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Biomedical subjects

R A Rudick

Publications and source records attributed to R A Rudick.

17 recordsLinked to original sources
PubMed1992

Low-dose (7.5 mg) oral methotrexate for chronic progressive multiple sclerosis. Design of a randomized, placebo-controlled trial with sample size benefits from a composite outcome variable including preliminary data on toxicity.

OBJECTIVE: To present a detailed description of (1) the study design of this ongoing trial, (2) advantages of using a composite outcome variable instead of multiple individual outcome measures, (3) treatment group characteristics at baseline, and (4) observed short-term methotrexate (MTX) toxicity. DESIGN: Randomized, double-masked, placebo-controlled intervention study. SETTING: Referral-based outpatient multidisciplinary multiple sclerosis (MS) clinic. PATIENTS: Participation offered to all clinically definite chronic progressive multiple sclerosis (CPMS) patients attending clinic ages 21 to 60, disease duration > 1 year, Expanded Disability Status Scale (EDSS) score 3.0 to 6.5 (ambulatory with moderate disability). Patients first stratified by EDSS 3.0 to 5.5 and 6.0 to 6.5, then randomized to MTX or placebo treatment. INTERVENTION: Weekly oral low-dose (7.5 mg) MTX or identical-appearing placebo for 2 years followed by a 1-year observation period. MAIN OUTCOME MEASURES: Sample size calculations undertaken prior to enrolling patients based upon a composite outcome variable consisting of designated change in any of the following functional measures: (1) EDSS, (2) Ambulation Index (AI), (3) Box and Block Test (BBT), and (4) 9-Hole Peg Test (9HPT). RESULTS: (1) Treatment group characteristics were comparable at baseline, (2) no patient has been withdrawn for adverse effects or lost to follow-up, (3) no significant short-term MTX toxicity has been observed. CONCLUSIONS: (1) The use of a composite outcome measure in the design of MS clinical trials is a promising alternative to multiple individual outcome measures that are relatively insensitive to detecting clinical change, (2) low-dose oral weekly MTX does not appear to be associated with significant short-term toxicity in CPMS. Conclusions regarding therapeutic efficacy of MTX in MS must await completion of this clinical trial.

Adult↗
PubMed1992

Magnetic resonance imaging lesion enlargement in multiple sclerosis. Disease-related activity, chance occurrence, or measurement artifact?

Magnetic resonance imaging (MRI) may demonstrate disease activity in a number of ways in patients with multiple sclerosis. Newly appearing MRI lesions, gadolinium-enhancing lesions, and enlargement of preexisting lesions are frequently taken as evidence of disease activity. Furthermore, serial MRI studies have been stated to be more sensitive than repeated neurologic examinations in detecting disease activity. We assessed the validity of using lesion enlargement as a measure of disease activity by repeatedly measuring the area of all MRI lesions in four patients with multiple sclerosis. The size-frequency distribution in all patients was similar, with 80% of the lesions measuring less than 0.67 cm2. The median coefficient of variation for three successive lesion measurements was inversely related to lesion area, ranging from 22.6% for the more common smaller lesions (less than 0.67 cm2) to 12.1% for larger lesions. Based on these coefficients of variation, a change in a particular lesion exceeding 45.2% for a baseline lesion smaller than 0.67 cm2 and 24.2% for a baseline lesion greater than or equal to 0.67 cm2 should be required to exclude a change due to measurement variability. It remains necessary to determine the number of lesions that must change when multiple lesions are present in the baseline MRI to reliably exclude chance occurrence when establishing MRI-evident disease activity. Guidelines for determining these criteria are presented, as are the limitations inherent in the statistical model employed to make these determinations.

Humans↗
PubMed1992

Cytokine secretion by multiple sclerosis monocytes. Relationship to disease activity.

Autoantigen recognition by specific T cells may initiate a tissue-specific immune response in multiple sclerosis (MS), which is a chronic inflammatory demyelinating disorder. During subsequent nonspecific immune amplification, interleukin 1 beta and tumor necrosis factor alpha are released by cells of the monocyte/macrophage lineage, with the potential to influence profoundly immune regulation systemically or within the central nervous system. Regulation of monocyte inflammatory gene expression may be relevant to the pathogenesis of MS. We investigated spontaneous secretion of interleukin 1 beta, tumor necrosis factor alpha, and prostaglandin E2 with the use of monocytes that we isolated from patients with active (n = 9) and stable (n = 9) MS and from age-matched normal controls (n = 9). The patient groups with MS were matched for age, duration of MS, and disease severity. Patients with active disease were within weeks of the onset of a clinical exacerbation. Monocytes were isolated by density gradient centrifugation, followed by adherence to plastic tissue culture flasks, resulting in a highly purified adherent monocyte preparation. Monocytes from patients with active disease spontaneously secreted less tumor necrosis factor alpha and less prostaglandin E2 compared with that in patients with stable MS, while interleukin 1 beta levels were below the level of assay sensitivity. Levels of interleukin 1 beta and tumor necrosis factor alpha increased to similar levels in response to lipopolysaccharide (0.1 mg/L), indicating that altered cell viability could not account for the observed differences. In response to lipopolysaccharide, prostaglandin E2 levels increased more significantly in patients with stable than active MS, suggesting differential sensitivity to stimuli of arachidonic acid metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Quality of life in multiple sclerosis. Comparison with inflammatory bowel disease and rheumatoid arthritis.

Multiple sclerosis (MS) and other chronic illnesses can drastically decrease quality of life (QOL), but there has been little systematic study of QOL in patients with chronic medical diseases. We analyzed QOL in 68 patients with MS, 164 patients with inflammatory bowel disease, and 75 patients with rheumatoid arthritis. The previously validated test instrument was a standardized interview consisting of 41 questions clustered in four subscales: functional and economic scale, social and recreational scale, affect and life in general scale, and medical problems scale. Patients were included in the study if they had a definite medical diagnosis and disease duration of 10 years or longer. In the patients with MS, Kurtzke's Expanded Disability Status Scale correlated strongly only with the medical problems score. Of Kurtzke's Functional System Scales, only the visual Functional System Scores was correlated with total QOL and subscale scores, suggesting that vision is strongly related to QOL. Duration of MS was unrelated to QOL scores. There were significant differences between patients with MS, inflammatory bowel disease, and rheumatoid arthritis on the subscale and total QOL scores. Results suggested that QOL was best in the inflammatory bowel disease group and worst in the MS group. Numerous statistically significant differences on individual questions were evident, suggesting that unique clinical profiles differentially characterize these diseases. Assessments of QOL are a meaningful addition to impairment scales, such as Kurtzke's Expanded Disability Status Scale. Furthermore, QOL scores may meaningfully measure the impact of a chronic medical disease, such as MS, compare the impacts of different diseases, and assess the effects of therapeutic intervention.

Activities of Daily Living↗
PubMed1992

Monocytes in active multiple sclerosis: intact regulation of HLA-DR density in vitro despite decreased HLA-DR density in vivo.

HLA-DR expression on circulating monocytes varies as a function of disease activity in patients with multiple sclerosis (MS), a putative immunopathological demyelinating disorder. Specifically, monocytes isolated from subjects with active MS exhibit reduced HLA-DR antigen density, and immunoregulatory aberrations such as impaired T lymphocyte-mediated suppression correlate strongly with this quantitative defect. To address the mechanism underlying this phenomenon, we compared in vitro regulation of HLA-DR by interferon beta (IFN beta), interferon gamma (IFN gamma), and lipopolysaccharide (LPS) in monocytes from patients with stable and active MS and normal individuals. Interferon-gamma and LPS enhanced monocyte expression of HLA-DR equally in both MS patient groups, suggesting that underexpression of HLA-DR in active MS was not explained by impaired in vivo monocyte responsiveness. Furthermore, interferon regulation of HLA-DR in normals and stable MS subjects was indistinguishable, indicating that aberrant interferon-mediated regulation of class II major histocompatibility complex (MHC) on circulating monocytes does not appear to be a characteristic of the MS disease state.

HLA-DR Antigens↗
PubMed1991

Diagnostic criteria for multiple sclerosis research involving multiply affected families.

Existing diagnostic criteria for multiple sclerosis present significant limitations when assessing multiplex families for three reasons: (1) restricting age of onset to 10 to 50 years is likely to exclude 10% of patients known to have a later onset, (2) diagnoses based on subjective information can potentially result in a false-positive diagnosis, and (3) including progressive myelopathies occurring within families, particularly when highly symmetrical, may result in the improper inclusion of genetically determined neurological diseases such as familial spastic paraparesis. The validity of any molecular genetic approach for determining disease susceptibility critically depends on diagnostic accuracy. We present adapted diagnostic criteria that address each of these diagnostic pitfalls unique to multiplex multiple sclerosis family research.

Family↗
PubMed1991

Sensitive competitive-binding ELISAs for quantifying free kappa and lambda light chains in cerebrospinal fluid.

Simple, sensitive, and fully standardized solid-phase enzyme-linked competitive binding immunoassays to quantify free kappa and lambda immunoglobulin light chains are described. The assays were developed to measure the concentration of free light chains in cerebrospinal fluid (CSF), in part because elevated levels of free kappa light chains have utility as a diagnostic marker for multiple sclerosis (MS). Polyclonal rabbit antibodies raised against pooled Bence Jones proteins are bound to solid-phase Staphylococcal protein A and used as the primary antisera in this assay. A pool of Bence Jones proteins isolated from the urine of 10 individuals with multiple myeloma are used as a biotin-labeled ligand and to develop a standard curve. The assays as described are sensitive to the low nanogram range and are specific for free kappa or lambda light chains. The assays were found to have acceptable precision, and results correlated highly with concentrations determined using competitive-binding radioimmunoassays previously described.

Binding, Competitive↗
PubMed1991

Interferon-beta specifically inhibits interferon-gamma-induced class II major histocompatibility complex gene transcription in a human astrocytoma cell line.

We established cultures of human astrocytes and astrocytoma cells from surgical specimens, to study regulation of class II major histocompatibility (MHC) complex antigen expression by interferons. Using these cultures we previously showed that expression of the class II MHC determinant HLA-DR could be induced by interferon-gamma and this induction was inhibited by interferon-beta. In this report, we extend these observations by showing that the inhibitory effect of interferon-beta on interferon-gamma induction of the class II MHC gene HLA-DR alpha was exerted at the transcriptional level, as documented by nuclear run-on experiments and confirmed with blot hybridization analysis. Astrocyte expression of intercellular adhesion molecule-1 (ICAM-1) was induced efficiently by interferon-gamma, but not by interferon-beta, and induction of ICAM-1 expression by interferon-gamma could not be impaired by interferon-beta, suggesting that the suppressive effect on induction of HLA-DR was relatively gene-specific. Furthermore, interferon-beta did not antagonize interferon-gamma induction of HLA-DR expression in human monocytes, suggesting that the inhibition observed in astrocytes was relatively tissue-specific.

Astrocytes↗
PubMed1990

The clinical course of multiple sclerosis during pregnancy and the puerperium.

Eight women with multiple sclerosis were followed up through pregnancy. Clinical conditions, T-cell subsets, and levels of immunoactive pregnancy-associated proteins were measured twice during the pregnancy and twice during the first postpartum year. None of the women's conditions worsened during pregnancy, although one woman reported a slight increase of symptoms. Six of the eight women experienced relapses within the first 7 weeks after delivery. The number and percent of CD8 suppressor T cells were lower, and the CD4 helper-CD8 suppressor T-cell ratio was higher in the pregnant patients with multiple sclerosis compared with pregnant control women throughout pregnancy and the first 6 months post partum. There was no evident relationship between these parameters and clinical disease activity. Levels of alpha-fetoprotein, alpha 2-pregnancy-associated glycoprotein, and pregnancy-associated plasma protein A, all immunosuppressive proteins associated with pregnancy, were not significantly different in pregnant patients with multiple sclerosis and pregnant controls without multiple sclerosis. The study suggested that the risk of clinical relapse after delivery may be higher than has been reported previously. Furthermore, although there were differences in suppressor T cells, they were not predictably linked to changes in clinical disease activity.

Adult↗
PubMed1990

Stereotactic biopsy of an active multiple sclerosis lesion. Immunocytochemical analysis and neuropathologic correlation with magnetic resonance imaging.

Stereotactic biopsy of an active multiple sclerosis lesion in a 23-year-old patient with unilateral symptoms and an isolated high-signal-intensity magnetic resonance abnormality yielded 10 serial tissue cores (1.0 x 0.5 cm) spanning 40 mm within and around the lesion. We performed semiquantitative analysis of lymphocyte phenotype, using antisera to CD3, CD4, CD8, and CD22 molecules, in 11 separate perivascular cuffs in three tissue sections from the lesion edge. Total cells in the cuffs varied from 10 to 100; ratios of CD4+/CD8+ cells in individual cuffs varied from 1.3 to 4.7. Although intense parenchymal infiltrates bordered the least cellular cuffs, parenchymal and perivascular cell phenotypes were indistinguishable, arguing against selective trafficking of lymphocytes into tissue. Individual microfoci of cells displaying CD45RA, CD25, and TQ1 antigens were present. The remarkable phenotypic heterogeneity of T lymphocytes in the multiple sclerosis lesion border is consistent with exposure in situ to a diversity of differentiating stimuli. Histologic demyelination correlated very closely with the signal-intensity abnormality observed on magnetic resonance imaging. These studies provide unusual insight into the histologic and immunocytochemical morphologic appearance of the active multiple sclerosis plaque.

Adult↗
PubMed1990

Helping patients live with multiple sclerosis. What primary care physicians can do.

Patients with multiple sclerosis (MS) may experience progressive problems of many kinds, often over decades. Ambulation, muscle strength and coordination, bladder function, vision, behavior, and cognition may eventually be affected. The diagnosis is based on clinical features and laboratory studies, but no definitive test exists. The rate of misdiagnosis may be as high as 30%. Treatment consists of pharmacotherapy for symptoms, therapy for the disease itself, and experimental therapies. Long-term management of MS can be a worthwhile challenge for primary care physicians. Helpful resources include neurologists with an interest in the disease, regional treatment and rehabilitation centers, and local MS societies.

Adrenal Cortex Hormones↗
PubMedDate not supplied

Volume T1-weighted gradient echo MRI in multiple sclerosis patients.

Three-dimensional (3D) volume turbo fast low angle shot (FLASH) techniques have become available which produce heavily T1-weighted images, similar to inversion recovery scans, utilizing the appropriate flip angle and inversion time. The purpose of this study was to compare the sensitivity of a rapid volume gradient echo technique [3D magnetization prepared rapid acquisition gradient echo (MP RAGE)] in identifying multiple sclerosis (MS) plaques with a conventional T2-weighted spin echo (SE) sequence. Ten patients with clinical MS were evaluated. Patients underwent a routine examination consisting of an axial T2-weighted SE sequence (2,500,22/90) and a coronal 3D MP RAGE, 10/4/10, acquired as 128 two mm partitions. In six patients, area measurements of 22 plaques were determined on both the axial T2-weighted SE examinations and the axial reformatted MP RAGE examinations. The overall number of plaques utilizing each technique was approximately the same. One hundred twenty-two plaques were visualized for the 3D MP RAGE sequence, and 128 plaques for the T2-weighted SE sequence. There were differences in detection of plaques in different regions, with plaques in gray matter better demonstrated utilizing the conventional T2-weighted SE sequence. Plaques in the corpus callosum, pons, and brachia pontis were better demonstrated utilizing 3D MP RAGE. No significant difference was found between the areas measured on the MP RAGE sequence and on the T2-weighted SE sequence. Three-dimensional MP RAGE provides a sensitive and complementary method to conventional T2-weighted SE sequences in the evaluation of patients with MS.

Adult↗
PubMedDate not supplied

Stereotactic biopsy of non-neoplastic lesions in adults.

Stereotactic biopsy of intracranial lesions has been used primarily for the diagnosis of neoplastic lesions. A series of 158 consecutive stereotactic biopsies performed at The Cleveland Clinic Foundation resulted in 28 diagnoses of non-neoplastic disorders (18%). The majority of these were infectious, inflammatory, or demyelinating disorders. Stereotactic biopsy alone was diagnostic in 17 cases (61%), and biopsy in conjunction with clinical and laboratory data established definitive diagnoses in six cases (22%). All 23 definitive diagnoses led to modifications in patient management. Permanent neurologic morbidity occurred in only two patients (7%). We maintain that this procedure is underused. Stereotactic biopsy is safe, accurate, and useful for diagnosis of non-neoplastic neurologic disorders when the diagnosis is unclear by conventional means. In such cases, its use can lead to early diagnosis and treatment.

Adult↗
PubMedDate not supplied

Experimental therapies for multiple sclerosis: current status.

Multiple sclerosis is the most common cause of nontraumatic disability affecting young adults in the United States. Its etiology remains unclear, but evidence points to alteration of normal immune system function in the pathogenesis of this illness. This article reviews the results of clinical trials of experimental therapeutic agents in multiple sclerosis. The background and action of each treatment are described, and the clinical experience with each agent is reviewed. Obstacles to evaluating the effectiveness of treatment methods in MS and challenges to the design of future clinical trials and the interpretation of trial outcomes are discussed.

Azathioprine↗
PubMedDate not supplied

Pharmacotherapy of multiple sclerosis: current status.

Pharmacotherapy plays an important part in the overall management of patients with multiple sclerosis. Most therapies directed at altering the natural history of the underlying disease process are only partially effective or are controversial or experimental. However, many effective symptomatic therapies are available to the clinician. The action and uses of corticosteroids in multiple sclerosis are discussed, and approaches to the treatment of spasticity, paroxysmal disorders, bladder dysfunction, cerebellar ataxia, neurobehavioral manifestations, fatigue, and acute and chronic pain in patients with multiple sclerosis are examined.

Acute Disease↗