PubMed Health⌕ Search

Biomedical subjects

J Antel

Publications and source records attributed to J Antel.

At least 37 records · Page 2Linked to original sources
PubMed1998

Synthesis, pharmacological characterization, and quantitative structure-activity relationship analyses of 3,7,9,9-tetraalkylbispidines: derivatives with specific bradycardic activity.

A series of 3,7,9,9-tetraalkyl-3,7-diazabicyclo[3.3.1]nonane derivatives (bispidines) was synthesized and identified as potential antiischemic agents. Pharmacological experiments in vitro as well as in vivo are described, and the results are listed. For selection of those compounds fitting best to the desired profile of a specific bradycardic antianginal agent--decrease in heart rate without affecting contractility and blood pressure--these results were scored and ranked. Quantitative structure--activity relationship (QSAR) analyses were performed and discussed a posteriori by means of Hansch, nonelementary discriminant and factor analysis to get insight into the molecular features determining the biological profile. Highly significant equations were obtained, indicating hydrophobic and steric effects. Both pharmacological ranking and QSAR considerations showed compound 6 as the optimum within the structural class under investigation. Compound 6 (tedisamil, KC8857) has been selected as the most promising compound and was chosen for further pharmacological and clinical investigations as an antiischemic drug.

Animals↗
PubMed1998

Improved correlation between scores on the expanded disability status scale and cerebral lesion load in relapsing-remitting multiple sclerosis. Results of the application of new imaging methods.

We hypothesized that a better correlation between MRI and clinical measures of neurological disability using the expanded disability status scale (EDSS) in multiple sclerosis could be obtained by assessing lesion load only in and around the corticospinal tracts, since the EDSS is weighted towards motor and ambulatory deficits. Multiple sclerosis lesions in cerebral MRIs from 39 patients with relapsing-remitting multiple sclerosis were manually painted using a three-dimensional computer display tool and mapped into a standardized three-dimensional coordinate space. Total lesion load was then measured. A mask to expose only the corticospinal tract was extracted from an MRI atlas and used to measure lesion load in the corticospinal tract. To account for the residual anatomical variability among the different MRI volumes after stereotaxic transformation, the corticospinal tract mask was dilated to various degrees and the lesion load remeasured. Spearman's rank correlation coefficient was used to calculate the correlation between the EDSS and total lesion load and corticospinal tract lesion load and between the EDSS subscores and total lesion load and corticospinal tract lesion load. Spearman's rank correlation coefficient between the EDSS and total lesion load was 0.6, probably reflecting the rather broad EDSS range represented in the study. The highest correlation of 0.67 was between the EDSS and corticospinal tract lesion load, dilated with a blurring kernel of 8-10 mm. The pyramidal subscore alone showed a weaker correlation with total lesion load, and with corticospinal tract lesion load, than did the overall EDSS, possibly reflecting the narrow range of disability in these subscores in patients with EDSS scores of 1-6.5. The imperfect correlation between the EDSS and corticospinal tract lesion load suggests that factors other than cerebral T2-weighted lesion volume are important determinants of disability.

Brain↗
PubMed1997

The role of MRI in clinical trials of multiple sclerosis: comparison of image processing techniques.

Magnetic resonance imaging (MRI) has received considerable attention in recent years over its potential for providing indices of multiple sclerosis activity and progression in clinical trials of new pharmaceuticals. The perceived advantages of MRI-derived measurements include greater objectivity, sensitivity, and reproducibility when compared with clinical rating scales. Clinical scales are also somewhat biased toward lesions affecting locomotion. However, the myriad permutations of MRI acquisition parameters, analysis methodologies, and disease indices demand careful consideration when employing MRI. Moreover, the use of MRI in research into the basic mechanisms of a disease may have different requirements than its use in a clinical trial setting. Consequently, a conference was held, sponsored by the US and Canadian multiple sclerosis societies, to review the present status of various MRI processing strategies and their potential role in clinical trials. Thirteen laboratories from North America and Europe as well as regulatory agencies and statistical consultants made formal presentations followed by extended discussion. This report presents the conclusions reached and recommendations for further action that emerged from the meeting.

Clinical Trials as Topic↗
PubMed1997

Recommendations from the National Multiple Sclerosis Society Clinical Outcomes Assessment Task Force.

This article provides recommendations from the National Multiple Sclerosis Society's Clinical Outcomes Assessment Task Force. The Task Force was appointed in 1994 and charged with recommendending improved approaches for clinical outcomes assessment in future controlled clinical trials. The recommendations herein follow extensive deliberation and data analysis during 2.5 years. General principles and desirable measurement attributes were used to assess alternative measurement techniques and clinical scales. On the basis of the analysis of existing multiple sclerosis (MS) data sets, a new measurement approach is proposed. The approach is based on quantitative functional composites that consist of simple quantitative measures from the major clinical dimensions of MS combined into a single score. Quantitative functional composites are likely to provide improved precision and sensitivity in future MS clinical trials. Studies necessary to further refine quantitative functional composites as useful MS clinical trial outcomes are delineated.

Clinical Trials as Topic↗
PubMed1996

Expression of the activation marker urokinase plasminogen-activator receptor in cultured human central nervous system microglia.

The ability of microglia to migrate through central nervous system (CNS) tissue requires proteolytic degradation of components of the extracellular matrix. Urokinase plasminogen activator (uPA), when bound to its cell surface receptor (uPAR), is an active cell surface protease. uPAR expression has been associated with cell activation. Cultured human microglia express surface uPAR. uPAR expression was found to be associated predominately with spindle- or bipolarshaped microglia. The addition of lipopolysaccharide (LPS) to microglial cultures enhanced the proportion of uPAR expression and shifted cell morphology to the elongated spindle or bipolar shape. When microglia were examined immediately ex vivo, uPAR surface expression could not be detected. Similarly, uPAR transcripts detected by reverse transcription-polymerase chain reaction techniques were found in cultured, but not ex vivo, microglia. Microglia isolated from a patient with multiple sclerosis (MS) displayed a large amount of uPAR+ cells. These cells were predominantly spindle or bipolar in nature. These findings suggest that uPAR surface expression is associated with microglial activation. Surface expression of uPAR and associated cell surface protease activity may provide a mechanism for microglial migration and may be important in the pathophysiology of MS.

Adult↗
PubMed1996

Clinical outcomes assessment in multiple sclerosis.

This article represents initial deliberation of an international task force appointed by the US National Multiple Sclerosis Society to develop recommendations for optimal clinical assessment tools for multiple sclerosis clinical trials. Presented within this article are the key issues identified by the task force during its initial year of deliberation. These include the precise purpose for a clinical assessment tool, the clinical dimensions to be measured in a multidimensional outcome measure, desirable attributes of an optimal clinical outcome measure, the complexities of multidimensional outcome measures, the relative merits of categorical clinical ratings and quantitative functional assessments, and a number of other important design issues that relate to the use of a multidimensional outcome measure. An action plan for analysis of existing data is summarized, as are the plans for more detailed recommendations from the task force.

Clinical Trials as Topic↗
PubMed1996

Assessment of lesion pathology in multiple sclerosis using quantitative MRI morphometry and magnetic resonance spectroscopy.

Quantitative measurement of MRI-defined brain lesions can provide an index of the extent and activity of disease in multiple sclerosis patients. However, the relationships between these indices and clinical features are not well-understood. Heterogeneity of the pathological changes underlying MRI lesions may be an important factor determining the correlation between MRI lesion volumes and clinical measures. Recent studies have suggested that with magnetic resonance spectroscopy (MRS), it may be possible to define chemical changes that better reflect the pathological changes in multiple sclerosis. Here we report results of combined quantitative brain T2-weighted MRI lesion volume and proton MRS examinations that demonstrate heterogeneity of the chemical pathology underlying brain lesions in patients selected on the basis of similar clinical disability but differing with respect to the presence or absence of clinical relapses. We examined 29 patients with disease characterized by either clear relapses with at least partial remissions (RR) or secondary, chronic progression after an earlier history of a more relapsing and remitting course (SP). Total hemispheric lesion volume was greater (P < 0.04) in the RR (32.5 +/- 20.9 cm3) than in the SP (16.2 +/- 9.0 cm3) patients, despite the longer duration of disease in the latter group. Central brain N-acetyl aspartate: creatine (NAA:Cr) ratios were reduced relative to normal controls (4.0 +/- 0.3, n = 19) by similar amounts in the two patients groups (RR, 3.1 +/- 0.5; SP, 3.2 +/- 0.4; P < 0.0001). The ratio lesion volume:(NAA:Cr) was greater for the RR group (11.7 +/- 9.3 cm3) than for the SP group (5.4 +/- 3.3 cm3, P < 0.05), implying a greater average degree of axonal loss per unit lesion volume defined by MRI for subjects in the SP group or, alternatively, a greater proportion of lesions without axonal damage or loss in the RR group. Our results emphasize a limitation of using T2-weighted MRI lesion volume alone and suggest that combined analysis of MR-based chemical and imaging data might allow improved non-invasive assessment of lesion pathology in order to better understand its relationship to clinical features of multiple sclerosis.

Adult↗
PubMed1994

Human microglial cells have phenotypic and functional characteristics in common with both macrophages and dendritic antigen-presenting cells.

Resting microglia comprise up to 13% of the cells in human central nervous system (CNS) white matter. Their large number and dendritic morphology make them ideally suited to survey the CNS for noxious stimuli. Upon activation microglia gradually lose dendritic processes and transform into typical phagocytic macrophages. Microglia have been implicated as the main antigen presenting cell within the CNS, and appear to be of central importance as effectors and regulators of demyelination. To further characterize the capacity for immune reactivity within the human CNS, we have studied several characteristics of microglia, both in situ and in vitro. We find that human microglia have ultrastructural, phenotypic (CD11c, CD68, acid phosphatase), and functional (FcR and CR mediated phagocytosis) properties typical for cells of the monocyte lineage. Our data indicate that microglia also have properties in common with dendritic antigen-presenting cells. Electron microscopy studies show extended dendritic cell processes on cultured microglia, and microglia are, like dendritic cells, negative for the monocyte markers nonspecific esterase, endogenous peroxidase, CD14, and RFD7. Microglia constitutively express HLA-DR in situ, and express the dendritic cell marker RFD1 upon activation. Coculturing of microglia with CD4+ T cells results in clustering of T cells around microglia and initiation of a mixed lymphocyte reaction, both distinguishing features of dendritic cells. These functional properties of microglia may be of importance for the maintenance of an immunologic response in the CNS, an organ where dendritic cells, in contrast to other organs, have not previously been identified.

Adult↗
PubMed1994

Reactive microglia in multiple sclerosis lesions have an increased expression of receptors for the Fc part of IgG.

Receptors for the Fc part of IgG, FcRI (CD64), FcRII (CD32), and FcRIII (CD16) were studied by indirect immunoperoxidase staining of cryostat sections from normal and multiple sclerosis (MS) brains. Microglia in the parenchyma of normal white matter had a dendritic morphology, and were weakly stained by monoclonal antibodies (mAbs) to FcRI, FcRII, and FcRIII. In active MS lesions reactive microglia were strongly stained by the mAbs 32.2 (FcRI), IV-3 (FcRII), and 3G8 (FcRIII). Perivascular macrophages were stained by all anti-FcR mAbs in both normal white matter and in MS lesions, whereas endothelial cells were stained by the anti-FcRIII mAb only. The FcR on microglia and perivascular macrophages may be of functional importance in antibody-dependent cell-mediated cytotoxicity (ADCC), phagocytosis, and local immunoregulation. FcR on endothelium may be of importance in binding and transportation of immune complexes into the CNS. FcR mediated functions may consequently be highly relevant to the pathogenesis of MS.

Adult↗
PubMed1994

Cytokine production by cells in cerebrospinal fluid during experimental allergic encephalomyelitis in SJL/J mice.

Cytokine production by T cells in the cerebrospinal fluid (CSF) and central nervous system (CNS) of SJL/J mice during myelin basic protein (MBP)-induced experimental allergic encephalomyelitis (EAE) was examined. Reverse transcriptase/polymerase chain reaction (RT/PCR) was used to measure interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) mRNA levels from perfused CNS tissue (brain and spinal cord) and from cells isolated from CSF. Animals were grouped according to EAE severity, ranging from asymptomatic (adjuvant only) to severe disease (paralysis or severe paresis). Cytokine signals, normalized to actin, were almost undetectable in control tissues, and only slightly elevated in whole CNS tissue from animals with mild EAE. Both cytokine messages were strongly upregulated in CNS tissues derived from severely affected animals, consistent with previous observations correlating disease progression with infiltration by memory/effector CD4+ T cells, the major source of these cytokines. This cytokine upregulation was specific to the CNS, since other organs from the same animals did not express significant levels of IL-2 and IFN-gamma. CSF was obtained from the cisterna magna of unperfused mice and verified as such by absence of red blood cells (RBCs) and by immunoglobulin concentration orders of magnitude lower than in serum. Cytokine message was measured in RNA isolated from cells in CSF. Levels of IL-2 and IFN-gamma mRNA in CSF cells were significantly elevated in mild EAE and strongly upregulated in severe disease, correlating with those in total CNS tissue. These results confirm the CSF as representative of the immune status of the CNS and indicate a role for IL-2 and IFN-gamma in inflammatory CNS disease.

Animals↗
PubMed1994

Immune regulatory and effector properties of human adult microglia studies in vitro and in situ.

Monocytes, macrophages, and brain microglia are the primary cell types most readily demonstrated to be infected in CNS lesions of patients infected with HIV (Koenig et al., 1986). Microglia are implicated in mediating CNS immune regulation and neural tissue injury associated with the AIDS-dementia syndrome. This report describes the isolation and characterization of microglia from the adult human central nervous system (CNS), and the assessment of microglial immune accessory/effector functions, some of which might be altered in CNS infectious and autoimmune diseases. In our studies we have compared the in vitro properties of microglia with peripheral blood monocytes/macrophages, and with astrocytes, a CNS cell type also implicated in contributing to immune regulatory and effector functions. Additionally, we have compared phenotypic features of resident microglia in situ with monocytes and macrophages that have infiltrated the CNS during the course of CNS inflammation. Our results suggest that adult human derived parenchymal microglia represent a unique cell of monocytic origin that can be distinguished both in vitro and in situ from monocytes/macrophages recently infiltrating into the CNS and from perivascular macrophages/microglial cells. Our data demonstrate that parenchymal microglia express several immune accessory/adhesion molecules that can provide second signals for CD4+T cell stimulation. Furthermore, microglia can synthesize cytokines and reactive oxygen species that may augment ongoing pathology in the CNS of AIDS patients. Infection of resident brain microglia could augment microglial immune accessory/effector functions possibly contributing to pathology seen in HIV dementia.

Adult↗
PubMed1994

Fc receptors for IgG on cultured human microglia mediate cytotoxicity and phagocytosis of antibody-coated targets.

We have utilized surgically resected human central nervous system (CNS) tissue to determine the expression and functions of Fc receptors (Fc gamma R) on individual cell types found within the CNS. We observed all three classes of Fc gamma R on microglial cells in situ and in vitro, but not on astrocytes or oligodendrocytes. Incubation of cultured microglia with immune complexes (antibody-coated red blood cells) induced phagocytosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and oxidative bursts. We also found that microglia have the capability to produce T cell stimulatory soluble mediators after Fc gamma R crosslinking. These functional responses were enhanced by pretreatment of the microglia with interferon-gamma (IFN-gamma). Our results implicate microglial effector responses triggered by interaction of Fc gamma R with opsonized antigens as potential mediators of tissue injury within the CNS. Such injury may be particularly applicable to multiple sclerosis, an inflammatory demyelinating disease characterized by intrathecal production of immunoglobulins and cytokines.

Adult↗
PubMed1994

Phenotypic differences between human monocytes/macrophages and microglial cells studied in situ and in vitro.

This report describes a phenotypic differentiation pattern conceived to distinguish invading monocytes from resident microglia in frozen and formalin-fixed human CNS. Phagocytic cells in normal and diseased CNS (multiple sclerosis and encephalitis) were studied immunohistochemically with a panel of antibodies, and phenotypic characteristics were compared with cultured monocytes/macrophages and microglia. Monocytes/macrophages were positive for the markers non-specific esterase, myeloperoxidase, L1, lysozyme, RFD7, and CD14, whereas microglia were negative for the same markers. Both populations of cells were positive for CD11c and CD68. Our results indicate that invading monocytes/macrophages mainly have a perivascular location in active multiple sclerosis lesions, whereas invading monocytes/macrophages also infiltrate the parenchyma in acute inflammatory CNS diseases such as in encephalitis.

Acute Disease↗
PubMed1994

HLA class II molecules (HLA-DR, -DP, -DQ) on cells in the human CNS studied in situ and in vitro.

Human leucocyte antigen (HLA) class II molecules expressed by antigen-presenting cells (APC) are major restriction elements in the interaction between APC and T cells of the CD4+ subtype. To explore the immune accessory function of cells in the central nervous system (CNS), we studied the expression of HLA-DR, -DP, and -DQ molecules on CNS cells in situ and in vitro. Reactive microglia and perivascular cells in multiple sclerosis lesions expressed all three HLA class II molecules, whereas microglia in the normal CNS expressed HLA-DR only. All three HLA class II molecules were up-regulated on cultured microglia after stimulation with interferon-gamma (IFN-gamma). Microglial stimulation of allogeneic CD4+ T cells in a mixed lymphocyte reaction (MLR) was effectively blocked using anti-HLA-DR monoclonal antibodies (mAb) but not using anti-HLA-DQ mAb. HLA class II-positive astrocytes and endothelial cells were not identified in normal or diseased CNS. Cultured astrocytes stimulated with IFN-gamma could, however, be induced to express HLA class II antigens of all subtypes, although great variability was observed between different donors. Our results indicate that although both microglia and astrocytes are capable of expressing all HLA class II subtypes in vitro, subtype expression differs between normal and pathological states in situ. Such selective expression may be associated with functional properties.

Adult↗
PubMed1991

Proton magnetic resonance spectroscopy for metabolic characterization of plaques in multiple sclerosis.

We are investigating the potential of in vivo proton magnetic resonance spectroscopy for noninvasive characterization of the chemical pathology of plaques in magnetic resonance brain images from patients with multiple sclerosis. Spectra localized to chronic, irreversible plaques showed a decrease in the ratio of N-acetyl/creatine resonance intensities relative to normal-appearing white matter. Spectra localized to active plaques showed different metabolite changes as compared with spectra from identical, plaque-free volumes in the contralateral hemispheres. Some active plaques showed either no abnormalities or only an increase in tissue lactate. Spectra from others showed an increased ratio of choline/creatine resonance intensities, with or without a decreased N-acetyl/creatine resonance intensity ratio. In one case, serial observations showed an evolution of changes in spectra from a single plaque from an increased choline/creatine ratio to a decreased N-acetyl/creatine ratio. These observations suggest that proton magnetic resonance spectroscopy may be able to distinguish acute or active from chronic plaques and to characterize the pathologic evolution of active plaques by measurement of local tissue metabolite levels.

Choline↗
PubMed1990

Proton magnetic resonance spectroscopy of human brain in vivo in the evaluation of multiple sclerosis: assessment of the load of disease.

Image localized, water-suppressed proton magnetic resonance spectra were obtained from affected brain in patients with multiple sclerosis. In patients with moderate to severe chronic disease, spectra revealed a decreased ratio of N-acetylaspartate to creatine resonance intensities. A normal ratio was obtained from a large recently symptomatic MRI plaque that resolved without sequelae. We propose that the observed metabolite changes can be useful as an index of irreversible CNS injury.

Aspartic Acid↗
PubMed1988

Activated suppressor cell function in multiple sclerosis--clinical correlations.

Activated suppressor cell function mediated by either freshly isolated peripheral blood mononuclear cells (MNCs), freshly isolated CD8+ lymphocytes or by CD8+ cell lines, has previously been found to be reduced compared to controls in multiple sclerosis (MS) patients with progressive disease (MS-P). In this study, we found that suppressor activity mediated by CD8+ cell lines, derived from MS patients with stable disease (MS-S) patients and maintained in culture for 14 days, was significantly greater (45 +/- 6%) compared to that mediated by MS-P patients' CD8+ cells (11 +/- 4%, P less than 0.005). The MS-S suppressor values were, however, suggestively reduced compared to controls (60 +/- 6%, P less than 0.05). MNC-mediated suppressor values for the MS-S group (61 +/- 5%) did not differ from the control group (67 +/- 6%). Values for the MS-P group (7 +/- 6%) were significantly reduced compared to MS-S and control groups. Cytotoxic activity mediated by CD8+ cell lines showing defective suppressor function did not differ from control values. The cell lines in MS and control did not differ with respect to their rate of proliferation in the presence of IL-2 and OKT3. Suppressor function in this assay was ablated if exogenous IL-2 was removed from the culture media. These data suggest that defective activated suppressor function is characteristic of the progressive form of MS, although a suppressor defect is also partially expressed in stable MS patients when CD8+ cell lines are studied.

Adult↗