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Biomedical subjects

D W Paty

Publications and source records attributed to D W Paty.

At least 55 records · Page 3Linked to original sources
PubMed1995

Urinary myelin basic protein-like material as a correlate of the progression of multiple sclerosis.

In the multicenter, randomized, placebo-controlled trial of alternate-day injections of recombinant interferon beta-1b in relapsing-remitting multiple sclerosis (MS), urine specimens were collected periodically from all patients (n = 64) in two of the clinical test sites over the 2 years of the study. Urine specimens were also collected over two consecutive 24-hour periods from 43 patients from a third center. Urine samples were assayed for their content of myelin basic protein-like material (MBPLM), the level of which was correlated with clinical changes, cranial magnetic resonance imaging results, and the development of progressive disease. Concordant changes in creatinine values affected some of the relationships of MBPLM. The level of urinary MBPLM correlated with a chronic progressive course and with the number of lesions and the total lesion area on cranial magnetic resonance images. A rise in the level of urinary MBPLM appeared to antedate the clinical transition from a relapsing-remitting to a chronic progressive course. By chance, the randomized entry of patients led to significant differences in urinary MBPLM levels among the three treatment groups, thus precluding correlation studies of treatment effects. However, the patient group from which 24-hour specimens were collected showed that the patients with relapsing-remitting MS changing to a chronic progressive course, and more specifically, those patients with chronic progressive MS receiving placebo, had the highest values of urinary MBPLM. These findings indicate that urinary MBPLM may offer an objective test and possibly serve as a surrogate marker for detecting or predicting the failure of remission or the transition to a progressive phase of MS.

Analysis of Variance↗
PubMed1995

Correlations between changes in disability and T2-weighted brain MRI activity in multiple sclerosis: a follow-up study.

We obtained two conventional unenhanced T2-weighted brain MRI scans, separated by an interval of 24 to 36 months, in 281 patients with multiple sclerosis (MS). At the time of each scan, clinical disability was rated using the Kurtzke Expanded Disability Status Scale (EDSS). Changes in disability between the two examinations correlated weakly but significantly with the number of new (Spearman's rank correlation coefficient = 0.13; p = 0.02) and enlarging (Spearman's rank correlation coefficient = 0.18; p = 0.002) MRI lesions. This result suggests that brain T2-weighted MRI is a useful supplementary marker of disease activity in definitive (phase III) clinical treatment trials in MS.

Adult↗
PubMed1995

Differential effects of beta and gamma interferons on expression of major histocompatibility complex antigens and intercellular adhesion molecule-1 in cultured fetal human astrocytes.

We investigated the modulatory effects of human interferon beta (IFN-beta) and gamma (IFN-gamma) on expression of class I and II major histocompatibility complex (MHC) antigens and intercellular adhesion molecule-1 (ICAM-1) in fetal human astrocytes in culture using flow cytometry and immunocytochemistry. Under the baseline condition, class I MHC antigen and ICAM-1 were expressed in a moderate number (23 to 76%) of astrocytes, whereas class II MHC antigen was expressed in only a small number (0.3 to 8%) of astrocytes. Following a 72-hour treatment with IFN-gamma (10 to 100 U/ml), expression of all three antigens increased greatly. Expression of class I MHC antigen was also elevated by exposure to IFN-beta (10 and 100 IU/ml). However, IFN-beta did not significantly induce expression of class II MHC antigen or ICAM-1. Furthermore, IFN-beta significantly reduced IFN-gamma-induced expression of class II MHC antigen but not of class I MHC antigen or of ICAM-1. The differential effects of IFN-beta and IFN-gamma on expression of class I and II MHC antigens and ICAM-1 in fetal human astrocytes suggest that interferons serve as modulators of astrocyte function at sites of inflammation in the human CNS.

Abortion, Legal↗
PubMed1995

Recombinant human interferon beta in the treatment of relapsing-remitting and secondary progressive multiple sclerosis.

Two multicenter, randomized, double-blind, placebo-controlled phase III studies to evaluate the safety and efficacy of 6 and 12 MIU of recombinant human interferon beta (r-hIFN-beta) (Rebif) given subcutaneously three times per week, in patients with MS, are described. In one study, patients with relapsing-remitting multiple sclerosis are treated for 24 months; the primary efficacy end point is the number of exacerbations. In the other study patients with secondary progressive multiple sclerosis are treated for 36 months; the primary efficacy end point is time to sustained progression in disability as determined by the Expanded Disability Status Scale (EDSS). Both studies are conducted in centers in Europe, Australia and Canada.

Adjuvants, Immunologic↗
PubMed1994

Pregnancy and multiple sclerosis. A prospective study.

OBJECTIVE: To conduct a prospective assessment of pregnancy on women with multiple sclerosis (MS), focusing on pregnancy outcome and relapses during gestation and up to 6 months after delivery. DESIGN: Expected numbers of relapses were based on data for (1) "self-controls": the mothers ("cases") themselves prior to becoming pregnant and (2) "matched controls": female patients with MS "matched" to the mothers for year of birth, age of MS onset, MS type, MS course, and initial MS symptom(s). SETTING: Cases and controls were identified from an ambulatory care MS clinic that serves the province of British Columbia, Canada. PATIENTS OR OTHER PARTICIPANTS: Women with a diagnosis of MS who attended the MS clinic during 1982 through 1986 and subsequently became pregnant during 1982 through 1989 inclusive were included in this study as cases. Matched controls were women with MS who attended the MS clinic during the same period but did not become pregnant. RESULTS: No significant increase in relapse rate was found for cases during the first two trimesters of gestation. The number of relapses was significantly less than expected during the third trimester compared with matched controls (chi 2 = 6.80, df = 1, P < .02), but not compared with self-controls (chi 2 = 3.39, df = 1, P > .05). The observed number of relapses for the 6 months after delivery did not differ significantly from expected (self-controls: chi 2 = 2.84, df = 2, P > .05; matched controls: chi 2 = 1.76, df = 2, P > .05). CONCLUSION: These data suggest that neither pregnancy nor the 6-month period after delivery is a risk factor for relapse in MS. They are consistent with previous observations that, in the long term, pregnancy does not influence subsequent MS disability.

Female↗
PubMed1994

The interferon-beta 1b clinical trial and its implications for other trials.

This trial was monitored by both clinical and magnetic resonance imaging (MRI) methods. Clinical effect was a 30% reduction in relapse rate in the group treated with a high dose. The MRI activity rate was reduced by a median of 70% in both treatment groups. The burden of disease measure showed a clear-cut dose effect in the 2-year analysis. Future trials must be monitored by MRI. In addition, placebo controls will continue to be necessary in most trials, especially if long-term effects are to be measured.

Brain↗
PubMed1993

The effect of corticosteroids for acute optic neuritis on the subsequent development of multiple sclerosis. The Optic Neuritis Study Group.

BACKGROUND: Optic neuritis is often the first clinical manifestation of multiple sclerosis, but little is known about the effect of corticosteroid treatment for optic neuritis on the subsequent risk of multiple sclerosis. METHODS: We conducted a multicenter study in which 389 patients with acute optic neuritis (and without known multiple sclerosis) were randomly assigned to receive intravenous methylprednisolone (250 mg every six hours) for 3 days followed by oral prednisone (1 mg per kilogram of body weight) for 11 days, oral prednisone (1 mg per kilogram) alone for 14 days, or placebo for 14 days. Neurologic status was assessed over a period of two to four years. The patients in the first group were hospitalized for three days; the others were treated as outpatients. RESULTS: Definite multiple sclerosis developed within the first two years in 7.5 percent of the intravenous-methyl-prednisolone group (134 patients), 14.7 percent of the oral-prednisone group (129 patients), and 16.7 percent of the placebo group (126 patients). The adjusted rate ratio for the development of definite multiple sclerosis within two years in the intravenous-methylprednisolone group was 0.34 (95 percent confidence interval, 0.16 to 0.74) as compared with the placebo group and 0.38 (95 percent confidence interval, 0.17 to 0.83) as compared with the oral-prednisone group. The beneficial effect of the intravenous-steroid regimen appeared to lessen after the first two years of follow-up. Signal abnormalities on magnetic resonance imaging (MRI) of the brain were a strong indication of risk for the development of definite multiple sclerosis (adjusted rate ratio in patients with three or more lesions, 5.53; 95 percent confidence interval, 2.41 to 12.66). The beneficial effect of treatment was most apparent in patients with abnormal MRI scans at entry. CONCLUSIONS: In patients with acute optic neuritis, treatment with a three-day course of high-dose intravenous methylprednisolone (followed by a short course of prednisone) reduces the rate of development of multiple sclerosis over a two-year period.

Acute Disease↗
PubMed1993

A population-based study of multiple sclerosis in twins: update.

This study is a 7.5-year follow-up of a population-based series of twins with multiple sclerosis (MS) whose mean age now exceeds 50 years. The twin pairs were identified through the Canadian nationwide system of MS clinics and were drawn from a population of 5,463 patients. After 7.5 years, the monozygotic concordance rate increased from 25.9 to 30.8% and the dizygotic-like sex concordance rate from 2.4 to 4.7%. These results are very similar to those of other population-based studies and to our own modified replication twin data reported here. We interpret the data to mean that MS susceptibility is genetically influenced, and a single dominant or even a single recessive gene is unlikely to account for this effect. The difference in concordance rates suggests that at least two or more genes are operative. These data also have important implications for the nature of the environmental effect(s) in MS susceptibility. Most monozygotic twins are discordant even after a correction for age and magnetic resonance imaging findings. This unambiguously demonstrates the powerful effect of nonheritable factors.

Adult↗
PubMed1993

Spin-spin relaxation in experimental allergic encephalomyelitis. Analysis of CPMG data using a non-linear least squares method and linear inverse theory.

We have used the CPMG pulse sequence to measure proton T2 values and water content in spinal cord and brain samples from Hartley guinea pigs inoculated to produce experimental allergic encephalomyelitis (EAE). Relaxation data were fitted using minuit, a non-linear curve fitting routine. Three exponentials provided the best fit to spinal cord data (10 ms (13%), 76 ms (57%), 215 ms (30%)) and two exponentials for brain tissue (10 ms (4%), 92 ms (96%)). Least squares algorithms were also used to analyse the spinal cord data in terms of discrete and smooth distributions of relaxation times. The discrete least squares solutions consisted of three to five isolated spikes between 0.010 and 0.300 s. This type of solution was difficult to interpret in terms of water reservoirs. Smooth solutions consisted of two broad peaks, a small peak with a T2 near 0.010 s and a larger peak near 0.100 s. The integral ratio of the larger to the smaller peak was 7.092 +/- 1.782 for normal tissue, and increased to a maximum of 16 with increasing parenchymal cellular infiltration and demyelination. The short T2 peak has been assigned to water in the hydration layers of the myelin sheath. The width of the longer T2 peak was sensitive to tissue heterogeneity. The least squares and smooth distribution analysis models could be used to distinguish samples with extensive parenchymal infiltration from normal tissue, even though only a maximum of 60% of the tissue was affected.(ABSTRACT TRUNCATED AT 250 WORDS)

Algorithms↗
PubMed1993

The use of magnetic resonance imaging in monitoring interferon therapy of multiple sclerosis.

Magnetic resonance imaging (MRI) was used to evaluate the efficacy of systemic lymphoblastoid interferon therapy in chronic progressive multiple sclerosis. The clinical outcome of this trial has been reported previously. Thirty-six patients with chronic progressive multiple sclerosis were treated with interferon daily for 6 months and 27 received placebo. Patients had MRI at the outset of the study and after 6 and 24 months. Lesion activity and changes in lesion load were determined. As the study progressed, both the interferon- and the placebo-treated group developed more active lesions. There was no difference in lesion activity between the two groups. Comparison of lesion load, however, showed a trend toward improvement after 6 months for the interferon-treated group. This difference between the two groups had disappeared by the end of the study. We conclude that lymphoblastoid interferon was not effective in decreasing active MRI-detected lesions or in decreasing MRI lesion load in patients with chronic progressive multiple sclerosis.

Adult↗
PubMed1993

Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. II. MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial. UBC MS/MRI Study Group and the IFNB Multiple Sclerosis Study Group.

We performed yearly MRI analyses on 327 of the total 372 patients in a multicenter, randomized, double-blind, placebo-controlled trial of interferon beta-1b (IFNB). Clinical results are presented in the preceding companion paper. Baseline MRI characteristics were the same in all treatment groups. Fifty-two patients at one center formed a cohort for frequent MRIs (one every 6 weeks) for analysis of disease activity. The MRI results support the clinical results in showing a significant reduction in disease activity as measured by numbers of active scans (median 80% reduction, p = 0.0082) and appearance of new lesions. In addition, there was an equally significant reduction in MRI-detected burden of disease in the treatment as compared with placebo groups (mean group difference of 23%, p = 0.001). These results demonstrate that IFNB has made a significant impact on the natural history of MS in these patients.

Adult↗
PubMed1993

Magnetic resonance in multiple sclerosis.

Magnetic resonance and various chemical measurements, such as spectroscopy, are being systematically applied to both multiple sclerosis and the experimental model (experimental allergic encephalitis). The dynamic aspects of multiple sclerosis pathology can be visualized on serial magnetic resonance imaging scans, and enhancement techniques help distinguish another type of activity by showing a leaky blood-brain barrier in acute lesions. Quantitative measures applied to the image also appear to provide an index of the burden of disease both in individual patients and in groups. A combination of the dynamic information available from serial studies and the quantitative information concerning burden of disease promises to provide both sensitivity and objectivity to standard outcome measures in multiple sclerosis. In addition, natural history studies of the evolution of magnetic resonance imaging and spectroscopy will revolutionize our understanding of the evolution of the actual tissue changes in multiple sclerosis pathology that can be characterized during life.

Animals↗