor Cells, Cultured
Show Abstract · Added December 10, 2013
Immunization of C57BL/6 (B6) mice with heat-killed Sendai virus generates a Sendai virus-specific CD8+ T cell response. This suggests that APC have the capacity to take up and present exogenous (nonreplicative) Sendai virus Ag on MHC class I molecules. Little is known about the intracellular requirements for processing of this form of Ag and its presentation on MHC class I. Therefore, we have studied the processing and presentation of heat-killed Sendai virus Ag on MHC class I molecules in splenic APC. Heat-killed Sendai virus Ags were efficiently processed by normal B6 as well as by TAP-1(-/-) splenic APC. Presentation was MHC class I restricted, since no presentation was seen by APC from TAP-1/beta2m-/- mice that lack expression of MHC class I. Presentation occurred even in the presence of brefeldin A, but was blocked by cytochalasin D as well as chloroquine. Finally, B6 as well as TAP-1(-/-) splenic APC, loaded with heat-killed Sendai virus Ag in vitro, primed naive CD8+ T cells in vivo. These studies suggest the existence of a TAP-independent pathway for Ag presentation on MHC class I in normal splenic APC, bearing many similarities with the MHC class II pathway for Ag presentation. The present results are discussed in relation to the events underlying the processing and presentation of exogenous Ag on MHC class I, the molecular basis for CD8+ T cell priming during viral infections, and prospects for vaccine development.
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16 MeSH Terms
Changes in malaria incidence after mass drug administration in Nicaragua.
Garfield RM, Vermund SH
(1983) Lancet 2: 500-3
MeSH Terms: Adolescent, Antimalarials, Child, Child, Preschool, Chloroquine, Health Education, Humans, Infant, Malaria, Nicaragua, Plasmodium falciparum, Plasmodium vivax, Primaquine, Seasons
Show Abstract · Added March 5, 2014
Mass drug administration (MDA) in 1981 reduced the incidence rates of both Plasmodium vivax and P falciparum infection in Nicaragua. Impact on P vivax cases lasted for four months and on P falciparum for seven. Subtherapeutic primaquine doses, the shorter extrinsic cycle of P vivax in the insect vector, and the timing of MDA at a high-transmission period of the year may explain the limited effects of the campaign. Positive results of the anti-malaria campaign included improvements in case-finding and routine surveillance, the apparent prevention of at least 9200 malaria cases, the training of some 70 000 antimalaria volunteers, and the participation of about 70% of the population in anti-malarial activities.
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14 MeSH Terms
Chloroquine affects biosynthesis of Ia molecules by inhibiting dissociation of invariant (gamma) chains from alpha-beta dimers in B cells.
Nowell J, Quaranta V
(1985) J Exp Med 162: 1371-6
MeSH Terms: B-Lymphocytes, Cell Line, Chloroquine, Histocompatibility Antigens Class II, Humans, Immunoglobulin Heavy Chains, Immunoglobulin gamma-Chains
Show Abstract · Added March 27, 2014
Biosynthetic conversion of Ia oligomers from three chains (alpha, beta, gamma) to two (alpha, beta) before surface expression was inhibited in B lymphoid cells by treatment with chloroquine, resulting in the accumulation of Ia complexes composed of mature alpha and beta chains, and gamma chains at various states of sialylation. Other stages of Ia biosynthesis and processing appeared unaffected, indicating that chloroquine selectively interfered with the gamma chain dissociating mechanism itself. Similar effects were also observed with ammonium chloride. Because of the nature of such lysosomotropic agents, these results suggest that an intracellular acidic compartment may be involved in processing Ia oligomers to accomplish dissociation from gamma chains. Since chloroquine is known to inhibit Ia-restricted antigen presentation in accessory cells, our results raise the possibility that the pathways of antigen processing and Ia biosynthesis may use some common intracellular compartments.
1 Communities
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7 MeSH Terms