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Biomedical subjects

L A Stone

Publications and source records attributed to L A Stone.

At least 19 recordsLinked to original sources
PubMed2004

Randomized multicenter trial of natalizumab in acute MS relapses: clinical and MRI effects.

BACKGROUND: Relapses in multiple sclerosis (MS) can cause significant neurologic disability. Natalizumab (Antegren) is a humanized anti-alpha4-integrin antibody that inhibits the trafficking of leukocytes across endothelium by blocking binding of alpha4beta1-integrin to vascular cell adhesion molecule-1. OBJECTIVE: To assess the effects of a single dose of IV natalizumab administered soon after the onset of MS relapses. METHODS: In this randomized, double-blind, multicenter trial, the effects of a single dose of IV natalizumab administered soon after the onset of MS relapses were assessed. MS patients (n = 180) in acute relapse were randomly assigned to receive a single dose of natalizumab 1 or 3 mg/kg or placebo and were followed for 14 weeks. RESULTS: There was no difference in Expanded Disability Status Scale (EDSS) score change over time between treatment and placebo groups. In all three groups, approximately half of patients showed EDSS improvement after 2 weeks, rising to 67% by 8 weeks. EDSS improved by a mean value of 0.8 point at week 1, 1.2 points at week 4, and 1.6 points at week 8 in the natalizumab group compared with EDSS improvement of 1.0 point at week 1, 1.6 points at week 4, and 1.6 points at week 8 in the placebo group. A significant decrease in Gd-enhancing lesion volume was seen in both active treatment groups at weeks 1 and 3 compared with placebo. CONCLUSIONS: A single dose of IV natalizumab did not hasten clinical recovery after relapse, although a significant decrease in Gd-enhancing lesion volume was observed at 1 and 3 weeks after treatment. These MRI findings are consistent with prior studies of natalizumab and support its further investigation as an agent for the treatment of MS.

Acute Disease↗
PubMed1999

A safety and pharmacokinetic study of intravenous natalizumab in patients with MS.

A phase 1, randomized, placebo-controlled, five-level dose escalation safety and tolerability and pharmacokinetic study of a single IV dose of natalizumab was performed. Doses of 0.03 to 3.0 mg/kg natalizumab or placebo were studied in 28 stable relapsing-remitting or secondary-progressive MS. All doses were safe and well tolerated in MS. Serum concentrations of natalizumab are detectable for 3 to 8 weeks after a single 1- or 3-mg/kg IV dose and justify controlled efficacy studies.

Adult↗
PubMed1997

Increases in soluble VCAM-1 correlate with a decrease in MRI lesions in multiple sclerosis treated with interferon beta-1b.

Interferon beta-1b reduces clinical exacerbations and disease activity in multiple sclerosis as shown by magnetic resonance imaging, but the mechanism of action is unknown. We investigated the correlation between the levels of soluble adhesion molecules and a reduction in contrast-enhancing lesions on gadopentetate dimeglumine magnetic resonance images after treatment with interferon beta-1b. We determined levels of soluble vascular cell adhesion molecule-1, intercellular adhesion molecule-1, E-selectin, L-selectin, and tumor necrosis factor receptor (60 kd) in monthly serum samples from patients with definite multiple sclerosis before and during treatment with interferon beta-1b. The level of soluble adhesion molecules was correlated with the number of newly enhancing lesions on monthly contrast-enhanced images. Levels of soluble vascular cell adhesion molecule during treatment were significantly increased compared to control or pretreatment values. The median levels (ng/ml) of this adhesion molecule were 580.3 (range; 373.0-640.7) for the healthy subjects, and 551.4 (489.7-875.5) for patients prior to treatment and 847.9 (591.5-1,232.9) during treatment. Levels of the other soluble adhesion molecules and soluble tumor necrosis factor receptor were not significantly changed during treatment. The increase in soluble vascular cell adhesion molecule correlated with a decrease in the number of contrast-enhancing lesions on magnetic resonance images. These data suggest a novel mechanism of action for interferon beta-1b by direct interference with the adhesion cascade, which may prevent activated T cells from trafficking into the central nervous system.

Adult↗
PubMed1997

Clinical safety of serial monthly administrations of gadopentetate dimeglumine in patients with multiple sclerosis: implications for natural history and early-phase treatment trials.

Serial contrast magnetic resonance imaging (MRI) has played an increasingly important role in understanding natural-history and early-treatment trials of multiple sclerosis patients. The purpose of this study is to determine whether the serial administration of gadopentetate dimeglumine at the conventional dose has any demonstrable effect on routine hematologic or serum chemistries. This study followed 56 patients with multiple sclerosis in a longitudinal natural-history trial using contrast-enhanced MRI scans over a four-year period between 1988 and 1993. Patients received between 3 and 53 doses of gadopentetate dimeglumine at 0.1 mmol/kg intravenously. A retrospective review of regular blood screening tests over this period identified no significant effect either on routine hematologic studies, as defined by complete blood count (hemoglobin, hematocrit, platelet and white blood cell counts, and mean corpuscular volume); standard serum chemistry studies, including electrolytes (sodium, potassium, chloride) and renal and liver function tests; or serum iron profiles. We conclude, therefore, that serial contrast-enhanced MRIs can be used safely as an outcome measure for Phase I/II evaluations of new therapies for multiple sclerosis.

Adult↗
PubMed1997

Interferon beta results in immediate reduction of contrast-enhanced MRI lesions in multiple sclerosis patients followed by weekly MRI.

Interferon beta-1a and -1b reduce the frequency and severity of clinical exacerbations, and reduce both T2-weighted and contrast-enhanced MRI activity in patients with multiple sclerosis (MS). Several recent reports suggest that at the initiation of treatment there may be transient worsening of symptoms associated with the induction of interferon gamma-secreting cells. We studied eight MS patients with weekly brain MRI's after starting interferon beta treatment, and found immediate reduction in the number of contrast-enhancing lesions. Several patients did experience recurrence of previous symptoms without concomitant opening of the blood brain barrier on contrast-enhanced MRI. These data suggest that the symptoms described after the initiation of interferon beta are not associated with new disease activity, but rather may be related to preexisting lesions. This has implications for both understanding the immunopathogenesis of the disease and for its treatment.

Adult↗
PubMed1997

Characterization of MRI response to treatment with interferon beta-1b: contrast-enhancing MRI lesion frequency as a primary outcome measure.

MRI is a valuable tool to examine the pathophysiology and natural history of multiple sclerosis (MS), and several large multicenter trials have utilized MRI as a secondary outcome measures. We previously examined the effect of interferon beta-1b on contrast-enhancing lesions on MRI using a baseline versus treatment design, and found that on treatment there is a reduction in mean frequency of enhancing lesions over the group. Using an expanded number of patients and the same trial design, we examined the individual response to treatment more extensively. We find that the effect seen previously is still present, and that there is heterogeneity in the amount of decrease in contrast-enhancing lesions. This expanded number of patients and trial design allows for the discussion of new criteria for individual response to treatment, which are applied in the current trial. These approaches may be useful in the examination, early testing, and comparison of experimental therapeutic agents in MS as well as in the characterization of patients who do or do not have a response seen on MRI.

Adjuvants, Immunologic↗
PubMed1996

Expression pattern of activation and adhesion molecules on peripheral blood CD4+ T-lymphocytes in relapsing-remitting multiple sclerosis patients: a serial analysis.

We studied the expression of various cell surface molecules (CD25, CD28, CD29, CD45RO, CD56, LFA-1, VLA-4) on peripheral blood CD4+ T-cells in 6 relapsing-remitting multiple sclerosis (RR-MS) patients. Furthermore, changes in the expression pattern of these surface markers during intervals of increased disease activity, which was measured by gadolinium (Gd-DTPA) magnetic resonance imaging (MRI) were examined. Although several patients showed signs of increased disease activity during the observation period, this was not paralleled by a relevant change in the expression of these activation and adhesion molecules.

Adult↗
PubMed1996

Humpty Dumpty.

Explore the source record for details and available documents.

Adolescent↗
PubMed1996

MRI studies of multiple sclerosis: implications for the natural history of the disease and for monitoring effectiveness of experimental therapies.

The use of magnetic resonance imaging (MRI) in multiple sclerosis (MS) has increased in our understanding of the natural history of the disease course and has provided and important tool for the analysis of new experimental therapies. Studies using MRI as well as pathological studies of MS indicate that the first event in the development of a new MS lesion as seen on T2 weighted images is disruption of the blood brain barrier (BBBD) which can be demonstrated by areas of increased signal on T1 weighted images done after the administration of gadolinium DTPA. When GdDTPA enhanced MRIs are used to monitor disease activity in patients with mild relapsing remitting MS, a considerable degree of disease activity is observed in clinically stable patients. These findings indicate that MS is an active and progressive disease in most patients even during the earliest phases of the disease and before significant clinical disability has occurred. MRI is also an important tool in evaluating new therapies. Using simple baseline vs treatment designs evidence for an effect of a new treatment on MRI parameters such as Gd-DTPA enhanced measure of BBBD can be achieved using a small study cohort and over a short duration. Together these advances should lead to more rapid progress in the understanding of MS and in identifying new treatments.

Adult↗
PubMed1995

The effect of interferon-beta on blood-brain barrier disruptions demonstrated by contrast-enhanced magnetic resonance imaging in relapsing-remitting multiple sclerosis.

Magnetic resonance imaging (MRI) has been a valuable tool to understand the pathophysiology and natural history of multiple sclerosis (MS), and increasing attention is focusing on the use of MRI findings as outcome measures in treatment trials in MS. The recently completed trial of interferon-beta-1b (IFN-beta 1b) demonstrated a decrease in accumulation of diseased tissue on T2-weighted images and a reduction in new lesions on T2-weighted images. To examine the effect of IFN-beta 1b on blood-brain barrier (BBB) breakdown, and to provide additional insights into the usefulness of MRI in the evolution of effectiveness of experimental treatments in MS, we used the contrast-enhanced lesion frequency of 7-month baseline MRIs compared with the enhanced lesion frequency for 6-month treatment period MRIs in 14 relapsing-remitting (RR) MS patients. Longer baselines were also available for analysis in a subset of 8 patients, as these patients had been followed by monthly MRI in a natural history study for up to 4 years prior to the current study. A significant reduction in the total or new enhancing lesion frequency was detected in the patients analyzed as a whole, and 13 of 14 of the patients demonstrated a reduction in enhancing lesion frequency on treatment over the 6 months studied. These findings suggest that IFN-beta has a mechanism of action that at least temporarily inhibits the opening of the BBB in RRMS patients. This trial also illustrates the usefulness of a baseline versus treatment trial design to evaluate the effect of drug therapy in MS.

Adult↗
PubMed1995

Changes in the amount of diseased white matter over time in patients with relapsing-remitting multiple sclerosis.

MRI is a sensitive technique for assessing disease activity in MS. Diseased white matter (WM) can be identified on T2-weighted images, and active disease is reflected by abnormalities in the blood-brain barrier (BBB) shown on T1-weighted images after administration of paramagnetic contrast agents. Active disease may be demonstrated by contrast-enhanced MRI in patients with early, mild relapsing-remitting (RR) MS even during periods of clinical stability, which indicates that MS is an active process even during the early phase of the illness. To examine the amount of abnormal WM at frequent intervals over time, we studied seven mildly affected RRMS patients, all of whom had frequent contrast-enhancing lesions. These RRMS patients were imaged monthly for 26 to 36 months at 1.5 tesla; the area of abnormal increased WM signal was calculated by image-processing software that utilizes both the T2- and T1-weighted images. All patients showed fluctuations over time in amount of abnormal WM signal, which reflected factors such as the amount of BBB breakdown (measured by number or area of enhancing lesions) and measurement error. All seven RRMS patients, however, showed an overall increase in abnormal WM. Because of the fluctuations between individual measurements, the increase was most accurately reflected when the mean of the first 6 months' measurements was compared with the mean of the final 6 months' measurements, or when a linear regression model was applied.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Blood-brain barrier disruption on contrast-enhanced MRI in patients with mild relapsing-remitting multiple sclerosis: relationship to course, gender, and age.

MRI has provided insight into the pathophysiology and course of MS, particularly through the use of a paramagnetic contrast agent that allows visualization of blood-brain barrier (BBB) breakdown. Neither the overall frequency of BBB breakdown in MS patients nor the characteristics associated with BBB breakdown in MS are known. We studied 68 relapsing-remitting MS (RRMS) patients with three monthly MRIs to examine these questions. Seventy-eight percent of the RRMS patients studied had evidence of BBB breakdown on at least one MRI. While there was a great deal of variability among patients in terms of mean enhancing lesion frequency, BBB breakdown was associated with younger age at onset of disease, measured by age at first symptom or age at diagnosis, and more severe disease as measured by Expanded Disability Status Scale scores equal to or greater than 4.0. We found no relationship between BBB breakdown and duration of disease or gender. We conclude that BBB breakdown is a relatively common phenomenon in RRMS patients and may be most commonly found in patients with more aggressive disease and younger onset. These findings have implications for clinical trials that use MRI as an outcome measure.

Adolescent↗
PubMed1994

Correlation of clinical features and findings on cranial magnetic resonance imaging with urinary myelin basic protein-like material in patients with multiple sclerosis.

Immunoreactive material that appears to be a peptide encompassing all or a portion of residues 80 to 89 of myelin basic protein is present in normal unconcentrated urine and is increased in certain patients with multiple sclerosis (MS). Compared with normal controls, urines collected randomly from 158 MS patients or in a clinical research unit from 8 patients with MS had higher mean values of urinary MBP-like material (MBPLM). The level of MBPLM in urine showed no direct relationship to MBPLM in cerebrospinal fluid and did not correlate with clinical relapses of disease. In the other neurological disease control group (26 patients), some patients with other inflammatory diseases, but not stroke or early phase Guillain-Barré syndrome, also showed elevations. Among the subtypes of MS, those with secondary chronic progressive disease had the highest values. Urinary MBPLM showed no definite correlation with or effect of treatment with glucocorticoids and immunosuppressants except that a lower level of urinary MBPLM showed a weak relationship with improvement following treatment with methylprednisolone/prednisone. In a serial study of 8 patients with unenhanced cranial magnetic resonance imaging and 20 patients with gadolinium-enhanced cranial magnetic resonance imaging, urinary MBPLM did not show a direct correlation with new or enhancing lesions. Urinary MBPLM does not parallel acute myelin damage but appears to reflect an ongoing process, possibly linked to attempted efforts at remyelination.

Adult↗
PubMed1994

Serial contrast-enhanced magnetic resonance imaging in patients with early relapsing-remitting multiple sclerosis: implications for treatment trials.

Serial monthly contrast-enhanced MRIs were performed in 10 early relapsing-remitting patients with multiple sclerosis and 2 patients with chronic progressive disease for a period of 12 to 55 months. MRI was performed at 1.5 T using contiguous 5-mm slices with pre- and postgadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) T1-weighted and T2-weighted images. New and total number of Gd-DTPA-enhancing lesions were numbered and counted and lesion areas were correlated to an increase of > or = 0.5 in Expanded Disability Status Scale (EDSS) scores. The frequency of enhancing lesions varied from patient to patient; however, there was a correlation between a burst of enhancing lesion number and area above the individual's mean lesion frequency to an increase in EDSS score. A bootstrap analysis of the lesion count was performed to develop a statistical basis for determining population sizes for treatment trials. These results provide a basis for the potential use of contrast-enhanced MRI as a primary outcome measure in phase II treatment trials involving patients with relapsing-remitting MS.

Adult↗
PubMed1993

Clinical worsening in multiple sclerosis is associated with increased frequency and area of gadopentetate dimeglumine-enhancing magnetic resonance imaging lesions.

It is now well established that clinically stable patients with relapsing-remitting multiple sclerosis have ongoing disease activity when evaluated by serial gadolinium-enhanced (Gd-DTPA) magnetic resonance imaging (MRI) scans. Despite this, the relationship between clinical disease and MRI lesions, though suspected, has not been extensively documented. The relationship between Gd-DTPA MRI lesions and clinical disease was examined in this study of 9 patients with mild relapsing-remitting multiple sclerosis (Expanded Disability Status Scale [EDSS] < 3.5) who had 24 to 37 monthly Gd-DTPA MRI scans, neurological examinations, and EDSS score assignments. The area and frequency of Gd-DTPA lesions were examined during months with and without clinical worsening as measured by EDSS. Forty-one episodes of clinical worsening were noted during the study. A significant association was observed between these periods of clinical worsening and MRI parameters, including increases in total number, number of new lesions, and the total area of enhancement. Logistic regression analysis showed a significant effect of the number and area of Gd-DTPA MRI lesions on both the onset and continuation of clinical worsening, confirming an important relationship between clinical disease and an increase in cerebral Gd-DTPA MRI activity. A relationship with long-term disability was suggested, but cannot be confirmed without longer follow-up of these patients.

Adult↗
PubMed1991

The coexistence of tics and dystonia.

We studied nine patients with motor and phonic tics and other features of Tourette's syndrome, who developed persistent dystonia in addition to their tics. All, except one, were males (mean age, 35.8 years; range, 8 to 59 years), and had onset of tics prior to age 18 years (mean age, 9 years; range, 1.5 to 17 years). None of the patients were treated with neuroleptic drugs prior to the onset of dystonia. Torticollis and blepharospasm were the most common forms of dystonia. Seven patients had a history of tics in first degree relatives. While these patients were seen in a specialized movement disorder clinic and may, therefore, represent a population with atypical and more severe symptoms, the high prevalence rate of dystonia (5.0% of all patients with Tourette's syndrome seen in the clinic) suggests that some patients with tics may have an increased risk for dystonia.

Adolescent↗
PubMed1991

Vitamin D receptors and compensatory tissue growth in spontaneously diabetic BB rats.

Untreated diabetic (BB) rats exhibited compensatory intestinal growth which was associated with hyperplasia and was accompanied by an increase in unoccupied vitamin D receptors. Although vitamin D receptors were increased, low circulating 1,25-dihydroxy-vitamin D3 [1,25(OH)2D3] prevented amplification of the action of 1,25(OH)2D3, as evidenced by reductions in calbindin D-9K and alkaline phosphatase activity in the BB rat intestine compared to control. In the kidney, a lesser degree of compensatory growth was observed which was not associated with hyperplasia, and no significant effect of diabetes on vitamin D receptors or calbindin D-28K was observed. These studies suggest tissue-specific changes in 1,25(OH)2D3 metabolism during spontaneous diabetes which may be related to the hyperplasia which occurs during compensatory tissue growth.

Animals↗