Kappa free light chains is a valid tool in the diagnostics of MS: A large multicenter study.

OBJECTIVE: To validate kappa free light chain (KFLC) and lambda free light chain (LFLC) indices as a diagnostic biomarker in multiple sclerosis (MS). METHODS: We performed a multicenter study including 745 patients from 18 centers (219 controls and 526 clinically isolated syndrome (CIS)/MS patients) with a known oligoclonal IgG band (OCB) status. KFLC and LFLC were measured in paired cerebrospinal fluid (CSF) and serum samples. Gaussian mixture modeling was used to define a cut-off for KFLC and LFLC indexes. RESULTS: The cut-off for the KFLC index was 6.6 (95% confidence interval (CI) = 5.2-138.1). The cut-off for the LFLC index was 6.9 (95% CI = 4.5-22.2). For CIS/MS patients, sensitivity of the KFLC index (0.88; 95% CI = 0.85-0.90) was higher than OCB (0.82; 95%CI = 0.79-0.85; p < 0.001), but specificity (0.83; 95% CI = 0.78-0.88) was lower (OCB = 0.92; 95% CI = 0.89-0.96; p < 0.001). Both sensitivity and specificity for the LFLC index were lower than OCB. CONCLUSION: Compared with OCB, the KFLC index is more sensitive but less specific for diagnosing CIS/MS. Lacking an elevated KFLC index is more powerful for excluding MS compared with OCB but the latter is more important for ruling in a diagnosis of CIS/MS.

Facing privacy in neuroimaging: removing facial features degrades performance of image analysis methods.

BACKGROUND: Recent studies have created awareness that facial features can be reconstructed from high-resolution MRI. Therefore, data sharing in neuroimaging requires special attention to protect participants' privacy. Facial features removal (FFR) could alleviate these concerns. We assessed the impact of three FFR methods on subsequent automated image analysis to obtain clinically relevant outcome measurements in three clinical groups. METHODS: FFR was performed using QuickShear, FaceMasking, and Defacing. In 110 subjects of Alzheimer's Disease Neuroimaging Initiative, normalized brain volumes (NBV) were measured by SIENAX. In 70 multiple sclerosis patients of the MAGNIMS Study Group, lesion volumes (WMLV) were measured by lesion prediction algorithm in lesion segmentation toolbox. In 84 glioblastoma patients of the PICTURE Study Group, tumor volumes (GBV) were measured by BraTumIA. Failed analyses on FFR-processed images were recorded. Only cases in which all image analyses completed successfully were analyzed. Differences between outcomes obtained from FFR-processed and full images were assessed, by quantifying the intra-class correlation coefficient (ICC) for absolute agreement and by testing for systematic differences using paired t tests. RESULTS: Automated analysis methods failed in 0-19% of cases in FFR-processed images versus 0-2% of cases in full images. ICC for absolute agreement ranged from 0.312 (GBV after FaceMasking) to 0.998 (WMLV after Defacing). FaceMasking yielded higher NBV (p = 0.003) and WMLV (p ≤ 0.001). GBV was lower after QuickShear and Defacing (both p < 0.001). CONCLUSIONS: All three outcome measures were affected differently by FFR, including failure of analysis methods and both "random" variation and systematic differences. Further study is warranted to ensure high-quality neuroimaging research while protecting participants' privacy. KEY POINTS: • Protecting participants' privacy when sharing MRI data is important. • Impact of three facial features removal methods on subsequent analysis was assessed in three clinical groups. • Removing facial features degrades performance of image analysis methods.

Vaccines and multiple sclerosis.

An association between certain vaccinations and onset or relapse of multiple sclerosis (MS) has been debated. Based on PubMed, we made a thorough literature review and included all relevant studies, 51 on MS and 15 on optic neuritis (ON). Case studies were excluded. With the exception of a live vaccine against yellow fever, vaccinations appear safe in untreated patients with MS and ON. However, most studies were underpowered, and small risks cannot be excluded. One study of BCG vaccination after the first demyelinating event showed even a reduced risk of developing MS. Further studies are needed to fully exclude a causal association.

Cerebrospinal fluid neurofilament light chain levels predict visual outcome after optic neuritis.

BACKGROUND: Optic neuritis is a good model for multiple sclerosis relapse, but currently no tests can accurately predict visual outcome. OBJECTIVE: The purpose of this study was to examine whether cerebrospinal fluid (CSF) biomarkers of tissue damage and remodelling (neurofilament light chain (NF-L), myelin basic protein, osteopontin and chitinase-3-like-1) predict visual outcome after optic neuritis. METHODS: We included 47 patients with optic neuritis as a first demyelinating episode. Patients underwent visual tests, optical coherence tomography (OCT), magnetic resonance imaging (MRI) and lumbar puncture. Biomarkers were measured in CSF by enzyme-linked immunosorbent assay (ELISA). Patients were followed up six months after onset and this included visual tests and OCT. Outcome measures were inter-ocular differences in low contrast visual acuity (LCVA), retinal nerve fibre layer (RNFL) and ganglion cell layer+inner plexiform layer (GC-IPL) thicknesses. RESULTS: CSF NF-L levels at onset predicted inter-ocular differences in follow-up LCVA (ß=13.8, p=0.0008), RNFL (ß=5.6, p=0.0004) and GC-IPL (ß=4.0, p=0.0008). The acute-phase GC-IPL thickness also predicted follow-up LCVA (ß=12.9, p=0.0021 for NF-L, ß=-1.1, p=0.0150 for GC-IPL). Complete/incomplete remission was determined based on LCVA from 30 healthy controls. NF-L had a positive predictive value of 91% and an area under the curve (AUC) of 0.79 for incomplete remission. CONCLUSION: CSF NF-L is a promising biomarker of visual outcome after optic neuritis. This could aid neuroprotective/regenerative medical advancements.

Cerebrospinal fluid chitinase-3-like 2 and chitotriosidase are potential prognostic biomarkers in early multiple sclerosis.

BACKGROUND AND PURPOSE: The role of chitinases and chitinase-like proteins in multiple sclerosis (MS) is currently unknown; however, cerebrospinal fluid (CSF) levels of chitinase 3-like 1 (CHI3L1) predict prognosis in early MS. Whether this applies to other chitinases and chitinase-like proteins is yet to be established. Our objective was to investigate the potential of chitinase 3-like 2 (CHI3L2) and chitotriosidase as prognostic biomarkers in optic neuritis (ON) as the first demyelinating episode and to evaluate the ability of CHI3L2 to predict long-term MS risk and disability. METHODS: In a prospective cohort of 73 patients with ON as a first demyelinating episode and 26 age-matched healthy controls levels of CHI3L2 and chitotriosidase in CSF were explored by enzyme-linked immunosorbent assay. Associations with magnetic resonance imaging white matter lesions, CSF oligoclonal bands, immunoglobulin G index and leukocyte count were investigated. Long-term MS risk and disability (Expanded Disability Status Scale, Multiple Sclerosis Functional Composite components) were examined in a retrospective cohort of 78 patients with ON as the first demyelinating episode (mean follow-up 14 years). The predictive ability of CHI3L2 was compared with CHI3L1. RESULTS: Cerebrospinal fluid levels of CHI3L2 and chitotriosidase were significantly elevated in patients with ON and were associated with MS risk measures. CHI3L2 levels predicted MS development after ON (hazard ratio 1.95, P = 0.00039, Cox regression) and cognitive impairment by the Paced Auditory Serial Addition Test (P = 0.0357, linear regression) at follow-up. In a multivariate analysis of MS risk, CHI3L2 performed better than CHI3L1. CONCLUSIONS: CHI3L2 and chitotriosidase are promising biomarkers in patients with a first demyelinating episode. Our findings thus support a role for these proteins as biomarkers in early MS.

Minocycline added to subcutaneous interferon ß-1a in multiple sclerosis: randomized RECYCLINE study.

BACKGROUND AND PURPOSE: Combining different therapies may improve disease control in patients with relapsing-remitting multiple sclerosis (RRMS). This study assessed the efficacy and safety of minocycline added to subcutaneous (sc) interferon (IFN) ß-1a therapy. METHODS: This was a double-blind, randomized, placebo-controlled multicentre study. Within 3 months (±1 month) of starting sc IFN ß-1a 44 µg three times weekly, patients with RRMS were randomized to minocycline 100 mg twice daily or placebo, added to sc IFN ß-1a, for 96 weeks. The primary efficacy endpoint was the time to first qualifying relapse. Secondary efficacy endpoints were the annualized relapse rate for qualifying relapses, the number of new/enlarging T2-weighted lesions and change in brain volume [magnetic resonance imaging (MRI) was performed only in a few selected centres]. In addition, a number of tertiary efficacy endpoints were assessed. RESULTS: One hundred and forty-nine patients received minocycline and 155 received placebo; MRI data were available for 23 and 27 patients, respectively. The time to first qualifying relapse did not differ significantly for minocycline versus placebo (hazard ratio 0.85; 95% confidence interval 0.53, 1.35; log-rank = 0.50; P = 0.48). There were no statistically significant differences between the two groups on other efficacy endpoints, although some numerical trends in favour of minocycline were observed. No unexpected adverse events were reported, but more patients discontinued because of adverse events with minocycline versus placebo. CONCLUSION: Minocycline showed no statistically significant beneficial effect when added to sc IFN ß-1a therapy.

Cerebrospinal fluid levels of chitinase 3-like 1 and neurofilament light chain predict multiple sclerosis development and disability after optic neuritis.

BACKGROUND: Cerebrospinal fluid (CSF) biomarkers have been suggested to predict multiple sclerosis (MS) after clinically isolated syndromes, but studies investigating long-term prognosis are needed. OBJECTIVE: To assess the predictive ability of CSF biomarkers with regard to MS development and long-term disability after optic neuritis (ON). METHODS: Eighty-six patients with ON as a first demyelinating event were included retrospectively. Magnetic resonance imaging (MRI), CSF leukocytes, immunoglobulin G index and oligoclonal bands were registered. CSF levels of chitinase-3-like-1, osteopontin, neurofilament light-chain, myelin basic protein, CCL2, CXCL10, CXCL13 and matrix metalloproteinase-9 were measured by enzyme-linked immunosorbent assay. Patients were followed up after 13.6 (range 9.6-19.4) years and 81.4% were examined, including Expanded Disability Status Scale and MS functional composite evaluation. 18.6% were interviewed by phone. Cox regression, multiple regression and Spearman correlation analyses were used. RESULTS: Forty-six (53.5%) developed clinically definite MS (CDMS) during follow-up. In a multivariate model MRI (p=0.0001), chitinase 3-like 1 (p=0.0033) and age (p=0.0194) combined predicted CDMS best. Neurofilament light-chain predicted long-term disability by the multiple sclerosis severity scale (p=0.0111) and nine-hole-peg-test (p=0.0202). Chitinase-3-like-1 predicted long-term cognitive impairment by the paced auditory serial addition test (p=0.0150). CONCLUSION: Neurofilament light-chain and chitinase-3-like-1 were significant predictors of long-term physical and cognitive disability. Furthermore, chitinase-3-like-1 predicted CDMS development. Thus, these molecules hold promise as clinically valuable biomarkers after ON as a first demyelinating event.

Quality control for retinal OCT in multiple sclerosis: validation of the OSCAR-IB criteria.

BACKGROUND: Retinal optical coherence tomography (OCT) permits quantification of retinal layer atrophy relevant to assessment of neurodegeneration in multiple sclerosis (MS). Measurement artefacts may limit the use of OCT to MS research. OBJECTIVE: An expert task force convened with the aim to provide guidance on the use of validated quality control (QC) criteria for the use of OCT in MS research and clinical trials. METHODS: A prospective multi-centre (n = 13) study. Peripapillary ring scan QC rating of an OCT training set (n = 50) was followed by a test set (n = 50). Inter-rater agreement was calculated using kappa statistics. Results were discussed at a round table after the assessment had taken place. RESULTS: The inter-rater QC agreement was substantial (kappa = 0.7). Disagreement was found highest for judging signal strength (kappa = 0.40). Future steps to resolve these issues were discussed. CONCLUSION: Substantial agreement for QC assessment was achieved with aid of the OSCAR-IB criteria. The task force has developed a website for free online training and QC certification. The criteria may prove useful for future research and trials in MS using OCT as a secondary outcome measure in a multi-centre setting.

Neuroprotective and anti-inflammatory mechanisms are activated early in optic neuritis.

OBJECTIVE: The aim of the study was to investigate the expression of different immunological mediators in blood and CSF in patients with acute ON and to estimate whether they were implicated in pro- or anti-inflammatory or even regulatory reactions in comparison with a healthy control group (HC). METHODS: Sixty-four patients between 18 and 59 years of age suffering by acute ON, onset of <4 weeks, were included in the study. Visual tests and brain magnetic resonance imaging (MRI) were performed in ON. Blood and CSF samples were collected from untreated patients and from a gender- and age-matched voluntary HC (n = 32). The mRNA expression of distinct cytokines and neurotrophic factors was assessed by semi/quantitative real-time PCR (RT-PCR). RESULTS: Brain- and glial cell-derived neurotrophic factor (BDNF and GDNF) and interleukin 10 (IL-10) expression was significantly increased in the CSF compared to the blood in both ON and HC (P < 0.001). In the CSF increased levels of BDNF and GDNF of the ON group were positively correlated with the presence of oligoclonal bands (OB). Additionally, patients with gadolinium (gd+) lesions on brain MRI showed increased levels of IL-5 in blood (P = 0.03). CONCLUSION: Our data indicate that both immuno-regulatory and neuroprotective mechanisms may potentially take place relatively early in the course of the ON. The presence of neurotrophic factors in healthy CSF and their overexpression already during the acute phase of ON supports the alertness of CNS defence mechanisms ready to be activated during degenerative events, such as destruction of the myelin.

The socioeconomic consequences of optic neuritis with and without multiple sclerosis: a controlled national study.

OBJECTIVES: Optic neuritis (ON) often precedes multiple sclerosis (MS). MS is associated with a significant socioeconomic burden. However, the burden of ON with and without MS before and after its diagnosis has never been calculated. METHODS: Using complete national records from the Danish National Patient Registry (1998-2006), we identified 1677 patients with ON and compared them with 6708 randomly selected citizens matched for age, sex and geography. A societal perspective is taken towards the cost analyses. Costs included in the analysis are those of the health sector, including all contacts with primary and secondary sectors, and the use and costs of drugs. Productivity losses included labour supply and income. All social transfer payments were also calculated. RESULTS: Patients with ON had higher rates of contact with healthcare services, medication use and income from employment, all of which incurred a higher socioeconomic cost. Employed patients had lower income than control subjects. The total annual excess costs relative to matched controls were €3501 for ON patients and €9215 for patients with a dual diagnosis of ON and MS. The ON and ON+MS patients received an annual mean excess social transfer income of €1175 and €4619. ON/ON+MS patients presented social and economic consequences up to 8 years before diagnosis, and these increased after the diagnosis was established. CONCLUSIONS: ON, especially if combined with a diagnosis of MS, has a significant socioeconomic consequence for the individual patient and for society. Productivity losses are a far more important economic factor than health sector costs.

Immune system alterations in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis is a disease of which the underlying cause and pathogenesis are unknown. Cumulatative data clearly indicates an active participation by the immune system in the disease. An increasingly recognized theory suggests a non-cell autonomous mechanism, meaning that multiple cells working together are necessary for the pathogenesis of the disease. Observed immune system alterations could indicate an active participation in this mechanism. Damaged motor neurons are able to activate microglia, astrocytes and the complement system, which further can influence each other and contribute to neurodegeneration. Infiltrating peripheral immune cells appears to correlate with disease progression, but their significance and composition is unclear. The deleterious effects of this collaborating system of cells appear to outweigh the protective aspects, and revealing this interplay might give more insight into the disease. Markers from the classical complement pathway are elevated where its initiator C1q appears to derive primarily from motor neurons. Activated microglia and astrocytes are found in close proximity to dying motor neurons. Their activation status and proliferation seemingly increases with disease progression. Infiltrating monocytes, macrophages and T cells are associated with these areas, although with mixed reports regarding T cell composition. This literature review will provide evidence supporting the immune system as an important part of ALS disease mechanism and present a hypothesis to direct the way for further studies.

Antibodies to calnexin and mutated calreticulin are common in human sera.

PURPOSE OF THE STUDY: Calreticulin is an endoplasmic reticulum chaperone protein, which is involved in protein folding and in peptide loading of major histocompatibility complex class I molecules together with its homolog calnexin. Mutated calreticulin is associated with a group of hemopoietic disorders, especially myeloproliferative neoplasms. Currently only the cellular immune response to mutated calreticulin has been described, although preliminary findings have indicated that antibodies to mutated calreticulin are not specific for myeloproliferative disorders. These findings have prompted us to characterize the humoral immune response to mutated calreticulin and its chaperone homologue calnexin. PATIENTS AND METHODS: We analyzed sera from myeloproliferative neoplasm patients, healthy donors and relapsing-remitting multiple sclerosis patients for the occurrence of autoantibodies to wild type and mutated calreticulin forms and to calnexin by enzyme-linked immunosorbent assay. RESULTS: Antibodies to mutated calreticulin and calnexin were present at similar levels in serum samples of myeloproliferative neoplasm and multiple sclerosis patients as well as healthy donors. Moreover, a high correlation between antibodies to mutated calreticulin and calnexin was seen for all patient and control groups. Epitope binding studies indicated that cross-reactive antibodies bound to a three-dimensional epitope encompassing a short linear sequence in the C-terminal of mutated calreticulin and calnexin. CONCLUSION: Collectively, these findings indicate that calreticulin mutations may be common and not necessarily lead to onset of myeloproliferative neoplasm, possibly due to elimination of cells with mutations. This, in turn, may suggest that additional molecular changes may be required for development of myeloproliferative neoplasm.

Tau protein: a possible prognostic factor in optic neuritis and multiple sclerosis.

BACKGROUND: Tau protein has been proposed as biomarker of axonal damage leading to irreversible neurological impairment in MS. CSF concentrations may be useful when determining risk of progression from ON to MS. OBJECTIVE: To investigate the association between tau protein concentration and 14-3-3 protein in the cerebrospinal fluid (CSF) of patients with monosymptomatic optic neuritis (ON) versus patients with monosymptomatic onset who progressed to multiple sclerosis (MS). To evaluate results against data found in a complete literature review. METHODS: A total of 66 patients with MS and/or ON from the Department of Neurology of Glostrup Hospital, University of Copenhagen, Denmark, were included. CSF samples were analysed for tau protein and 14-3-3 protein, and clinical and paraclinical information was obtained from medical records. RESULTS: The study shows a significantly increased concentration of tau protein in CSF from patients with relapsing-remitting MS and patients monosymptomatic at onset who progressed to MS, but interestingly no increased tau protein concentration in monosymptomatic ON. The concentration of tau protein was significantly correlated to Expanded Disability Status Scale score. No 14-3-3 protein was detected in any CSF sample. CONCLUSIONS: The results of this study invite further exploration of the possible role of tau protein as a prognostic factor to predict progression from ON to MS in future studies.

Virus-specific antibody indices may supplement the total IgG index in diagnostics of multiple sclerosis.

Intrathecal antibody synthesis to viruses is associated with multiple sclerosis (MS). Here, IgG levels to Epstein-Barr virus (EBV) BamHI-A rightward frame 1 (BARF1), EBV nuclear antigen 1 (EBNA1), mumps virus (MuV) nucleoprotein (NuP), measles virus (MeV) NuP and rubella virus (RuV) capsid protein (CaP) were found to be elevated in serum and cerebrospinal fluid (CSF) of MS patients compared to healthy controls (HCs), whereas the opposite was found for cytomegalovirus (CMV) pp52. Strong correlations between serum and CSF IgG were seen for MeV, CMV and RuV in both MS patients and HCs. The antigen panel obtained high sensitivity (81%) and specificity (86%), demonstrating that antigen panels may supplement the total IgG index used in MS diagnosis.

Oligoclonal bands predict multiple sclerosis after optic neuritis: a literature survey.

BACKGROUND: Multiple sclerosis (MS) is an autoimmune disease resulting in inflammation and demyelination of neurones in the central nervous system (CNS). The first sign of MS is often monosymptomatic optic neuritis (MON). Cerebrospinal fluid from a patient with MS analysed by electrophoresis often shows a split to form so called oligoclonal bands (OCBs). OCBs consist of proteins from activated lymphocytes and plasma cell clones. OBJECTIVES: The aim of this study was to review the published literature on OCBs in MON patients and perform a meta-analysis of the studies in order to assess the utility of OCB determination in patients with MON in the prediction of their risk of MS. METHODS: Review and meta-analysis of the results of 10 published studies. RESULTS: OCBs as a predictive test had a sensitivity of 73-100% (mean 88.5%), a specificity of 41-90% (mean 57%) and OR-values between 2.75 and 171 (mean 34.2). The areal under the summary receiver operator characteristic (ROC) curve was 0.89 (unweighted) and 0.82 (weighted). The studies showed large heterogeneity in the diagnostic accuracy. CONCLUSION: This literature-based meta-analysis provides evidence that OCBs may have a high predictive value for the development of MS in patients with MON. Standardization of laboratory methods and diagnostic criteria would help bring out the full clinical potential of the test. To elucidate the predictive value of OCBs versus MRI, we recommend that a similar meta-analysis of studies of MRI in MON be performed.

A community health worker program for the prevention of malaria in eastern Kenya.

OBJECTIVE: To assess whether the development and implementation of a community health worker (CHW) project in rural Kenya was associated with an increase in knowledge about malaria and the use of insecticide-treated nets (ITNs) in children under five years of age. METHODS: A baseline knowledge and behavior questionnaire, adopted from the Kenyan Demographic Health Survey, was conducted in August 2007 by Kenyan health officials in 75 villages. Two CHWs were chosen from each village and trained in appropriate use of ITNs. The CHWs provided educational sessions and ITNs to mothers in their respective villages. A follow-up survey was conducted in March 2008 of all families with children less than five years of age within randomly selected villages. The main questions addressed during the follow-up survey included knowledge about malaria and the practice of correctly using ITNs. FINDINGS: There were 267 surveys compiled for knowledge assessment before the intervention and 340 in the post-intervention analysis with an approximate 99% family participation rate. Of the families surveyed, 81% correctly knew the cause for malaria before the study and 93% after the CHW intervention (p < 0.01). Of those surveyed before the intervention, 70% owned and correctly used mosquito nets compared with 88% after the CHW intervention (p < 0.01). CONCLUSIONS: There was a significant increase in knowledge about malaria and use of ITNs after the implementation of the CHW program.

The value of conventional high-field MRI in MS in the light of the McDonald criteria: a literature review.

The diagnosis of MS is based on the revised McDonald criteria and is multidisciplinary. Both clinical and paraclinical measures are included. High-field magnetic resonance imaging (MRI) is becoming increasingly available and it is therefore necessary to clarify possible advantages of high-field MRI in MS. The aim of this paper was to review MRI studies in MS where a direct comparison of MRI at high field with MRI at 1-1.5 tesla (T) had been performed. The studies evaluated were found by searching Pubmed with relevant terms including MeSH terms. The reviewed studies all found the conspicuity of lesions to be better at high field. Of the seven studies, six found more and bigger lesions at high-field MRI. In the present paper, the relevant MRI sequences are evaluated in detail. The detection of more lesions at high-field strength did not seem to lead to earlier diagnosis of clinically definite multiple sclerosis. Further larger studies of patients with clinically isolated syndromes are needed to settle the question of a diagnostic consequence of high-field imaging in MS. We suggest that the next revision of the McDonald diagnostic criteria include a recommendation of field strength.

Highly sensitive quantification of optic neuritis intrathecal biomarker CXCL13.

BACKGROUND: Elevation of CXCL13, a key regulator of B-cell recruitment in cerebrospinal fluid (CSF) is implicated in multiple sclerosis (MS). OBJECTIVE: to evaluate if measurement of CXCL13 using a highly sensitive assay is of value in acute optic neuritis (ON) patients for the prediction of later MS. METHOD: CXCL13 was measured by Simoa in two independent treatment-naïve ON cohorts, a training cohort (TC, n = 33) originating from a population-based cohort, a validation cohort (VC, n = 30) consecutively collected following principles for population studies. Prospectively, 14/33 TC and 12/30 VC patients progressed to MS (MS-ON) while 19/33 TC and 18/30 VC patients, remained as isolated ON (ION). RESULTS: CXCL13 was detectable in all samples and were higher in ON compared with healthy controls (HC) (p = 0.012). In the TC, CSF levels in MS-ON were higher compared with ION patients and HC (p = 0.0001 and p<0.0001). In the VC, we confirmed the increase of CXCL13 in MS-ON compared to ION (p = 0.0091). Logistic regression analysis revealed an area under receiver operating characteristic curve of 0.83 [95% C.I: 0.73-0.93]. CONCLUSIONS: The highly sensitive CXCL13 Simoa assay demonstrated ability to identify ON patients and separate MS-ON from ION, and predictive diagnostic values indicates a promising potential of this assay.

Fas preassociation required for apoptosis signaling and dominant inhibition by pathogenic mutations.

Heterozygous mutations encoding abnormal forms of the death receptor Fas dominantly interfere with Fas-induced lymphocyte apoptosis in human autoimmune lymphoproliferative syndrome. This effect, rather than depending on ligand-induced receptor oligomerization, was found to stem from ligand- independent interaction of wild-type and mutant Fas receptors through a specific region in the extracellular domain. Preassociated Fas complexes were found in living cells by means of fluorescence resonance energy transfer between variants of green fluorescent protein. These results show that formation of preassociated receptor complexes is necessary for Fas signaling and dominant interference in human disease.

A search for new MRI criteria for dissemination in space in subjects with a clinically isolated syndrome.

The International Panel on the Diagnosis of Multiple Sclerosis (MS) incorporated the Barkhof/Tintoré (B/T) magnetic resonance criteria into their diagnostic scheme to provide evidence of dissemination in space of central nervous system lesions, a prerequisite for diagnosing MS in patients who present with clinically isolated syndromes (CIS). Although specific for MS, the B/T criteria were criticised for their low sensitivity and relative complexity in clinical use. We used lesion characteristics at onset from 349 CIS patients in logistic regression and recursive partitioning modelling in a search for simpler and more sensitive criteria, while maintaining current specificity. The resulting models, all based on the presence of periventricular and deep white matter lesions, performed roughly in agreement with the B/T criteria, but were unable to provide higher diagnostic accuracy based on information from a single scan. Apparently, findings from contrast-enhanced and follow-up magnetic resonance scans are needed to improve the diagnostic algorithm.