An association between autoreactive antibodies and anti-interferon-beta antibodies in multiple sclerosis

Approximately 5-25% of interferon-beta (IFN-beta) treated multiple sclerosis (MS) patients develop anti-IFN-beta neutralizing antibodies (NAb) but the patient-specific variables associated with the risk of developing anti-IFN-beta antibodies are poorly understood. Anti-IFN-beta NAb are a subset of anti-IFN-beta binding antibodies (BAb) and all patients with NAb generally have high levels of associated BAb. The purpose of this research was to assess the association between autoreactive antibodies (ARAB) and the risk of developing anti-IFN-beta BAb in MS patients. This was a retrospective study that included consecutive patients diagnosed with clinically definite MS evaluated at our center and considered appropriate for IFN-beta therapy. The patients were tested for various subtypes of antiphospholipid antibodies (APLA) including anti-phosphatidylethanolamine (APE), anti-phosphatidylserine (APS), and anti-cardiolipin (ACA) antibodies, and other ARAB, antinuclear and anti-neutrophilic cytoplasmic antibodies, anti-thyroid peroxidase antibodies (ATA), anti-SS-A and anti-SS-B antibodies. BAb levels were assessed using a commercial binding ELISA assay. A total of 33 patients (mean age: 45.4 years, 85% female) were enrolled; 15 patients were negative and 18 patients were positive for BAb. APLA or ATA were present in 95% (17 of 18 patients) of patients positive for BAb. In comparison, APLA or ATA occurred in only 27% (four of 15 patients) of patients in the BAb negative group. The associations between the occurrence of BAb and the occurrence of high APLA or ATA were significant (chi2 = 13.4, P<0.001in Fisher exact test). The odds ratio for the association was 46.8 (with a 95% confidence interval range of 4.6-475). No significant correlations were found for other ARAB. The presence of autoreactive antibodies, particularly APLA and ATA is associated with increased risk of occurrence of IFN-beta BAb in MS patients on long-term IFN-beta therapy.     

Clinical and MRI correlates of autoreactive antibodies in multiple sclerosis patients

BACKGROUND: Autoreactive antibodies (ARAB) occur more frequently in patients with multiple sclerosis (MS) than in general population and the presence of these antibodies often causes uncertainty regarding the disease course, response to therapy and the diagnosis of MS. METHODS: Retrospective analyses of the ARAB, clinical and MRI data of a consecutive patient cohort of MS and clinically isolated syndrome (CIS) patients were conducted. The patients were evaluated for an extensive panel that included various subtypes of antiphospholipid antibody (APLA) including anti-phosphatidylethanolamine (APE), anti-phosphatidylserine (APS), anti-beta-2-glycoprotein-1 (ABGP), anti-cardiolipin (ACA), and several other ARAB such as antinuclear antibody (ANA), anti-neutrophilic cytoplasmic antibodies (ANCA), anti-thyroid peroxidase antibodies (ATA), anti-SS-A, and anti-SS-B antibodies. Quantitative MRI analysis was performed in a subgroup of MS patients measuring T2-lesion volume (LV), T1 black hole LV and brain parenchymal fraction (BPF). RESULTS: A total of 137 patients (mean age 44.7, 84% female) with either MS (n=111; age: mean 46.5+/-S.D. 10.3 years; disease duration: mean 13.0+/-S.D. 10.4 years; EDSS: mean 3.2+/-S.D. 1.9) or CIS (n=26; age: mean 37.7+/-S.D. 7.8 years; disease duration: mean 1.3+/-S.D. 1.1 years; EDSS: mean 1.0+/-S.D. 0.7) were enrolled. Among MS patients, 82 were RRMS, 26 SPMS, and 3 had PPMS. Seventy-seven (69%) of MS patients showed presence of one or more ARAB. The proportion of MS patients with APLA was 55% (61 patients); IgM subtype was most frequent. Co-occurrence of ACA and APE was more frequent in SPMS as compared to RRMS (15.4% vs. 1.2%, p=0.012). The proportion of CIS patients with ARAB was 75% with IgM subtype being the most frequent. However, the ARAB in majority of CIS patients (9 out of 14, 64%) were transient on repeated testing. In a subgroup of 62 MS patients, quantitative MRI analysis showed significantly higher T2-LV in patients with positive APLA (15.1 ml for APLA positive vs. 6.75 ml for APLA negative) after correcting for the disease duration (p=0.048). The patients with ATA also had significantly higher T2-LV after correction for disease duration (19.0 ml vs.8.5, p=0.044). CONCLUSIONS: ARAB were present in more than two thirds of MS and CIS patients although most of APLA in CIS were transient. The presence of APLA in MS patients was associated with higher T2-LV.     

Response to oral β-carotene supplementation in patients with cystic fibrosis: a 16-month follow-up study

The aim of this study was to determine the efficacy of long-term oral β -carotene supplementation for correcting impaired β -carotene status in cystic fibrosis patients. Thirty-five patients (2.3-30.5 years of age) with coefficients of fat absorption of 46-96% (median 88%) received β -carotene 0.5 mg/kg daily and were followed over a 16-month treatment period. Baseline plasma β -carotene concentrations in patients (meanSD, 0.090.06 μ mol/1) were significantly lower than those of age-matched controls (0.860.56 μ mol/1) ( p < 0.0001). Concentrations increased rapidly and reached a plateau at or before 3 weeks that was maintained throughout the study period. Values obtained at 3 weeks (0.890.64 μ mol/1) were significantly higher ( p < 0.0001) than those at baseline and did not differ from controls. Plasma retinol and α -tocopherol concentrations increased during the observation period, but remained within normal ranges. Plasma retinyl palmitate, which was below the detection limit in all but one patient at baseline, did not increase. Thus oral β -carotene supplementation is effective and normalizes β -carotene status of cystic fibrosis patients without evidence of significant side effects. β -Carotene, cystic fibrosis, LDL-cholesterol, oral supplementation, retinol, α-tocopherol     

Comparison of the Goldmann-Weekers Dark Adaptometer™ and LKC Technologies Scotopic Sensitivity Tester-1™

The standard for dark adaptation has long been the Goldmann-Weekers Dark Adaptometer (Haag-Streit). More recently, portable, relatively inexpensive LED-based dark adaptometers have become commercially available. These devices have potential use in areas with limited resources to screen for night-blindness, commonly caused worldwide by vitamin A deficiency. In order to determine the sensitivity to detecting changes in night vision, this study compared one such device, LKC Technologies Scotopic Sensitivity Tester-1 (SST- 1) to the Goldmann-Weekers in patients with hereditary retinal degeneration and loss of rod function. Dark-adapted final thresholds and rod full-field ERG responses were obtained from 87 patients and 24 normal subjects. Linear regression analysis, discrepancy analysis, and receiver operator characteristic curves for both devices show that the SST-1 quantifies psychophysical rod function nearly as well as the Goldmann-Weekers, within some limitations. We conclude, therefore, that the SST-1 is a viable alternative to the Goldmann-Weekers for the screening of night-blinding retinal disorders.     

Shape discrimination in age-related macular degeneration

PURPOSE: Recent studies suggest that a global shape-discrimination task is sensitive to neural undersampling and/or irregular sampling, but is not affected by normal aging. In this study, the ability of patients with age-related macular degeneration (AMD) to perform the shape-discrimination task was examined. METHODS: Twenty patients with AMD (age range, 66-81 years) were selected on the basis of Snellen visual acuity of 20/50 or better in at least one eye and prior clinical documentation. A control group consisted of 10 older subjects (age range, 61-93 years) with normal findings in a fundus examination. Radial frequency (RF) patterns were used as stimuli. A spatial paradigm and a temporal two-alternative, forced-choice (2AFC) staircase paradigm were used. In each trial, two RF patterns (one deformed and one undeformed) were presented, and patients were asked to identify the deformed pattern. The peak spatial frequency of RF patterns was 5 cyc/deg; the radial modulation frequency was 8 cyc/360 degrees; mean radii were 0.5 degrees, 1 degrees, 2.0 degrees, or 2.5 degrees; and stimulus contrast was 80%. Thresholds for detecting the deformation were estimated by a maximum-likelihood fitting procedure. RESULTS: Thirty-five of 40 eyes with AMD had 20/50 or better acuity. Among them, 29 eyes had early AMD (drusen, hyperpigmentation, hypopigmentation), 5 had extrafoveal geographic atrophy, and 1 had exudative AMD. With the spatial 2AFC, 91% (32/35) of eyes with AMD showed significant elevation of the threshold for detecting radial deformation of RF patterns when compared with normal control eyes. With the temporal 2AFC, 97% (31/32) of eyes with AMD showed significant threshold elevations, and the degree of the deficit in the shape discrimination did not correlate significantly with visual acuity loss (r = 0.3, P = 0.094). Comparison of the severity of AMD with shape-discrimination performance revealed that the average detection threshold of the eyes with extrafoveal geographic atrophy was significantly higher than that of the eyes with drusen only (P < 0.01), even though average acuity showed no significant difference. CONCLUSIONS: Patients with AMD had significant deficits in performing the global shape-discrimination task. The dissociation of shape discrimination with visual acuity suggests that the shape-discrimination task may provide distinguishable information about the integrity of the photoreceptor mosaic in AMD.     

Accurate prediction of BRCA1 and BRCA2 heterozygous genotype using expression profiling after induced DNA damage.

PURPOSE: In this study, the differential gene expression changes following radiation-induced DNA damage in healthy cells from BRCA1/BRCA1 mutation carriers have been compared with controls using high-density microarray technology. We aimed to establish if BRCA1/BRCA2 mutation carriers could be distinguished from noncarriers based on expression profiling of normal cells. EXPERIMENTAL DESIGN: Short-term primary fibroblast cultures were established from skin biopsies from 10 BRCA1 and 10 BRCA2 mutation carriers and 10 controls, all of whom had previously had breast cancer. The cells were subjected to 15 Gy ionizing irradiation to induce DNA damage. RNA was extracted from all cell cultures, preirradiation and at 1 hour postirradiation. For expression profiling, 15 K spotted cDNA microarrays manufactured by the Cancer Research UK DNA Microarray Facility were used. Statistical feature selection was used with a support vector machine (SVM) classifier to determine the best feature set for predicting BRCA1 or BRCA2 heterozygous genotype. To investigate prediction accuracy, a nonprobabilistic classifier (SVM) and a probabilistic Gaussian process classifier were used. RESULTS: In the task of distinguishing BRCA1 and BRCA2 mutation carriers from noncarriers and from each other following radiation-induced DNA damage, the SVM achieved 90%, and the Gaussian process classifier achieved 100% accuracy. This effect could not be achieved without irradiation. In addition, the SVM identified a set of BRCA genotype predictor genes. CONCLUSIONS: We conclude that after irradiation-induced DNA damage, BRCA1 and BRCA2 mutation carrier cells have a distinctive expression phenotype, and this may have a future role in predicting genotypes, with application to clinical detection and classification of mutations.