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1.
Anesth Analg ; 98(6): 1595-1603, 2004 Jun.
Article in English | MEDLINE | ID: mdl-15155311

ABSTRACT

UNLABELLED: We compared the effect of S(+)-ketamine to remifentanil, both in combination with propofol, on the neurocognitive outcome after open-heart surgery in 106 patients. A battery of neurocognitive tests was administered before surgery and 1 and 10 wk after surgery. Fourteen patients (25%) in the control group and 10 patients (20%) in the S(+)-ketamine group had 2 or more tests with a cognitive deficit (decline by at least one preoperative SD of that test in all patients) 10 wk after surgery (P = 0.54). Z-scores were calculated for all tests. No significantly better performance could be detected in the S(+)-ketamine group, except for the Trailmaking B test 10 wk after surgery. We conclude that S(+)-ketamine offers no greater neuroprotection compared with remifentanil during open-heart surgery. IMPLICATIONS: N-methyl-D-aspartic acid receptors play an important role during ischemic brain injury. We could not demonstrate that S(+)-ketamine resulted in greater neuroprotective effects compared with remifentanil during cardiopulmonary bypass procedures when both were combined with propofol.


Subject(s)
Cardiopulmonary Bypass/methods , Cognition Disorders/prevention & control , Ketamine/therapeutic use , Neuroprotective Agents/therapeutic use , Pain, Postoperative/drug therapy , Aged , Chi-Square Distribution , Cognition Disorders/psychology , Female , Humans , Ketamine/pharmacology , Male , Middle Aged , Neuroprotective Agents/pharmacology , Neuropsychological Tests/statistics & numerical data , Pain, Postoperative/psychology , Piperidines/pharmacology , Piperidines/therapeutic use , Propofol/pharmacology , Propofol/therapeutic use , Prospective Studies , Remifentanil
2.
J Neuroimmunol ; 104(1): 1-9, 2000 Apr 03.
Article in English | MEDLINE | ID: mdl-10683508

ABSTRACT

The expression of leukocyte adhesion molecules in the intact brains of mice with experimental autoimmune encephalitis (EAE) was visualized by Magnetic Resonance Imaging (MRI) through the use of a new, target-specific MR contrast agent. Antibody-conjugated paramagnetic liposomes (ACPLs) were designed to achieve in vivo targeting of molecules expressed on vascular endothelium, while providing sufficient signal enhancement at these sites for detection by MRI. ACPLs targeted to intercellular adhesion molecule-1 (ICAM-1), an endothelial leukocyte receptor upregulated on cerebral microvasculature during EAE, were administered to diseased mice. Fluorescence microscopy confirmed that fluorescently-tagged ACPLs were localized to central nervous system (CNS) microvasculature in a pattern consistent with ICAM-1 upregulation described immunohistochemically. High resolution MRI of mouse brains ex vivo demonstrated that ACPL binding conferred significant enhancement of signal intensity (SI) as compared to control images. These results suggest that ACPLs can be used as MRI contrast agents to visualize specific molecules expressed on vascular endothelium during disease.


Subject(s)
Autoimmune Diseases/diagnosis , Autoimmune Diseases/metabolism , Encephalitis/diagnosis , Encephalitis/metabolism , Intercellular Adhesion Molecule-1/metabolism , Magnetic Resonance Imaging , Animals , Antibodies, Monoclonal , Drug Carriers , Endothelium, Vascular/metabolism , Gadolinium/administration & dosage , Liposomes , Mice , Mice, Inbred Strains , Microscopy, Fluorescence , Tissue Distribution
3.
Curr Opin Immunol ; 9(6): 872-83, 1997 Dec.
Article in English | MEDLINE | ID: mdl-9492992

ABSTRACT

The discovery that functionally heterogeneous CD4+ T-cell subsets secrete different cytokines offers an explanation for the ability of certain T cells to mediate a predominant cell-mediated immune response versus a humoral response often accompanied by allergic manifestations. Th1 cells, important for cell-mediated immunity by their production of IL-2, IFN-gamma and lymphotoxin, have been implicated in the immunopathology of certain organ-specific autoimmune diseases whereas a role as regulators has been suggested for IL-4 and IL-10 producing Th2 cells. Recent findings, however, beg re-evaluation of the direct role of Th2 cells in the induction or maintenance of tolerance, whereas evidence for the role of a distinct subset of regulatory T cells producing TGF-beta to suppress cell-mediated immunopathology is compelling.


Subject(s)
Autoimmunity/immunology , CD4-Positive T-Lymphocytes/immunology , T-Lymphocyte Subsets/immunology , Animals , CD4 Antigens/immunology , Cytokines/immunology , Humans
4.
Nature ; 379(6563): 343-6, 1996 Jan 25.
Article in English | MEDLINE | ID: mdl-8552189

ABSTRACT

Following induction of experimental encephalomyelitis with a T-cell clone, L10C1, that is specific for the myelin basic protein epitope p87-99, the inflammatory infiltrate in the central nervous system contains a diverse collection of T cells with heterogeneous receptors. We show here that when clone L10C1 is tolerized in vivo with an analogue of p87-99, established paralysis is reversed, inflammatory infiltrates regress, and the heterogeneous T-cell infiltrate disappears from the brain, with only the T-cell clones that incited disease remaining in the original lesions. We found that antibody raised against interleukin-4 reversed the tolerance induced by the altered peptide ligand. Treatment with this altered peptide ligand selectively silences pathogenic T cells and actively signals for the efflux of other T cells recruited to the site of disease as a result of the production of interleukin-4 and the reduction of tumour-necrosis factor-alpha in the lesion.


Subject(s)
Encephalomyelitis/drug therapy , Myelin Basic Protein/therapeutic use , Amino Acid Sequence , Animals , Base Sequence , Brain/immunology , Encephalomyelitis/immunology , Epitopes , Immune Tolerance , Interleukin-4/immunology , Mice , Molecular Sequence Data , Myelin Basic Protein/immunology , Paralysis/immunology , Peptide Fragments/therapeutic use , T-Lymphocytes/immunology
5.
Mol Med ; 1(7): 795-805, 1995 Nov.
Article in English | MEDLINE | ID: mdl-8612202

ABSTRACT

BACKGROUND: We previously demonstrated the local production of the pleiotropic cytokine interleukin-6 (IL-6) in the central nervous system (CNS) in experimental autoimmune encephalomyelitis (EAE), an animal model for the human disease multiple sclerosis. MATERIALS AND METHODS: To assess the role of IL-6 in autoimmune CNS inflammation, we administered neutralizing antibodies to IL-6 in the EAE model. Their effect was examined at the clinical and histopathological level. Levels of administered antibody and IL-6 bioactivity were followed in serum and cerebrospinal fluid (CSF). RESULTS: Systemically administered antibodies penetrated into the fluid CSF in animals in which EAE was induced. Administration of anti-IL-6 reduced the development of actively induced as well as adoptively transferred EAE and was associated with increased levels of IL-6 activity in the CSF and to a lesser extent in the serum. Anti-IL-6 was still effective when given 1 day before the onset of disease signs in adoptively transferred EAE. The disease-reducing effect of anti-IL-6 was also reflected at the pathological level by the absence of inflammatory infiltrates in the CNS. CONCLUSIONS: Our study indicates that IL-6 plays an important role in autoimmune CNS inflammation. However, due to the complex nature of the in vivo interactions of administered antibodies, the disease-reducing effect of the anti-IL-6 antibodies could be caused by neutralization of IL-6 activity or by enhancement of IL-6 activity via induction of higher IL-6 levels in the CNS.


Subject(s)
Central Nervous System/metabolism , Encephalomyelitis, Autoimmune, Experimental/etiology , Interleukin-6/metabolism , Amino Acid Sequence , Animals , Antibodies/therapeutic use , Biological Assay , Cell Transplantation , Central Nervous System/pathology , Disease Models, Animal , Encephalomyelitis, Autoimmune, Experimental/drug therapy , Female , Inflammation/drug therapy , Inflammation/etiology , Interleukin-6/blood , Interleukin-6/cerebrospinal fluid , Interleukin-6/immunology , Lymph Nodes/cytology , Lymph Nodes/immunology , Mice , Mice, Inbred Strains , Molecular Sequence Data , Multiple Sclerosis/drug therapy , Multiple Sclerosis/etiology , Rats
6.
J Clin Invest ; 94(6): 2177-82, 1994 Dec.
Article in English | MEDLINE | ID: mdl-7989572

ABSTRACT

Gelatinases, belonging to the matrix metalloproteases, contribute to tissue destruction in inflammatory demyelinating disorders of the central nervous system such as multiple sclerosis. We used experimental autoimmune encephalomyelitis (EAE) as an animal model to evaluate the effect of a hydroxamate matrix metalloprotease inhibitor (GM 6001) on inflammatory demyelination. A single dose of the inhibitor, given intraperitoneally, provided sufficient levels in the cerebrospinal fluid of animals with EAE to induce at least a partial inhibition of the gelatinase activity in the cerebrospinal fluid. When administered daily either from the time of disease induction or from the onset of clinical signs, GM 6001 suppressed the development or reversed clinical EAE in a dose-dependent way, respectively. Animals returned to the same clinical course as the nontreated group after cessation of treatment. Animals treated from the onset of clinical signs had normal permeability of the blood-brain barrier, compared with the enhanced permeability in nontreated animals. These results indicate that matrix metalloprotease inhibition can reverse ongoing EAE. This effect appears to be mediated mainly through restoration of the damaged blood-brain barrier in the inflammatory phase of the disease, since, the degree of demyelination and inflammation did not differ between the treatment groups.


Subject(s)
Autoimmune Diseases/therapy , Demyelinating Diseases/therapy , Dipeptides/therapeutic use , Encephalomyelitis/therapy , Metalloendopeptidases/antagonists & inhibitors , Animals , Blood-Brain Barrier , Dipeptides/cerebrospinal fluid , Disease Models, Animal , Dose-Response Relationship, Drug , Female , Gelatinases/cerebrospinal fluid , Injections, Intraperitoneal , Mice , Mice, Inbred Strains , Permeability
7.
Trends Microbiol ; 2(7): 250-4, 1994 Jul.
Article in English | MEDLINE | ID: mdl-8081652

ABSTRACT

The association of infection with autoimmune diseases is enigmatic, partly because cause and effect are difficult to establish in chronic diseases. Microorganisms might initiate multiple sclerosis and trigger relapses of disease. Superantigens might be involved in autoimmunity through the (re)activation of T cells, including autoreactive cells, expressing certain T cell receptor beta chain variable regions.


Subject(s)
Bacterial Infections/immunology , Multiple Sclerosis/immunology , Superantigens/immunology , Bacterial Infections/complications , Humans , Models, Biological , Multiple Sclerosis/microbiology , Receptors, Antigen, T-Cell/immunology
8.
J Neurosci Res ; 36(4): 432-40, 1993 Nov 01.
Article in English | MEDLINE | ID: mdl-7505841

ABSTRACT

Gelatinases in inflammatory demyelinating diseases of the central nervous system (CNS) were studied using actively induced experimental autoimmune encephalomyelitis (EAE) in mice as a model system. Clinical disease scores correlated in time and in intensity with pathology parameters such as cytosis in the cerebrospinal fluid (CSF), inflammatory infiltrates, and demyelination in the CNS. Zymographic analysis was employed to measure gelatinases A and B in the CSF from individual animals. According to their apparent molecular weight (MW), gelatinases A and B appeared with a MW of 65 and 95 kDa, respectively. The 65 kDa form was present in all samples, even in those derived from non-induced animals, whereas the 95 kDa form was present only in samples from animals developing EAE. The levels of 95 and 65 kDa gelatinase correlated with the CSF cytosis. In vitro digestion of myelin basic protein (MBP) with gelatinase B and analysis of the cleavage products by protein sequence analysis pinpointed two cleavage sites in conserved regions of MBP. Gelatinase production within the CNS may constitute an important pathogenic mechanism for both the disruption of the blood-brain barrier and the destruction of myelin, as observed in several neuroinflammatory disorders.


Subject(s)
Collagenases/cerebrospinal fluid , Encephalomyelitis, Autoimmune, Experimental/enzymology , Myelin Basic Protein/metabolism , Amino Acid Sequence , Animals , Brain Stem/pathology , Cerebellum/pathology , Edetic Acid/pharmacology , Guinea Pigs , Matrix Metalloproteinase 9 , Mice , Molecular Sequence Data , Molecular Weight , Myelin Basic Protein/chemistry , Phenanthrolines/pharmacology , Protease Inhibitors/pharmacology , Spinal Cord/pathology , Time Factors
9.
Nature ; 365(6447): 642-4, 1993 Oct 14.
Article in English | MEDLINE | ID: mdl-7692305

ABSTRACT

The role of infection in the pathogenesis of clinical relapses that occur in most autoimmune diseases, including multiple sclerosis, remains to be established. Experimental autoimmune encephalomyelitis (EAE) serves as a model for multiple sclerosis, with episodes of relapsing paralysis. In certain strains of mice, T-lymphocytes expressing the V beta 8 T-cell receptor (TCR) engage the amino-terminal epitope Ac1-11 of myelin basic protein, leading to EAE. The bacterial superantigen staphylococcal enterotoxin B (SEB) activates V beta 8-expressing T cells. Here we show that after immunization with Ac1-11, or after transfer of encephalitogenic T-cell lines or clones reactive to Ac1-11, SEB induces exacerbation or relapses of paralytic disease in mice that are in clinical remission following an initial episode of paralysis, and triggers paralysis in mice with subclinical disease. Tumour necrosis factor has a critical role in the mechanism underlying SEB-induced exacerbation of disease, because anti-tumour necrosis factor antibody given in vivo delays the onset of paralysis triggered by SEB. On reactivation of autoaggressive cells through their T-cell receptor, superantigens may induce clinical relapses of autoimmune disease.


Subject(s)
Encephalomyelitis, Autoimmune, Experimental/immunology , Enterotoxins/immunology , Paralysis/immunology , Superantigens/immunology , Amino Acid Sequence , Animals , Cell Line , Encephalomyelitis, Autoimmune, Experimental/physiopathology , Enterotoxins/pharmacology , Mice , Molecular Sequence Data , Myelin Basic Protein/immunology , Paralysis/physiopathology , Staphylococcus aureus , T-Lymphocytes/immunology , T-Lymphocytes/transplantation , Tumor Necrosis Factor-alpha/biosynthesis
10.
J Neuroimmunol ; 41(1): 29-34, 1992 Nov.
Article in English | MEDLINE | ID: mdl-1334098

ABSTRACT

A substrate conversion assay was used to detect gelatinase activity in the cerebrospinal fluid (CSF) of patients with various neurological disorders. Two main forms of gelatinase with an apparent molecular mass of 65 and 85 kDa, respectively, could be discerned. The high molecular mass gelatinase was detectable only in samples of patients with multiple sclerosis or other inflammatory neurological disorders. A statistically significant correlation was found between the level of the 85-kDa gelatinase and the CSF cytosis. This protease could play a role in the process of demyelination and breakdown of the blood-brain barrier in certain neurological disorders, such as multiple sclerosis.


Subject(s)
Central Nervous System Diseases/enzymology , Multiple Sclerosis/enzymology , Pepsin A/cerebrospinal fluid , Adult , Aged , Electrophoresis, Polyacrylamide Gel , Female , Gelatinases , Humans , Male , Middle Aged , Molecular Weight , Pepsin A/chemistry , Pepsin A/drug effects , Protease Inhibitors/pharmacology
11.
Eur J Immunol ; 20(1): 233-5, 1990 Jan.
Article in English | MEDLINE | ID: mdl-2307176

ABSTRACT

Interleukin 6 (IL6) is one of the major inflammation-associated cytokines. Elevated serum or tissue levels of IL6 have been reported to occur in several human diseases, including infections of the central nervous system (CNS), but not in non-infectious CNS inflammation, e.g. multiple sclerosis. While studying experimental autoimmune encephalomyelitis (EAE) as an animal model for autoimmune inflammation of the CNS, we found increased IL6 levels in the CNS of mice suffering from a lethal form of the disease. IL6 levels in the spleens and sera were not significantly increased. These findings are indicative of local production of IL6 in the CNS during EAE, and represent the first demonstration of IL6 production in non-infectious CNS inflammatory disease.


Subject(s)
Brain/metabolism , Encephalomyelitis, Autoimmune, Experimental/immunology , Interleukin-6/biosynthesis , Spinal Cord/metabolism , Animals , Female , Interleukin-6/blood , Interleukin-6/cerebrospinal fluid , Male , Mice , Spleen/metabolism
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