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Neurological Review |

Cellular Mechanisms of Central Nervous System Repair by Natural Autoreactive Monoclonal Antibodies FREE

Brent R. Wright, PhD; Arthur E. Warrington, PhD; Dale E. Edberg, PhD; Moses Rodriguez, MD
[+] Author Affiliations

Author Affiliations:Departments of Neurology (Drs Wright, Warrington, Edberg, and Rodriguez) and Immunology (Dr Rodriguez), Mayo Clinic College of Medicine, Rochester, Minnesota.


Section Editor: David E. Pleasure, MD

More Author Information
Arch Neurol. 2009;66(12):1456-1459. doi:10.1001/archneurol.2009.262.
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Published online

Natural autoreactive monoclonal IgM antibodies have demonstrated potential as therapeutic agents for central nervous system (CNS) disease. These antibodies bind surface antigens on specific CNS cells, activating intracellular repair-promoting signals. IgM antibodies that bind to surface antigens on oligodendrocytes enhanced remyelination in animal models of multiple sclerosis. IgM antibodies that bind to neurons stimulate neurite outgrowth and prevent neuron apoptosis. The neuron-binding IgM antibodies may have utility in CNS axon- or neuron-damaging diseases, such as amyotrophic lateral sclerosis, stroke, spinal cord injury, or secondary progressive multiple sclerosis. Recombinant remyelination-promoting IgM antibodies have been generated for formal toxicology studies and, after Food and Drug Administration approval, a phase 1 clinical trial. Natural autoreactive monoclonal antibodies directed against CNS cells represent novel therapeutic molecules to induce repair of the nervous system.

Figures in this Article

Natural autoreactive monoclonal IgM antibodies can promote central nervous system (CNS) protection and repair. These repair-promoting IgM antibodies have characteristics of classic natural autoreactive antibodies. For example, they are generally of the IgM isotype; encoded by germline genes with few somatic mutations; and polyreactive with low affinity with a range of structurally unrelated self and nonself antigens, specifically cytoskeleton, nuclear proteins, and DNA.1In addition, natural autoreactive monoclonal antibodies that promote CNS protection and repair bind specifically to surface plasma membrane antigens, which activate intracellular signals that promote neuron or glial cell survival2,3and cross the blood-brain barrier to accumulate within injured regions of the CNS.4Other independent investigators have also demonstrated that human natural autoreactive monoclonal antibodies cross the blood-brain barrier and localize to normal and injured CNS tissues in vivo.5The therapeutic human IgM antibodies bind to membrane antigens, which are destroyed following treatments that disrupt cellular architecture, including chemical/biochemical fixation, dehydration, solubilization, extraction or digestion, and physical/mechanical crush forces or extreme temperatures.6,7The human IgM antibodies demonstrate specific affinity only when membranes are maintained under live physiological conditions.68Cell signals are activated through direct antibody-protein-glycolipid binding interactions.2,3,911

We used a novel strategy to identify human monoclonal antibodies that promote remyelination.12Monoclonal antibodies were isolated from the serum samples of patients with monoclonal gammopathy. Selection criteria included a serum monoclonal immunoglobulin concentration of greater than 3 g/dL and a lack of neurologic or antibody-associated pathologies. We screened antibodies for binding to myelin in live CNS tissue slices and to the surface of live oligodendrocytes in culture.12Six of 52 serum-derived human IgM antibodies (sHIgM) and zero of 50 serum-derived human IgG antibodies bound in these assays. Two IgM antibodies (sHIgM22 and sHIgM46) promoted significant remyelination in vivo.12A recombinant version of sHIgM22, rHIgM22, was engineered by cloning the antibody variable region DNA sequence into an expression vector.9,13The antibody rHIgM22 promoted myelin repair in Theiler's virus infection–induced model of multiple sclerosis equal to the serum-derived form.9Gram quantities of GMP-grade rHIgM22 have been purified for formal toxicology studies prior to phase 1 clinical trials. Our development of rHIgM22 established an infrastructure for rapid translation of additional human antibodies from basic science to clinical therapies.

We successfully used the same strategy to identify additional human IgM antibodies for testing in other models of neurologic injury and disease. Two neuron-binding antibodies (sHIgM12 and sHIgM42) stimulated neurite extension.10A dendritic cell–binding antibody (B7DC XAb) mediated melanoma tumor clearance from lungs.14Several β-amyloid (Aβ1-40 and Aβ1-42)–binding human antibodies will be tested in animal models of Alzheimer disease. This strategy for identifying human antibodies that directly signal cells has the potential to generate therapeutic antibodies for a broad range of human diseases.

Several mouse IgM antibodies, including A2B5, O1, O4, HNK-1, SCH79.08, and SCH94.03, bind oligodendrocytes and promote remyelination in mouse models of multiple sclerosis (Table).7A2B5, O1, and O4 bind to surface glycolipid antigens on less differentiated oligodendrocytes.1517HNK-1, SCH79.08, SCH94.03, and rHIgM22 bind to antigens on the surface of relatively mature oligodendrocytes and myelin. We hypothesized that antibody-mediated remyelination required binding to oligodendrocyte membrane glycolipids.

Table Graphic Jump LocationTable. Properties of CNS-Reactive Signaling Antibodies

Binding IgM antibodies to CNS tissue from glycolipid knockout mice demonstrates that the molecules bound by rHIgM22 in CNS myelin depend on components of the glycolipid synthesis pathway. Binding of rHIgM22 to the plasma membrane requires the presence of a substrate of cerebroside sulfotransferase (Cst). Normally, the cerebroside galactosyltransferase (Cgt) enzyme converts ceramide to galactosylcerebroside in oligodendrocytes. Then the enzyme Cstconverts galactosylcerebroside to sulfatide. Immunofluorescence of live CNS tissue slices demonstrates the strong affinity of rHIgM22 for densely myelinated axons in wild-type mice (Figure 1). rHIgM22 and antibodies against myelin oligodendrocyte glycoprotein, expressed on mature myelin, bound to densely myelinated fiber tracts and to individual myelinated axons in the cerebellum. In contrast, rHIgM22 affinity for white matter tracts was abolished in CNS tissue from mice lacking sulfatide (Cst[−/−]).18Similarly, O4 antibody, which labels sulfatide, was absent in Cst(−/−)mice. In addition, rHIgM22 binding was not detected in other sulfatide-expressing tissues, including peripheral nervous system myelin and Schwann cells. These data support the hypothesis that rHIgM22 binding depends on 1 or more Cst-sulfated antigens present exclusively on the surface myelin of oligodendrocytes. rHIgM22 may target sulfatide or a number of sulfated antigens within the CNS, including glucosylcerebroside sulfate, lactosylceramind-3-sulfate, seminolipid, bis-sulphoganglio tetraosylceramide, and bis-sulphoganglio triaosylceramide. The data support the hypothesis that rHIgM22 recognizes a complex on oligodendrocytes dependent on 1 or more sulfated antigens at the myelin plasma membrane.

Place holder to copy figure label and caption
Figure 1.

Recombinant serum-derived human IgM22 (rHIgM22) binding interactions are dependent on a cerebroside sulfotransferase (Cst) substrate. O4 (sulfatide) (A and G), rHIgM22 (B and H), and myelin oligodendrocyte glycoprotein (MOG) (C and I) reactivity (original magnification ×100) are shown using fluorescein isothiocyanate conjugated immunostained, 4',6-diamidino-2-phenylindole (DAPI) counterstained (D-F and J-L) cerebellar sections (200 μm). Wild type (WT) showed O4, rHIgM22, and MOG reactivity. Cst(−/−)lacked O4 and rHIgM22 but showed MOG reactivity.

Graphic Jump Location

Oligodendrocytes express a repertoire of integrins during specific stages of development. Oligodendrocyte myelination correlates with the expression of laminin receptor α6β1 and vitronectin/fibronectin receptors αvβ1, αvβ3, αvβ5, and αvβ8.19Recent studies in collaboration with Jens Watzlawik, PhD, and Richard Pagano, PhD, at Mayo Clinic demonstrate a colocalization of rHIgM22 with β integrins on the plasma membrane of mature oligodendrocytes.

We propose that sulfated molecules and β integrin facilitate specific rHIgM22 binding to myelin and oligodendrocytes. In addition, the pentameric structure of the IgM molecule is necessary for remyelination and may be critical to cross-linking these antigens on the oligodendrocyte surface and inducing intracellular repair signals.

Two neuron-binding human IgM antibodies, sHIgM12 and sHIgM42, were identified using the strategy described earlier.10These antibodies supported in vitro CNS neurite extension equal to the potent neurite stimulatory molecule laminin. Both IgM antibodies bound to the surface of many types of cultured neurons but not to the surface of mature oligodendrocytes. Both IgM antibodies stimulated neurite extension in the presence of CNS myelin, which normally inhibits outgrowth. These 2 IgM antibodies are novel agents to promote neurite extension and are being tested in models of CNS disease where destructive of axons and neurons.

We propose that natural autoreactive antibodies activate endogenous cellular mechanisms to protect CNS neurons and oligodendrocytes. Remyelination-promoting IgM antibodies bind to the surface of oligodendrocytes. However, not all IgM antibodies that bind to oligodendrocytes promote remyelination. Oligodendrocyte binding did not perfectly predict the remyelinating potential of an IgM antibody in vivo. Therefore, IgM-mediated repair requires other mechanisms besides strict binding. Specific signaling events are also required. Antibody-mediated signaling in oligodendrocytes is mediated through membrane rearrangement and microdomain signaling.2Recent studies have demonstrated that mouse IgM antibody O4 and rHIgM22 bound to the surface of unfixed primary oligodendrocytes diffusely at 4°C. However, allowing membrane rearrangement at 15°C resulted in small punctate structures indicative of signaling microdomain clustering. sHIgM42 under the same conditions exhibited a similar punctate membrane pattern on neurons (Figure 2). Coincident with IgM-mediated membrane clustering on oligodendrocytes was the rapid activation of intracellular mitogen-activated protein kinases. The phosphorylation of several signaling proteins increased within 1 minute and persisted for 15 minutes in primary oligodendrocytes treated with rHIgM22.

Place holder to copy figure label and caption
Figure 2.

Neuron-binding antibody demonstrates temperature-dependent surface membrane rearrangement. Serum-derived human IgM42 (sHIgM42) binding, shown using fluorescein isothiocyanate conjugated immunostained cerebellar neurons, demonstrated native interactions at 0°C (A) and membrane rearrangements at 15°C (B). Note the formation of small punctuate immunolabeling along the neurites at 15°C but not at 0°C. rHIgM42 indicates recombinant sHIgM42.

Graphic Jump Location

The in vivo remyelination-promoting ability of an antibody correlated with its ability to induce transient calcium influx in oligodendrocytes in culture.3,9rHIgM22 binding to the oligodendrocyte plasma membrane induced signaling cascades that downregulated caspase-3 activation to prevent apoptosis. In addition, rHIgM22 altered gene expression on calcium influx through CNQX-sensitive AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid) channels in oligodendrocytes. The neuron-binding antibodies sHIgM12 and sHIgM42 demonstrated robust rescue of cultured neurons from hydrogen peroxide–induced apoptosis.

Strong parallels in character exist between remyelination-promoting IgM antibodies rHIgM22 and O4 and the neurite outgrowth–promoting IgM antibodies sHIgM42 and sHIgM12. This suggests a common membrane-rearrangement mechanism that recruits signaling molecules into clustered microdomains and ultimately leads to specific cell responses in vitro and in vivo (Figure 3).

Place holder to copy figure label and caption
Figure 3.

Mechanism of cellular central nervous system repair mediated by human monoclonal antibodies. IgM binding with glycolipids and proteins produces membrane rearrangements. Signaling pathways initiate calcium influx and mitogen-activated protein kinases while blocking caspase-3. Transcription promotes central nervous system protection and repair. P-MAPK indicates mitogen-activated protein kinase phosphorylation.

Graphic Jump Location

We propose this class of autoreactive antibodies activates the cellular process of CNS protection and repair through direct signaling cascades. Although each antibody reacts to unique cell-specific antigens, binding to the appropriate cells activates the target cell in a conserved manner. Defining the common signaling components regulating changes in specific cells may lead to an understanding of the underlying mechanism of antibody-induced repair and result in the design of better strategies to promote remyelination and protect axons.

Correspondence:Moses Rodriguez, MD, Department of Neurology, Mayo Clinic College of Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (rodriguez.moses@mayo.edu).

Accepted for Publication:February 18, 2009.

Author Contributions:Study concept and design: Wright, Warrington, and Rodriguez. Acquisition of data: Wright, Warrington, and Rodriguez. Analysis and interpretation of data: Wright, Warrington, Edberg, and Rodriguez. Drafting of the manuscript: Wright, Warrington, and Rodriguez. Critical revision of the manuscript for important intellectual content: Wright, Warrington, Edberg, and Rodriguez. Obtained funding: Warrington and Rodriguez. Administrative, technical, and material support: Rodriguez. Study supervision: Warrington and Rodriguez.

Financial Disclosure:Patents for promotion of remyelination are issued and owned by Mayo Clinic.

Funding/Support:This work was supported by National Institutes of Health grants R01 NS 24180, R01 NS 32129, P01 NS 38468, R01 CA 104996, and R01 CA096859; National Multiple Sclerosis Society grants RG 317 2-B-8 and CA 1011 A8-3; Multiple Sclerosis Society of Canada; Applebaum Foundation; Hilton Foundation; Peterson Foundation; and Acorda Therapeutics, Inc (Hawthorne, New York).

Coutinho  AKazatchkine  MDAvrameas  S Natural autoantibodies. Curr Opin Immunol 1995;7 (6) 812- 818
PubMed Link to Article
Howe  CLBieber  AJWarrington  AEPease  LRRodriguez  M Antiapoptotic signaling by a remyelination-promoting human antimyelin antibody. Neurobiol Dis 2004;15 (1) 120- 131
PubMed Link to Article
Paz Soldán  MMWarrington  AEBieber  AJ  et al.  Remyelination-promoting antibodies activate distinct Ca2+ influx pathways in astrocytes and oligodendrocytes: relationship to the mechanism of myelin repair. Mol Cell Neurosci 2003;22 (1) 14- 24
PubMed Link to Article
Pirko  ICiric  BGamez  J  et al.  A human antibody that promotes remyelination enters the CNS and decreases lesion load as detected by T2-weighted spinal cord MRI in a virus-induced murine model of MS. FASEB J 2004;18 (13) 1577- 1579
PubMed
Banks  WAFarr  SAMorley  JEWolf  KMGeylis  VSteinitz  M Anti-amyloid beta protein antibody passage across the blood-brain barrier in the SAMP8 mouse model of Alzheimer's disease: an age-related selective uptake with reversal of learning impairment. Exp Neurol 2007;206 (2) 248- 256
PubMed Link to Article
Miller  DJRodriguez  M A monoclonal autoantibody that promotes central nervous system remyelination in a model of multiple sclerosis is a natural autoantibody encoded by germline immunoglobulin genes. J Immunol 1995;154 (5) 2460- 2469
PubMed
Asakura  KMiller  DJPease  LRRodriguez  M Targeting of IgMkappa antibodies to oligodendrocytes promotes CNS remyelination. J Neurosci 1998;18 (19) 7700- 7708
PubMed
Miller  DJNjenga  MKParisi  JERodriguez  M Multi-organ reactivity of a monoclonal natural autoantibody that promotes remyelination in a mouse model of multiple sclerosis. J Histochem Cytochem 1996;44 (9) 1005- 1011
PubMed Link to Article
Mitsunaga  YCiric  BVan Keulen  V  et al.  Direct evidence that a human antibody derived from patient serum can promote myelin repair in a mouse model of chronic-progressive demyelinating disease. FASEB J 2002;16 (10) 1325- 1327
PubMed
Warrington  AEBieber  AJVan Keulen  VCiric  BPease  LRRodriguez  M Neuron-binding human monoclonal antibodies support central nervous system neurite extension. J Neuropathol Exp Neurol 2004;63 (5) 461- 473
PubMed
Howe  CLMayoral  SRodriguez  M Activated microglia stimulate transcriptional changes in primary oligodendrocytes via IL-1beta. Neurobiol Dis 2006;23 (3) 731- 739
PubMed Link to Article
Warrington  AEAsakura  KBieber  AJ  et al.  Human monoclonal antibodies reactive to oligodendrocytes promote remyelination in a model of multiple sclerosis. Proc Natl Acad Sci U S A 2000;97 (12) 6820- 6825
PubMed Link to Article
Warrington  AEBieber  AJCiric  BPease  LRVan Keulen  VRodriguez  M A recombinant human IgM promotes myelin repair after a single, very low dose. J Neurosci Res 2007;85 (5) 967- 976
PubMed Link to Article
Radhakrishnan  SNguyen  LTCiric  B  et al.  Immunotherapeutic potential of B7-DC (PD-L2) cross-linking antibody in conferring antitumor immunity. Cancer Res 2004;64 (14) 4965- 4972
PubMed Link to Article
Fredman  PMagnani  JLNirenberg  MGinsburg  V Monoclonal antibody A2B5 reacts with many gangliosides in neuronal tissue. Arch Biochem Biophys 1984;233 (2) 661- 666
PubMed Link to Article
Sommer  ISchachner  M Monoclonal antibodies (O1 to O4) to oligodendrocyte cell surfaces: an immunocytological study in the central nervous system. Dev Biol 1981;83 (2) 311- 327
PubMed Link to Article
Chou  DKIlyas  AAEvans  JECostello  CQuarles  RHJungalwala  FB Structure of sulfated glucuronyl glycolipids in the nervous system reacting with HNK-1 antibody and some IgM paraproteins in neuropathy. J Biol Chem 1986;261 (25) 11717- 11725
PubMed
Hirahara  YBansal  RHonke  KIkenaka  KWada  Y Sulfatide is a negative regulator of oligodendrocyte differentiation: development in sulfatide-null mice. Glia 2004;45 (3) 269- 277
PubMed Link to Article
Milner  RFrost  ENishimura  S  et al.  Expression of alpha vbeta3 and alpha vbeta8 integrins during oligodendrocyte precursor differentiation in the presence and absence of axons. Glia 1997;21 (4) 350- 360
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Recombinant serum-derived human IgM22 (rHIgM22) binding interactions are dependent on a cerebroside sulfotransferase (Cst) substrate. O4 (sulfatide) (A and G), rHIgM22 (B and H), and myelin oligodendrocyte glycoprotein (MOG) (C and I) reactivity (original magnification ×100) are shown using fluorescein isothiocyanate conjugated immunostained, 4',6-diamidino-2-phenylindole (DAPI) counterstained (D-F and J-L) cerebellar sections (200 μm). Wild type (WT) showed O4, rHIgM22, and MOG reactivity. Cst(−/−)lacked O4 and rHIgM22 but showed MOG reactivity.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Neuron-binding antibody demonstrates temperature-dependent surface membrane rearrangement. Serum-derived human IgM42 (sHIgM42) binding, shown using fluorescein isothiocyanate conjugated immunostained cerebellar neurons, demonstrated native interactions at 0°C (A) and membrane rearrangements at 15°C (B). Note the formation of small punctuate immunolabeling along the neurites at 15°C but not at 0°C. rHIgM42 indicates recombinant sHIgM42.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Mechanism of cellular central nervous system repair mediated by human monoclonal antibodies. IgM binding with glycolipids and proteins produces membrane rearrangements. Signaling pathways initiate calcium influx and mitogen-activated protein kinases while blocking caspase-3. Transcription promotes central nervous system protection and repair. P-MAPK indicates mitogen-activated protein kinase phosphorylation.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable. Properties of CNS-Reactive Signaling Antibodies

References

Coutinho  AKazatchkine  MDAvrameas  S Natural autoantibodies. Curr Opin Immunol 1995;7 (6) 812- 818
PubMed Link to Article
Howe  CLBieber  AJWarrington  AEPease  LRRodriguez  M Antiapoptotic signaling by a remyelination-promoting human antimyelin antibody. Neurobiol Dis 2004;15 (1) 120- 131
PubMed Link to Article
Paz Soldán  MMWarrington  AEBieber  AJ  et al.  Remyelination-promoting antibodies activate distinct Ca2+ influx pathways in astrocytes and oligodendrocytes: relationship to the mechanism of myelin repair. Mol Cell Neurosci 2003;22 (1) 14- 24
PubMed Link to Article
Pirko  ICiric  BGamez  J  et al.  A human antibody that promotes remyelination enters the CNS and decreases lesion load as detected by T2-weighted spinal cord MRI in a virus-induced murine model of MS. FASEB J 2004;18 (13) 1577- 1579
PubMed
Banks  WAFarr  SAMorley  JEWolf  KMGeylis  VSteinitz  M Anti-amyloid beta protein antibody passage across the blood-brain barrier in the SAMP8 mouse model of Alzheimer's disease: an age-related selective uptake with reversal of learning impairment. Exp Neurol 2007;206 (2) 248- 256
PubMed Link to Article
Miller  DJRodriguez  M A monoclonal autoantibody that promotes central nervous system remyelination in a model of multiple sclerosis is a natural autoantibody encoded by germline immunoglobulin genes. J Immunol 1995;154 (5) 2460- 2469
PubMed
Asakura  KMiller  DJPease  LRRodriguez  M Targeting of IgMkappa antibodies to oligodendrocytes promotes CNS remyelination. J Neurosci 1998;18 (19) 7700- 7708
PubMed
Miller  DJNjenga  MKParisi  JERodriguez  M Multi-organ reactivity of a monoclonal natural autoantibody that promotes remyelination in a mouse model of multiple sclerosis. J Histochem Cytochem 1996;44 (9) 1005- 1011
PubMed Link to Article
Mitsunaga  YCiric  BVan Keulen  V  et al.  Direct evidence that a human antibody derived from patient serum can promote myelin repair in a mouse model of chronic-progressive demyelinating disease. FASEB J 2002;16 (10) 1325- 1327
PubMed
Warrington  AEBieber  AJVan Keulen  VCiric  BPease  LRRodriguez  M Neuron-binding human monoclonal antibodies support central nervous system neurite extension. J Neuropathol Exp Neurol 2004;63 (5) 461- 473
PubMed
Howe  CLMayoral  SRodriguez  M Activated microglia stimulate transcriptional changes in primary oligodendrocytes via IL-1beta. Neurobiol Dis 2006;23 (3) 731- 739
PubMed Link to Article
Warrington  AEAsakura  KBieber  AJ  et al.  Human monoclonal antibodies reactive to oligodendrocytes promote remyelination in a model of multiple sclerosis. Proc Natl Acad Sci U S A 2000;97 (12) 6820- 6825
PubMed Link to Article
Warrington  AEBieber  AJCiric  BPease  LRVan Keulen  VRodriguez  M A recombinant human IgM promotes myelin repair after a single, very low dose. J Neurosci Res 2007;85 (5) 967- 976
PubMed Link to Article
Radhakrishnan  SNguyen  LTCiric  B  et al.  Immunotherapeutic potential of B7-DC (PD-L2) cross-linking antibody in conferring antitumor immunity. Cancer Res 2004;64 (14) 4965- 4972
PubMed Link to Article
Fredman  PMagnani  JLNirenberg  MGinsburg  V Monoclonal antibody A2B5 reacts with many gangliosides in neuronal tissue. Arch Biochem Biophys 1984;233 (2) 661- 666
PubMed Link to Article
Sommer  ISchachner  M Monoclonal antibodies (O1 to O4) to oligodendrocyte cell surfaces: an immunocytological study in the central nervous system. Dev Biol 1981;83 (2) 311- 327
PubMed Link to Article
Chou  DKIlyas  AAEvans  JECostello  CQuarles  RHJungalwala  FB Structure of sulfated glucuronyl glycolipids in the nervous system reacting with HNK-1 antibody and some IgM paraproteins in neuropathy. J Biol Chem 1986;261 (25) 11717- 11725
PubMed
Hirahara  YBansal  RHonke  KIkenaka  KWada  Y Sulfatide is a negative regulator of oligodendrocyte differentiation: development in sulfatide-null mice. Glia 2004;45 (3) 269- 277
PubMed Link to Article
Milner  RFrost  ENishimura  S  et al.  Expression of alpha vbeta3 and alpha vbeta8 integrins during oligodendrocyte precursor differentiation in the presence and absence of axons. Glia 1997;21 (4) 350- 360
PubMed Link to Article

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