Background: Beside the determination of oligoclonal bands (OCBs) as a diagnostic biomarker in multiple sclerosis (MS), the presence of an intrathecal production of antibodies against the neurotropic ...viruses measles (M), rubella (R) and Varicella-Zoster (Z), the so called MRZ reaction (MRZR) is an even more specific diagnostic biomarker in MS.
Methods: We compared and validated the determination of the MRZR in 97 cerebrospinal fluid (CSF) and serum sample pairs of a bead-based multiplexing technique and a classical enzyme-linked immunosorbent assay (ELISA).
Results: Conformity of 94% (M), 94% (R), 94% (Z), 96% (H) and 97% for the interpretation of the MRZR was obtained.
Conclusion: Based on our findings of high conformity between the multiplex technique and classical ELISA, as well as the time and cost savings multiplexing allows, we conclude that the multiplexing technique is applicable as a diagnostic tool for the determination of the MRZR.
The role of mitogen-activated protein kinase (MAPK) pathways in TGF-beta-induced myofibroblast transdifferentiation of human tenon fibroblasts (HTFs) was investigated to identify potential ...pharmacologic targets for the inhibition of scarring after glaucoma surgery.
TGF-beta-dependent activation of Smad2, p38, and Erk-1/2 was examined by Western blot analysis. TGF-beta-induced mRNA expression of collagen Ialpha1, fibronectin, and the myofibroblast transdifferentiation marker alpha smooth muscle actin (alpha-SMA) was analyzed by real-time RT-PCR. alpha-SMA protein expression and subcellular distribution were determined by Western blot analysis and immunofluorescence cytochemistry. Fibroblast contractility was assessed in three-dimensional collagen gel contraction assays, stress fiber assembly with rhodamine-phalloidin stains, and confocal microscopy. Cell proliferation was measured with an MTT assay. Specific pharmacologic kinase inhibitors were used to characterize the involvement of MAPK-dependent pathways.
TGF-beta stimulation of HTF induced a rapid and transient activation of Smad2 and Erk, whereas p38 activation was biphasic and sustained. After 24 hours of TGF-beta stimulation, increased levels of collagen Ialpha1, fibronectin, and alpha-SMA transcripts were detected. After 3 days of stimulation, HTF displayed increased alpha-SMA protein levels, enhanced contractility, and assembly of actin stress fibers. TGF-beta also induced HTF proliferation. Specific p38 inhibitors prevented all these aspects of TGF-beta-induced myofibroblastic transdifferentiation.
Pharmacologic inhibition of p38 abrogates TGF-beta-induced myofibroblast transdifferentiation, reduces extracellular matrix protein expression and HTF proliferation, and may therefore serve to inhibit scarring after glaucoma surgery.
A recent genome-wide association study reported five loci for which there was strong, but sub-genome-wide significant evidence for association with multiple sclerosis risk. The aim of this study was ...to evaluate the role of these potential risk loci in a large and independent data set of ≈ 20,000 subjects. We tested five single nucleotide polymorphisms rs228614 (MANBA), rs630923 (CXCR5), rs2744148 (SOX8), rs180515 (RPS6KB1), and rs6062314 (ZBTB46) for association with multiple sclerosis risk in a total of 8499 cases with multiple sclerosis, 8765 unrelated control subjects and 958 trios of European descent. In addition, we assessed the overall evidence for association by combining these newly generated data with the results from the original genome-wide association study by meta-analysis. All five tested single nucleotide polymorphisms showed consistent and statistically significant evidence for association with multiple sclerosis in our validation data sets (rs228614: odds ratio = 0.91, P = 2.4 × 10(-6); rs630923: odds ratio = 0.89, P = 1.2 × 10(-4); rs2744148: odds ratio = 1.14, P = 1.8 × 10(-6); rs180515: odds ratio = 1.12, P = 5.2 × 10(-7); rs6062314: odds ratio = 0.90, P = 4.3 × 10(-3)). Combining our data with results from the previous genome-wide association study by meta-analysis, the evidence for association was strengthened further, surpassing the threshold for genome-wide significance (P < 5 × 10(-8)) in each case. Our study provides compelling evidence that these five loci are genuine multiple sclerosis susceptibility loci. These results may eventually lead to a better understanding of the underlying disease pathophysiology.
Abstract Multiple sclerosis (MS) patients may experience severe local inflammatory skin reactions during disease-modifying therapy with subcutaneously injected interferon-β (IFN-β). It is common ...clinical practice to switch those patients to an intramuscularly administered formulation, where severe local skin reactions have not been described. Here we report a 42-year-old woman with stable relapsing–remitting MS, who was switched from subcutaneously to intramuscularly injected IFN-β1a due to abdominal skin necroses and slight multifocal lipoatrophy. After two years of complication-free therapy with intramuscular IFN-β1a, the patient slowly developed painful lobular panniculitis and severe lipoatrophy of both lateral thighs. A careful diagnostic workup identified misguided subcutaneous injections due to a wrong injection angle as the most plausible cause. Upon correction of her injection technique, pain and skin reddening resolved, while her disfiguring lipoatrophy was irreversible. This report should enhance awareness that severe skin adverse effects may also occur, although rarely, with IFN-β for intramuscular injection. Early recognition and correction of the injection technique may help to prevent severe complications.
A recent large-scale study in multiple sclerosis (MS) using the ImmunoChip platform reported on 11 loci that showed suggestive genetic association with MS. Additional data in sufficiently sized and ...independent data sets are needed to assess whether these loci represent genuine MS risk factors.
The lead SNPs of all 11 loci were genotyped in 10 796 MS cases and 10 793 controls from Germany, Spain, France, the Netherlands, Austria and Russia, that were independent from the previously reported cohorts. Association analyses were performed using logistic regression based on an additive model. Summary effect size estimates were calculated using fixed-effect meta-analysis.
Seven of the 11 tested SNPs showed significant association with MS susceptibility in the 21 589 individuals analysed here. Meta-analysis across our and previously published MS case-control data (total sample size n=101 683) revealed novel genome-wide significant association with MS susceptibility (p<5×10(-8)) for all seven variants. This included SNPs in or near LOC100506457 (rs1534422, p=4.03×10(-12)), CD28 (rs6435203, p=1.35×10(-9)), LPP (rs4686953, p=3.35×10(-8)), ETS1 (rs3809006, p=7.74×10(-9)), DLEU1 (rs806349, p=8.14×10(-12)), LPIN3 (rs6072343, p=7.16×10(-12)) and IFNGR2 (rs9808753, p=4.40×10(-10)). Cis expression quantitative locus effects were observed in silico for rs6435203 on CD28 and for rs9808753 on several immunologically relevant genes in the IFNGR2 locus.
This study adds seven loci to the list of genuine MS genetic risk factors and further extends the list of established loci shared across autoimmune diseases.
To the Editor:
In their letters about patients who were receiving oral dimethyl fumarate for the treatment of psoriasis, Ermis et al.
1
and van Oosten et al.
2
(April 25 issue) state that progressive ...multifocal leukoencephalopathy (PML) had been diagnosed in two patients. Dimethyl fumarate is the active ingredient in Fumaderm, which since 1994 has been registered for the treatment of psoriasis in Germany. Leukopenia and lymphopenia are known adverse effects of such therapy.
The summary of product characteristics for Fumaderm and current guidelines recommend that in all patients receiving the drug, a differential blood count should be obtained every 2 . . .
Abstract We report on a 51-year-old woman with episodic ataxia type 2 (EA2) and a novel CaV2.1 C-terminal single amino acid substitution (R2090Q). She had a 4-year history of acute episodes with ...ataxia, hemihypesthesia and hemicrania. Furthermore, fluctuating neuromuscular transmission abnormalities rarely described in patients with EA2 were clinically and electrophysiologically documented in this patient. Upon initiation of acetazolamide treatment she experienced a dose-dependent severe increase of attack frequency and severity along with a shorter attack duration, while she responded well to subsequent therapy with 4-aminopyridine.
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