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Find video protocols related to scientific articles indexed in Pubmed.
Testicular hypofunction and multiple sclerosis risk: A record-linkage study.
Ann. Neurol.
PUBLISHED: 08-30-2014
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The influence of gonadal hormones on multiple sclerosis (MS) is not well characterized and has thus far been investigated primarily in animal models or as a proposed therapeutic approach. We investigated a potential association between testicular hypofunction, as a proxy for low testosterone levels, and MS risk through analysis of linked English national Hospital Episode Statistics from 1999 to 2011. We report a strong positive association between testicular hypofunction and subsequent MS (rate ratio = 4.62, 95% confidence interval = 2.3-8.24, p < 0.0001). Future work should aim more directly to elucidate the relationship between testosterone levels and MS in both males and females. Ann Neurol 2014;76:625-628.
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Guidelines for uniform reporting of body fluid biomarker studies in neurologic disorders.
Neurology
PUBLISHED: 08-22-2014
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The aim of these guidelines is to make the process of reporting body fluid biomarker studies in neurologic disorders more uniform and transparent, in line with existing standards for reporting research in other biomedical areas. Although biomarkers have been around for decades, there are concerns over the high attrition rate of promising candidate biomarkers at later phases of development.
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HIV and lower risk of multiple sclerosis: beginning to unravel a mystery using a record-linked database study.
J. Neurol. Neurosurg. Psychiatr.
PUBLISHED: 08-06-2014
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Even though multiple sclerosis (MS) and HIV infection are well-documented conditions in clinical medicine, there is only a single case report of a patient with MS and HIV treated with HIV antiretroviral therapies. In this report, the patient's MS symptoms resolved completely after starting combination antiretroviral therapy and remain subsided for more than 12?years. Authors hypothesised that because the pathogenesis of MS has been linked to human endogenous retroviruses, antiretroviral therapy for HIV may be coincidentally treating or preventing progression of MS. This led researchers from Denmark to conduct an epidemiological study on the incidence of MS in a newly diagnosed HIV population (5018 HIV cases compared with 50?149 controls followed for 31?875 and 393?871 person-years, respectively). The incidence rate ratio for an HIV patient acquiring MS was low at 0.3 (95% CI 0.04 to 2.20) but did not reach statistical significance possibly due to the relatively small numbers in both groups. Our study was designed to further investigate the possible association between HIV and MS.
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Growth associated protein (GAP-43): Cloning and the development of a sensitive ELISA for neurological disorders.
J. Neuroimmunol.
PUBLISHED: 07-23-2014
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GAP-43 has been studied in the rodent and mammalian brain and shown to be present specifically in areas undergoing axonal elongation and synapse formation. GAP-43 was cloned using the baculovirus expression system and purified. A sandwich ELISA was developed using the recombinant GAP-43 as standard and validated. CSF GAP-43 levels were analysed in benign intracranial hypertension, movement disorders, multiple sclerosis, neuropathy, CNS infections, motor neuron disease, and headache (neurological controls). GAP-43 levels were low in all disorders analysed (in particular motor neuron disease; p=0.001, and movement disorders and multiple sclerosis; p<0.0001) compared to controls, aside from CNS infections. GAP-43 is preferentially reduced in the CSF of neurological disorders associated with neurodegeneration.
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Plasma neurofilament heavy chain levels and disease progression in amyotrophic lateral sclerosis: insights from a longitudinal study.
J. Neurol. Neurosurg. Psychiatr.
PUBLISHED: 07-11-2014
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To investigate the role of longitudinal plasma neurofilament heavy chain protein (NfH) levels as an indicator of clinical progression and survival in amyotrophic lateral sclerosis (ALS).
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Efficacy and safety of delayed-release dimethyl fumarate in patients newly diagnosed with relapsing-remitting multiple sclerosis (RRMS).
Mult. Scler.
PUBLISHED: 07-04-2014
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Delayed-release dimethyl fumarate (DMF) demonstrated efficacy and safety in the Phase 3 DEFINE and CONFIRM trials.
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Serum neurofilament light chain is a biomarker of human spinal cord injury severity and outcome.
J. Neurol. Neurosurg. Psychiatr.
PUBLISHED: 06-18-2014
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Neurofilaments (Nf) are major structural proteins that occur exclusively in neurons. In spinal cord injury (SCI), the severity of disease is quantified by clinical measures that have limited sensitivity and reliability, and no blood-based biomarker has been established to further stratify the degree of injury. We aimed to examine a serum-based NfL immunoassay as predictor of the clinical outcome in SCI.
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National survey of UK medical students on the perception of neurology.
BMC Med Educ
PUBLISHED: 03-27-2014
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Medical students perceive neurology to be a difficult subject, a phenomenon described as "neurophobia". Studies investigating student attitudes towards neurology have so far been limited by small sample sizes as a consequence of being conducted within a single medical school or region. We aimed to conduct the first national survey of the perception of neurology among UK medical students.
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Effects of Delayed-Release Dimethyl Fumarate (DMF) on Health-Related Quality of Life in Patients With Relapsing-Remitting Multiple Sclerosis: An Integrated Analysis of the Phase 3 DEFINE and CONFIRM Studies.
Clin Ther
PUBLISHED: 03-24-2014
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Delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) has been reported to have clinical and neuroradiologic efficacy in people with relapsing-remitting multiple sclerosis (RRMS) in the Phase 3 DEFINE and CONFIRM studies. An integrated analysis of data from DEFINE and CONFIRM was conducted to estimate more precisely the therapeutic effects of delayed-release DMF. Here we describe the impact of RRMS on health-related quality of life (HRQoL) at baseline and assess the effects of delayed-release DMF on prespecified HRQoL end points over 2 years.
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Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECTION): a multicentre, randomised, double-blind extension trial.
Lancet Neurol
PUBLISHED: 03-19-2014
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In the SELECT trial, disease activity was reduced in patients with multiple sclerosis who received daclizumab high-yield process (HYP) for 52 weeks. The primary aim of the SELECTION extension study was to assess the safety and immunogenicity of extended treatment with daclizumab HYP.
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Natalizumab to fingolimod washout in patients at risk of PML: when good intentions yield bad outcomes.
Neurology
PUBLISHED: 03-07-2014
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With more choices for multiple sclerosis (MS) disease-modifying therapies, data are urgently required to support clinical decisions regarding safe transitioning and sequencing of therapies. With more than 7 years of clinical experience, natalizumab has been confirmed as highly effective in reducing MS disease activity. However, natalizumab carries a risk of progressive multifocal leukoencephalopathy (PML),(1) with more than 400 cases of natalizumab-related PML to date.(2) Because 2 of the 3 initial natalizumab-associated PML cases were on the combination natalizumab plus interferon, the concern was that combining agents led to a heightened risk of infectious complications. In these early times, uncertainty revolved around 2 points: the theoretical risk of PML if natalizumab was transiently combined with another immune-altering agent and the value of transiently "reconstituting" CNS immune surveillance by washout of natalizumab in an effort to clear theoretical subclinical JC virus within the CNS.(3) The optimal length of natalizumab washout became the subject of intense consternation and debate, with no clear guidelines to inform practice. However, upon withdrawing natalizumab, resumption of disease activity was soon observed, beginning 3-4 months after the last dose of natalizumab.(4-10) Postnatalizumab return of disease raised concern that the washout may harm the patient by a severe relapse with incomplete recovery.
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Magnetization transfer ratio in the delayed-release dimethyl fumarate DEFINE study.
J. Neurol.
PUBLISHED: 02-13-2014
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We measured changes in brain magnetization transfer ratio (MTR) as a potential indicator of myelin density in brain tissue of patients with relapsing-remitting multiple sclerosis (RRMS) treated with delayed-release dimethyl fumarate (DMF) in the Phase 3 DEFINE study. DEFINE was a randomized, double-blind, placebo-controlled study in which patients with RRMS were randomized 1:1:1 to 2 years of treatment with delayed-release DMF 240 mg twice daily (BID) or three times daily (TID) or placebo. MTR was analyzed in whole brain and normal-appearing brain tissue (NABT) at baseline, week 24, 1 year, and 2 years in a subset of patients. MTR data from 392 patients were analyzed. Mean percentage reduction from baseline to 2 years in median whole brain MTR was -0.386 % in the placebo group vs increases of 0.129 % (p = 0.0027) and 0.096 % (p = 0.0051) in the delayed-release DMF BID and TID groups, respectively. Similarly, mean percentage reduction from baseline in median NABT MTR was -0.392 % with placebo vs increases of 0.190 % (p = 0.0006) and 0.115 % (p = 0.0029) with delayed-release DMF BID and TID, respectively. Post hoc analysis of data from patients with no new or enlarging T2 lesions (n = 147), or who experienced no relapses (n = 238), yielded similar results. In this analysis, increases in MTR in brain tissue most likely reflect increases in myelin density in response to delayed-release DMF. These data in patients with RRMS are consistent with preclinical studies that indicate a potential for cytoprotection and remyelination with delayed-release DMF treatment.
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Effects of delayed-release dimethyl fumarate on MRI measures in the Phase 3 DEFINE study.
J. Neurol.
PUBLISHED: 02-13-2014
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In the Phase 3 DEFINE study, delayed-release dimethyl fumarate (DMF) 240 mg twice (BID) and three times daily (TID) significantly reduced the mean number of new or enlarging T2-hyperintense lesions and gadolinium-enhancing (Gd+) lesion activity at 2 years in patients (MRI cohort; n = 540) with relapsing-remitting MS. The analyses described here expand on these results by considering additional MRI measures (number of T1-hypointense lesions; volume of T2-hyperintense, Gd+, and T1-hypointense lesions; brain atrophy), delineating the time course of the effects, and examining the generality of the effects across a diverse patient population. Reductions in lesion counts with delayed-release DMF BID and TID, respectively, vs. placebo were apparent by the first MRI assessment at 6 months [T2-hyperintense: 80 and 69 % reduction (both P < 0.0001); Gd+, 94 and 81 % reduction (both P < 0.0001); T1-hypointense: 58 % (P < 0.0001) and 48 % (P = 0.0005) reduction] and maintained at 1 and 2 years. Reductions in lesion volume were statistically significant beginning at 6 months for T2-hyperintense [P = 0.0002 (BID) and P = 0.0035 (TID)] and Gd+ lesions [P = 0.0059 (BID) and P = 0.0176 (TID)] and beginning at 1 year [P = 0.0126 (BID)] to 2 years [P = 0.0063 (TID)] for T1-hypointense lesions. Relative reductions in brain atrophy from baseline to 2 years (21 % reduction; P = 0.0449) and 6 months to 2 years (30 % reduction; P = 0.0214) were statistically significant for delayed-release DMF BID. The effect of delayed-release DMF on mean number of new or enlarging T2-hyperintense lesions and Gd+ lesion activity was consistent across pre-specified patient subpopulations. Collectively, these results suggest that delayed-release DMF favorably affects multiple aspects of MS pathophysiology.
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Cerebrospinal fluid analysis.
Handb Clin Neurol
PUBLISHED: 02-11-2014
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The cerebrospinal fluid (CSF) is a bodily fluid, which is both easily accessible and the most proximate to the pathological alterations of multiple sclerosis (MS). Consequently, the analysis of this fluid provides an important window into the pathological underpinnings of this disease. For example, for years, it has been known that the CSF of MS patients contains oligoclonal gamma immunoglobulins (IgG), which are synthesized within the central nervous system and presumably relate to the immune dysfunction, which is characteristically found in MS. This insight has lead to the introduction of highly-effective anti-B-cell therapies into the field of MS therapeutics. Moreover, the presence of an oligoclonal IgG response in the CSF, although not specific for MS, is a very sensitive finding and, as a result, its presence can be quite helpful for establishing an MS diagnosis in the right clinical context. In addition, this finding has predictive value. Thus, patients without a definite diagnosis who have CSF IgG bands are significantly more likely to develop definite MS compared to those patients without such a banding pattern. Other biological molecules can also be found in the CSF including neurofiliment, myelin basic protein (MBP), glial fibrillary acidic protein (GFAP), tau, neuronal cell adhesion molecule (NCAM), and the growth associated protein (GAP-43). However, the value of measuring these (and other) CSF constituents for both diagnostic and prognostic purposes and for following response to therapy is still to be determined.
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Neurofilament light antibodies in serum reflect response to natalizumab treatment in multiple sclerosis.
Mult. Scler.
PUBLISHED: 02-10-2014
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Increased levels of antibodies to neurofilament light protein (NF-L) in biological fluids have been found to reflect neuroinflammatory responses and neurodegeneration in multiple sclerosis (MS).
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A service development study of the assessment and management of fracture risk in Parkinson's disease.
J. Neurol.
PUBLISHED: 01-14-2014
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Parkinson's disease (PD) is associated with an increased risk of fragility fracture. FRAX and Qfracture are risk calculators that estimate the 10-year risk of hip and major fractures and guide definitive investigation for osteoporosis using dual X-ray absorptiometry (DEXA) imaging. It is unclear which PD patients should be considered for fracture risk assessment and whether FRAX or Qfracture should be used. Seventy-seven patients with PD were recruited in the movement disorders clinic. Data were collected on PD-related characteristics and fracture risk scores were calculated. Patients with previous osteoporotic fractures had a higher incidence of falls (p = 0.0026) and use of bilateral walking aids (p = 0.0187) in addition to longer disease duration (p = 0.0037). Selecting patients with falls in combination with either disease duration >5 years, bilateral walking aids, or previous osteoporotic fracture distinguished patients with and without previous osteoporotic fracture with specificity 67.7 % (95 % CI 55.0-78.8) and sensitivity 100.0 % (95 % CI 73.5-100.0). Qfracture calculated significantly higher fracture risk scores than FRAX for hip (p < 0.0001) and major (p = 0.0008) fracture in PD patients. Receiver operating characteristic curves demonstrated that FRAX outperformed Qfracture with an area under the curve of 0.84 (95 % CI 0.70-0.97, p = 0.0004) for FRAX and 0.68 (95 % CI 52-86, p = 0.0476) for Qfracture major fracture risk calculators. We suggest that falls in combination with either a disease duration longer than 5 years or bilateral walking aids or previous osteoporotic fracture should be used as red flags in PD patients to prompt clinicians to perform a FRAX fracture risk assessment in the neurology clinic.
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Multiple sclerosis in the Iranian immigrant population of BC, Canada: prevalence and risk factors.
Mult. Scler.
PUBLISHED: 01-14-2014
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There is a well-documented increase in the risk of multiple sclerosis (MS) when migrating from a region of low prevalence to one of high prevalence.
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The refinement of genetic predictors of multiple sclerosis.
PLoS ONE
PUBLISHED: 01-01-2014
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A recent genome wide association study (GWAS) demonstrated that more than 100 genetic variants influence the risk of multiple sclerosis (MS). We investigated what proportion of the general population can be considered at high genetic risk of MS, whether genetic information can be used to predict disease development and how the recently found genetic associations have influenced these estimates. We used summary statistics from GWAS in MS to estimate the distribution of risk within a large simulated general population. We profiled MS associated loci in 70 MS patients and 79 healthy controls (HC) and assessed their position within the distribution of risk in the simulated population. The predictive performance of a weighted genetic risk score (wGRS) on disease status was investigated using receiver operating characteristic statistics. When all known variants were considered, 40.8% of the general population was predicted to be at reduced risk, 49% at average, 6.9% at elevated and 3.3% at high risk of MS. Fifty percent of MS patients were at either reduced or average risk of disease. However, they showed a significantly higher wGRS than HC (median 13.47 vs 12.46, p?=?4.08×10(-10)). The predictive performance of the model including all currently known MS associations (area under the curve?=?79.7%, 95%CI?=?72.4%-87.0%) was higher than that of models considering previously known associations. Despite this, considering the relatively low prevalence of MS, the positive predictive value was below 1%. The increasing number of known associated genetic variants is improving our ability to predict the development of MS. This is still unlikely to be clinically useful but a more complete understanding of the complexity underlying MS aetiology and the inclusion of environmental risk factors will aid future attempts of disease prediction.
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Bradykinesia-akinesia incoordination test: validating an online keyboard test of upper limb function.
PLoS ONE
PUBLISHED: 01-01-2014
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The Bradykinesia Akinesia Incoordination (BRAIN) test is a computer keyboard-tapping task that was developed for use in assessing the effect of symptomatic treatment on motor function in Parkinson's disease (PD). An online version has now been designed for use in a wider clinical context and the research setting.
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Assessing treatment response to interferon-?: Is there a role for MRI?
Neurology
PUBLISHED: 12-11-2013
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Interferon-? (IFN-?) has been shown to reduce relapse rates in multiple sclerosis; however, the clinical response appears to vary among individuals. Can early MRI be used to identify those patients who have a poor response to treatment?
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Neurodegeneration progresses despite complete elimination of clinical relapses in a mouse model of multiple sclerosis.
Acta Neuropathol Commun
PUBLISHED: 12-10-2013
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Backgound: Multiple Sclerosis has two clinical phases reflecting distinct but inter-related pathological processes: focal inflammation drives the relapse-remitting stage and neurodegeneration represents the principal substrate of secondary progression. In contrast to the increasing number of effective anti-inflammatory disease modifying treatments for relapse-remitting disease, the absence of therapies for progressive disease represents a major unmet clinical need. This raises the unanswered question of whether elimination of clinical relapses will prevent subsequent progression and if so how early in the disease course should treatment be initiated. Experimental autoimmune encephalomyelitis in the Biozzi ABH mouse recapitulates the clinical and pathological features of multiple sclerosis including relapse-remitting episodes with inflammatory mediated demyelination and progressive disability with neurodegeneration. To address the relationship between inflammation and neurodegeneration we used an auto-immune tolerance strategy to eliminate clinical relapses in EAE in a manner analogous to the clinical effect of disease modifying treatments.
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Lesional-targeting of neuroprotection to the inflammatory penumbra in experimental multiple sclerosis.
Brain
PUBLISHED: 11-27-2013
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Progressive multiple sclerosis is associated with metabolic failure of the axon and excitotoxicity that leads to chronic neurodegeneration. Global sodium-channel blockade causes side effects that can limit its use for neuroprotection in multiple sclerosis. Through selective targeting of drugs to lesions we aimed to improve the potential therapeutic window for treatment. This was assessed in the relapsing-progressive experimental autoimmune encephalomyelitis ABH mouse model of multiple sclerosis using conventional sodium channel blockers and a novel central nervous system-excluded sodium channel blocker (CFM6104) that was synthesized with properties that selectively target the inflammatory penumbra in experimental autoimmune encephalomyelitis lesions. Carbamazepine and oxcarbazepine were not immunosuppressive in lymphocyte-driven autoimmunity, but slowed the accumulation of disability in experimental autoimmune encephalomyelitis when administered during periods of the inflammatory penumbra after active lesion formation, and was shown to limit the development of neurodegeneration during optic neuritis in myelin-specific T cell receptor transgenic mice. CFM6104 was shown to be a state-selective, sodium channel blocker and a fluorescent p-glycoprotein substrate that was traceable. This compound was >90% excluded from the central nervous system in normal mice, but entered the central nervous system during the inflammatory phase in experimental autoimmune encephalomyelitis mice. This occurs after the focal and selective downregulation of endothelial p-glycoprotein at the blood-brain barrier that occurs in both experimental autoimmune encephalomyelitis and multiple sclerosis lesions. CFM6104 significantly slowed down the accumulation of disability and nerve loss in experimental autoimmune encephalomyelitis. Therapeutic-targeting of drugs to lesions may reduce the potential side effect profile of neuroprotective agents that can influence neurotransmission. This class of agents inhibit microglial activity and neural sodium loading, which are both thought to contribute to progressive neurodegeneration in multiple sclerosis and possibly other neurodegenerative diseases.
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Hypovitaminosis-D and EBV: no interdependence between two MS risk factors in a healthy young UK autumn cohort.
Mult. Scler.
PUBLISHED: 11-05-2013
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Late Epstein-Barr virus infection and hypovitaminosis-D as environmental risk factors in the pathogenesis of multiple sclerosis are gaining great interest. We, therefore, tested for in-vivo interdependence between Epstein-Barr-virus (EBV)-status and 25-hydroxyvitamin D3 (25(OH)D3) -level in healthy young individuals from a United Kingdom (UK) autumn cohort. EBV-load was measured by quantitative polymerase chain reaction and 25(OH)D3 levels by isotope-dilution liquid chromatography-tandem mass spectrometry. This young, healthy UK autumn cohort showed surprisingly low levels of 25(OH)D3 (mean value: 40.5 nmol/L ± 5.02). Furthermore, we found that low 25(OH)D3 levels did not impact on EBV load and anti-EBV nuclear antigen-1 (EBNA-1) titers. However, we observed a correlation between EBV load and EBNA-1 titers. These observations should be of value in the study of the potential relationship between hypovitaminosis-D and EBV-status in the pathophysiology of multiple sclerosis.
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Quality of life outcomes with BG-12 (dimethyl fumarate) in patients with relapsing-remitting multiple sclerosis: The DEFINE study.
Mult. Scler.
PUBLISHED: 10-22-2013
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Oral BG-12 (dimethyl fumarate), approved for the treatment of the relapsing forms of MS, has demonstrated clinical efficacy with an acceptable safety profile in the Phase III "Determination of the Efficacy and Safety of Oral Fumarate in Relapsing-Remitting Multiple Sclerosis (RRMS)" (DEFINE) and "Comparator and an Oral Fumarate in RRMS" (CONFIRM) studies.
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Control of spasticity in a multiple sclerosis model using central nervous system-excluded CB1 cannabinoid receptor agonists.
FASEB J.
PUBLISHED: 10-11-2013
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The purpose of this study was the generation of central nervous system (CNS)-excluded cannabinoid receptor agonists to test the hypothesis that inhibition of spasticity, due to CNS autoimmunity, could be controlled by affecting neurotransmission within the periphery. Procedures included identification of chemicals and modeling to predict the mode of exclusion; induction and control of spasticity in the ABH mouse model of multiple sclerosis; conditional deletion of CB1 receptor in peripheral nerves; side-effect profiling to demonstrate the mechanism of CNS-exclusion via drug pumps; genome-wide association study in N2(129×ABH) backcross to map polymorphic cannabinoid drug pump; and sequencing and detection of cannabinoid drug-pump activity in human brain endothelial cell lines. Three drugs (CT3, SAB378 and SAD448) were identified that control spasticity via action on the peripheral nerve CB1 receptor. These were peripherally restricted via drug pumps that limit the CNS side effects (hypothermia) of cannabinoids to increase the therapeutic window. A cannabinoid drug pump is polymorphic and functionally lacking in many laboratory (C57BL/6, 129, CD-1) mice used for transgenesis, pharmacology, and toxicology studies. This phenotype was mapped and controlled by 1-3 genetic loci. ABCC1 within a cluster showing linkage is a cannabinoid CNS-drug pump. Global and conditional CB1 receptor-knockout mice were used as controls. In summary, CNS-excluded CB1 receptor agonists are a novel class of therapeutic agent for spasticity.-Pryce, G., Visintin, C., Ramagopalan, S. V., Al-Izki, S., De Faveri, L. E., Nuamah, R. A., Mein, C. A., Montpetit, A., Hardcastle, A. J., Kooij, G., de Vries, H. E., Amor, S., Thomas, S. A., Ledent, C., Marsicano, G., Lutz, B., Thompson, A. J., Selwood, D. L., Giovannoni, G., Baker, D. Control of spasticity in a multiple sclerosis model using central nervous system-excluded CB1 cannabinoid receptor agonists.
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DNase hypersensitive sites and association with multiple sclerosis.
Hum. Mol. Genet.
PUBLISHED: 10-02-2013
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Genome-wide association studies (GWASs) have shown that approximately 60 genetic variants influence the risk of developing multiple sclerosis (MS). Our aim was to identify the cell types in which these variants are active. We used available data on MS-associated single nucleotide polymorphisms (SNPs) and deoxyribonuclease I hypersensitive sites (DHSs) from 112 different cell types. Genomic intervals were tested for overlap using the Genomic Hyperbrowser. The expression profile of the genes located nearby MS-associated SNPs was assessed using the software GRAIL (Gene Relationships Across Implicated Loci). Genomic regions associated with MS were significantly enriched for a number of immune DHSs and in particular T helper (Th) 1, Th17, CD8+ cytotoxic T cells, CD19+ B cells and CD56+ natural killer (NK) cells (enrichment = 2.34, 2.19, 2.27, 2.05 and 1.95, respectively; P < 0.0001 for all of them). Similar results were obtained when genomic regions with suggestive association with MS and additional immune-mediated traits were investigated. Several new candidate MS-associated genes located within regions of suggestive association were identified by GRAIL (CARD11, FCRL2, CHST12, SYK, TCF7, SOCS1, NFKBIZ and NPAS1). Genetic data indicate that Th1, Th17, cytotoxic T, B and NK cells play a prominent role in the etiology of MS. Regions with confirmed and suggestive association have a similar immunological profile, indicating that many SNPs truly influencing the risk of MS actually fail to reach genome-wide significance. Finally, similar cell types are involved in the etiology of other immune-mediated diseases.
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Immune reactivity to neurofilament proteins in the clinical staging of amyotrophic lateral sclerosis.
J. Neurol. Neurosurg. Psychiatr.
PUBLISHED: 09-27-2013
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Neurofilament (NF) proteins detection in biological fluids as a by-product of axonal loss is technically challenging and to date relies mostly on cerebrospinal fluid (CSF) measurements. Plasma antibodies against NF proteins and particularly to their soluble light chain (NF-L) could be a more practical surrogate marker for disease staging in amyotrophic lateral sclerosis (ALS), an invariably fatal and clinically heterogeneous neuromuscular disorder.
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Effect of daclizumab high-yield process in patients with highly active relapsing-remitting multiple sclerosis.
J. Neurol.
PUBLISHED: 09-25-2013
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Patients with highly active relapsing-remitting multiple sclerosis (RRMS) are at greater risk for disease progression and may respond differently to MS therapeutics than those with less active disease. The current post hoc analysis evaluated the effects of daclizumab high-yield process (DAC HYP) vs. placebo in patients with highly active RRMS in the SELECT study. Highly active RRMS was defined as patients with ?2 relapses in the year before randomization and ?1 gadolinium-enhancing (Gd(+)) lesion at baseline. Because results were similar in the DAC HYP dose groups, data from the DAC HYP arms were pooled for analysis. Treatment with DAC HYP resulted in similar effects in highly active (n = 88) and less active (n = 506) RRMS patients. DAC HYP reduced the annualized relapse rate by 50 % and 51 % in the highly active (p = 0.0394) and less active (p < 0.0001) groups vs. placebo, respectively (interaction p = 0.82). DAC HYP reduced new/newly-enlarging T2 lesions (highly active RRMS 76 % reduction, p < 0.0001; less active RRMS 73 % reduction, p < 0.0001; interaction p = 0.18), the risk of having more Gd(+) lesions (highly active RRMS 89 % reduction, p < 0.0001; less active RRMS 86 % reduction, p < 0.0001; interaction p = 0.46), and sustained disability progression (highly active RRMS 88 % reduction, p = 0.0574; less active RRMS 46 % reduction, p = 0.0383; interaction p = 0.22) vs. placebo. DAC HYP efficacy was similar across the spectrum of MS disease activity as assessed prior to treatment initiation.
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Disease-activity-free status in patients with relapsing-remitting multiple sclerosis treated with daclizumab high-yield process in the SELECT study.
Mult. Scler.
PUBLISHED: 09-10-2013
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Daclizumab high-yield process (DAC HYP) is a humanized anti-CD25 monoclonal antibody that inhibits high-affinity interleukin-2 receptor signaling.
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PREDICT-PD: Identifying risk of Parkinsons disease in the community: methods and baseline results.
J. Neurol. Neurosurg. Psychiatr.
PUBLISHED: 07-04-2013
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To present methods and baseline results for an online screening tool to identify increased risk for Parkinsons disease (PD) in the UK population.
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Integrating multiple oestrogen receptor alpha ChIP studies: overlap with disease susceptibility regions, DNase I hypersensitivity peaks and gene expression.
BMC Med Genomics
PUBLISHED: 05-31-2013
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A wealth of nuclear receptor binding data has been generated by the application of chromatin immunoprecipitation (ChIP) techniques. However, there have been relatively few attempts to apply these datasets to human complex disease or traits.
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Inactive or moderately active human promoters are enriched for inter-individual epialleles.
Genome Biol.
PUBLISHED: 05-25-2013
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Inter-individual epigenetic variation, due to genetic, environmental or random influences, is observed in many eukaryotic species. In mammals, however, the molecular nature of epiallelic variation has been poorly defined, partly due to the restricted focus on DNA methylation. Here we report the first genome-scale investigation of mammalian epialleles that integrates genomic, methylomic, transcriptomic and histone state information.
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The effect of vitamin D-related interventions on multiple sclerosis relapses: a meta-analysis.
Mult. Scler.
PUBLISHED: 05-22-2013
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Observational studies have shown an association between lower vitamin D levels and higher risk of relapse among people with multiple sclerosis (MS). This has raised interest in potential clinical benefits of vitamin D supplementation in the management of MS. The objectives were to examine the effect of vitamin D based interventions on the relative risk of relapse in MS. Any randomised controlled trial assessing the effect on the relative risk of relapse of any formulation or dose of vitamin D, in participants with MS, was eligible. The inverse variance with random effects model in Review Manager 5.1 was used to calculate the odds ratio of relapses in high dose vitamin D treated patients vs. controls. Five studies were published as of September 2012, yielding a total of 129 high-dose vitamin D-treated patients and 125 controls. We found no significant association between high-dose vitamin D treatment and risk of MS relapse (OR 0.98, 95% CI 0.45-2.16). In conclusion, although no significant association between high-dose vitamin D treatment and risk of MS relapses was found, the studies were limited by several methodological limitations. Further larger, more prolonged studies are merited.
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Hospital admissions for vitamin D related conditions and subsequent immune-mediated disease: record-linkage studies.
BMC Med
PUBLISHED: 05-13-2013
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Previous studies have suggested that there may be an association between vitamin D deficiency and the risk of developing immune-mediated diseases.
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Comparison of two commercial ELISA systems for evaluating anti-EBNA1 IgG titers.
J. Med. Virol.
PUBLISHED: 04-18-2013
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High IgG titers against the Epstein-Barr virus nuclear antigen, EBNA-1, have been strongly correlated with the risk of developing multiple sclerosis. ELISAs are used frequently to measure EBNA-1 titers, however concerns remain regarding the accuracy of results. Ordering absolute results into rank quintiles for analysis may be preferable. Using 120 serum samples, two commercially available ELISAs (produced by DiaSorin and VirionSerion) were compared, both in terms of absolute results and rank quintiles. The positive predictive value of the VirionSerion ELISA was 99.1% when compared to the DiaSorin ELISA, however, the negative predictive value was 64.3%. Sensitivity and specificity were acceptable at 95.5% and 90.0%, respectively. There was poor correlation between absolute results, R(2) ?= 0.49; and the kappa coefficient for rank quintiles was low at 0.23. Although sensitivity and specificity appear adequate, the poor negative predictive value and kappa coefficient are of major concern. Care must be taken when selecting assays for experimental use.
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Validating a novel web-based method to capture disease progression outcomes in multiple sclerosis.
J. Neurol.
PUBLISHED: 04-08-2013
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The Expanded Disability Status Scale (EDSS) is the current gold standard for monitoring disease severity in multiple sclerosis (MS). The EDSS is a physician-based assessment. A patient-related surrogate for the EDSS may be useful in remotely capturing information. Eighty-one patients (EDSS range 0-8) having EDSS as part of clinical trials were recruited. All patients carried out the web-based survey with minimal assistance. Full EDSS scores were available for 78 patients. The EDSS scores were compared to those generated by the online survey using analysis of variance, matched pair test, Pearsons coefficient, weighted kappa coefficient, and the intra-class correlation coefficient. The internet-based EDSS scores showed good correlation with the physician-measured assessment (Pearsons coefficient = 0.85). Weighted kappa for full agreement was 0.647. Full agreement was observed in 20 patients who had EDSS scores ranging from 0 to 6; many of those with 100 % agreement had scores of 5.5-6 (n = 8).The intra-class coefficient was 0.844 overall for all cases. Internet-based FS and EDSS show good agreement with physician-measured scores. Agreement was better in patients with higher scores. Overall patient satisfaction with the web-based assessment was high. An internet-based assessment tool is likely to prove an invaluable tool in the long-term monitoring in MS.
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Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECT): a randomised, double-blind, placebo-controlled trial.
Lancet
PUBLISHED: 04-04-2013
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Daclizumab, a humanised monoclonal antibody, modulates interleukin-2 signalling by blocking the ? subunit (CD25) of the interleukin-2 receptor. We assessed whether daclizumab high-yield process (HYP) would be effective when given as monotherapy for a 1 year treatment period in patients with relapsing-remitting multiple sclerosis.
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A comparative study of CSF neurofilament light and heavy chain protein in MS.
Mult. Scler.
PUBLISHED: 03-25-2013
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There is a lack of reliable biomarkers of axonal degeneration. Neurofilaments are promising candidates to fulfil this task. We compared two highly sensitive assays to measure two subunits of the neurofilament protein (neurofilament light (NfL) and neurofilament heavy chain (NfH)).
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Serum levels of 25-hydroxy vitamin D in normal Biozzi and C57BL/6 mice and during the course of chronic relapsing experimental autoimmune encephalomyelitis (CR EAE).
Inflamm. Res.
PUBLISHED: 03-22-2013
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The aim of the study was to examine possible variations in the levels of 25-hydroxy vitamin D [25-(OH)D] in sera from normal Biozzi and C57BL/6 mice and during the course of chronic relapsing experimental autoimmune encephalomyelitis (CR EAE).
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Progression in multiple sclerosis is associated with low endogenous NCAM.
J. Neurochem.
PUBLISHED: 03-10-2013
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Multiple sclerosis (MS) is a CNS disorder characterized by demyelination and neurodegeneration. Although hallmarks of recovery (remyelination and repair) have been documented in early MS, the regenerative capacity of the adult CNS per se remains uncertain with the wide held belief that it is either limited or non-existent. The neural cell adhesion molecule (NCAM) is a cell adhesion molecule that has been widely implicated in axonal outgrowth, guidance and fasciculation. Here, we used in vitro and in vivo of MS to investigate the role of NCAM in disease progression. We show that in health NCAM levels decrease over time, but this occurs acutely after demyelination and remains reduced in chronic disease. Our findings suggest that depletion of NCAM is one of the factors associated with or possibly responsible for disease progression in MS.
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Bone health in chronic neurological diseases: a focus on multiple sclerosis and parkinsonian syndromes.
Pract Neurol
PUBLISHED: 03-08-2013
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The importance of bone health is increasingly recognised, and there is mounting evidence that neurological conditions are associated with a significantly increased risk of osteoporosis and fractures. This increase in risk is likely to be multifactorial. Multiple sclerosis and Parkinsons disease were identified in the Global Longitudinal Study of Osteoporosis in Women study as significantly associated with osteoporosis. Here, we discuss the literature on bone health, falls and fractures in MS and akinetic-rigid syndromes, and suggest strategies to investigate and manage bone health in the neurology clinic.
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Epstein-Barr virus and multiple sclerosis: association or causation?
Expert Rev Neurother
PUBLISHED: 03-02-2013
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Multiple sclerosis (MS) is a multifactorial disease in which both genetic and environmental factors and their interactions underlie causation. The current evidence base supports a strong association between Epstein-Barr virus (EBV) and MS, but potential causality remains strongly debated. It is not possible to exclude the possibility that an abnormal response to EBV infection is a consequence, rather than a cause, of the underlying pathophysiology of MS, or indeed that the association may be a reflection of a similar underlying disease mechanism. Substantial experimental progress is necessary to achieve consistency of molecular findings to complement the strong epidemiological association between EBV and MS, which cannot alone show causation. Collectively, the strength of the association between EBV and MS warrants careful development and trial of anti-EBV drugs to observe any effect on MS disease course.
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Cerebrospinal fluid oligoclonal bands in multiple sclerosis and clinically isolated syndromes: a meta-analysis of prevalence, prognosis and effect of latitude.
J. Neurol. Neurosurg. Psychiatr.
PUBLISHED: 02-21-2013
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Oligoclonal bands (OCBs) unique to the cerebrospinal fluid are used in the diagnosis of multiple sclerosis (MS). The precise prevalence of OCBs in MS and clinically isolated syndrome (CIS) is unknown. The influence of OCBs on clinical outcomes has not been quantified. OCB prevalence has been associated with latitude in a single study, if confirmed this would provide avenues for further study.
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Clinical efficacy of BG-12 (dimethyl fumarate) in patients with relapsing-remitting multiple sclerosis: subgroup analyses of the DEFINE study.
J. Neurol.
PUBLISHED: 02-20-2013
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In the double-blind, placebo-controlled, Phase 3 DEFINE study in patients with relapsing–remitting multiple sclerosis, oral BG-12 (dimethyl fumarate) significantly reduced the proportion of patients relapsed (primary endpoint), the annualized relapse rate (ARR), and confirmed disability progression (secondary endpoints) at two years compared with placebo. We investigated the efficacy of BG-12 240 mg twice daily (BID) and three times daily (TID) in patient subgroups stratified according to baseline demographic and disease characteristics including gender, age, relapse history, McDonald criteria, treatment history, expanded disability status scale score, T2 lesion volume, and gadolinium-enhancing lesions. The clinical efficacy of BG-12 was generally consistent across patient subgroups and reflected positive findings in the overall DEFINE study population. Treatment with BG-12 BID and TID reduced the proportion of patients relapsed and the ARR at two years compared with placebo in all patient subgroups. Reductions in the risk of relapse with BG-12 BID vs. placebo ranged from 68% [hazard ratio 0.32 (95% confidence interval (CI) 0.16-0.62)] to 26% [0.74 (0.51-1.09)] and from 66% [0.34 (0.23-0.50)] to 25% [0.75 (0.42-1.36)] with BG-12 TID vs. placebo. BG-12 also reduced the risk of disability progression at two years compared with placebo in most subgroups of patients treated with the BID dosing regimen and in all subgroups treated with the TID regimen. These analyses indicate that treatment with BG-12 is consistently effective across a wide spectrum of patients with relapsing–remitting multiple sclerosis with varied demographic and disease characteristics.
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Assessing interactions between HLA-DRB1*15 and infectious mononucleosis on the risk of multiple sclerosis.
Mult. Scler.
PUBLISHED: 02-14-2013
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Gene-environment interactions may shed light on the mechanisms underlying multiple sclerosis (MS). We pooled data from two case-control studies on incident demyelination and used different methods to assess interaction between HLA-DRB1*15 (DRB1-15) and history of infectious mononucleosis (IM). Individuals exposed to both factors were at substantially increased risk of disease (OR=7.32, 95% CI=4.92-10.90). In logistic regression models, DRB1-15 and IM status were independent predictors of disease while their interaction term was not (DRB1-15*IM: OR=1.35, 95% CI=0.79-2.23). However, interaction on an additive scale was evident (Synergy index=2.09, 95% CI=1.59-2.59; excess risk due to interaction=3.30, 95%CI=0.47-6.12; attributable proportion due to interaction=45%, 95% CI=22-68%). This suggests, if the additive model is appropriate, the DRB1-15 and IM may be involved in the same causal process leading to MS and highlights the benefit of reporting gene-environment interactions on both a multiplicative and additive scale.
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Autoimmune disease in people with multiple sclerosis and their relatives: a systematic review and meta-analysis.
J. Neurol.
PUBLISHED: 01-12-2013
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Additional autoimmune diseases in people with multiple sclerosis (MS) and their relatives have been studied many times. Studies have employed different designs, and yielded conflicting results. We performed a systematic review, and calculated overall risk of additional autoimmune diseases in people with MS and their first-degree relatives. PubMed and Web of Science were searched. Thyroid disease, diabetes, inflammatory bowel disease, psoriasis, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) were studied. A generic inverse variance model was used, and subgroup analysis was used to explore heterogeneity. The OR of thyroid disease was increased in both people with MS (OR 1.66; p < 0.00001) and their relatives (OR 2.38; p < 0.00001). A similar association was seen between MS and inflammatory bowel disease (OR 1.56; p < 0.0001) and psoriasis (OR 1.31; p < 0.0001), although not in relatives. There was no increase in the rate of either SLE or RA. Studies examining diabetes showed significant heterogeneity and evidence of publication bias. There is an increase in the rate of certain autoimmune diseases in people with MS and their first-degree relatives. However, this does not extend to all conditions studied. Given the nonspecific clinical presentation of thyroid disease, it should be considered in all people with MS presenting with nonspecific symptoms.
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Vitamin D receptor ChIP-seq in primary CD4+ cells: relationship to serum 25-hydroxyvitamin D levels and autoimmune disease.
BMC Med
PUBLISHED: 01-08-2013
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Vitamin D insufficiency has been implicated in autoimmunity. ChIP-seq experiments using immune cell lines have shown that vitamin D receptor (VDR) binding sites are enriched near regions of the genome associated with autoimmune diseases. We aimed to investigate VDR binding in primary CD4+ cells from healthy volunteers.
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Neuroprotection in a novel mouse model of multiple sclerosis.
PLoS ONE
PUBLISHED: 01-01-2013
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Multiple sclerosis is an immune-mediated, demyelinating and neurodegenerative disease that currently lacks any neuroprotective treatments. Innovative neuroprotective trial designs are required to hasten the translational process of drug development. An ideal target to monitor the efficacy of strategies aimed at treating multiple sclerosis is the visual system, which is the most accessible part of the human central nervous system. A novel C57BL/6 mouse line was generated that expressed transgenes for a myelin oligodendrocyte glycoprotein-specific T cell receptor and a retinal ganglion cell restricted-Thy1 promoter-controlled cyan fluorescent protein. This model develops spontaneous or induced optic neuritis, in the absence of paralytic disease normally associated with most rodent autoimmune models of multiple sclerosis. Demyelination and neurodegeneration could be monitored longitudinally in the living animal using electrophysiology, visual sensitivity, confocal scanning laser ophthalmoscopy and optical coherence tomography all of which are relevant to human trials. This model offers many advantages, from a 3Rs, economic and scientific perspective, over classical experimental autoimmune encephalomyelitis models that are associated with substantial suffering of animals. Optic neuritis in this model led to inflammatory damage of axons in the optic nerve and subsequent loss of retinal ganglion cells in the retina. This was inhibited by the systemic administration of a sodium channel blocker (oxcarbazepine) or intraocular treatment with siRNA targeting caspase-2. These novel approaches have relevance to the future treatment of neurodegeneration of MS, which has so far evaded treatment.
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Genetic background can result in a marked or minimal effect of gene knockout (GPR55 and CB2 receptor) in experimental autoimmune encephalomyelitis models of multiple sclerosis.
PLoS ONE
PUBLISHED: 01-01-2013
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Endocannabinoids and some phytocannabinoids bind to CB1 and CB2 cannabinoid receptors, transient receptor potential vanilloid one (TRPV1) receptor and the orphan G protein receptor fifty-five (GPR55). Studies using C57BL/10 and C57BL/6 (Cnr2 (tm1Zim)) CB2 cannabinoid receptor knockout mice have demonstrated an immune-augmenting effect in experimental autoimmune encephalomyelitis (EAE) models of multiple sclerosis. However, other EAE studies in Biozzi ABH mice often failed to show any treatment effect of either CB2 receptor agonism or antagonism on inhibition of T cell autoimmunity. The influence of genetic background on the induction of EAE in endocannabinoid system-related gene knockout mice was examined. It was found that C57BL/6.GPR55 knockout mice developed less severe disease, notably in female mice, following active induction with myelin oligodendrocyte glycoprotein 35-55 peptide. In contrast C57BL/6.CB2 (Cnr2 (Dgen)) receptor knockout mice developed augmented severity of disease consistent with the genetically and pharmacologically-distinct, Cnr2 (tm1Zim) mice. However, when the knockout gene was bred into the ABH mouse background and EAE induced with spinal cord autoantigens the immune-enhancing effect of CB2 receptor deletion was lost. Likewise CB1 receptor and transient receptor potential vanilloid one knockout mice on the ABH background demonstrated no alteration in immune-susceptibility, in terms of disease incidence and severity of EAE, in contrast to that reported in some C57BL/6 mouse studies. Furthermore the immune-modulating influence of GPR55 was marginal on the ABH mouse background. Whilst sedative doses of tetrahydrocannabinol could induce immunosuppression, this was associated with a CB1 receptor rather than a CB2 receptor-mediated effect. These data support the fact that non-psychoactive doses of medicinal cannabis have a marginal influence on the immune response in MS. Importantly, it adds a note of caution for the translational value of some transgenic/gene knockout and other studies on low-EAE susceptibility backgrounds with inconsistent disease course and susceptibility.
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Increased neurofilament light chain blood levels in neurodegenerative neurological diseases.
PLoS ONE
PUBLISHED: 01-01-2013
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Neuronal damage is the morphological substrate of persisting neurological disability. Neurofilaments (Nf) are cytoskeletal proteins of neurons and their release into cerebrospinal fluid has shown encouraging results as a biomarker for neurodegeneration. This study aimed to validate the quantification of the Nf light chain (NfL) in blood samples, as a biofluid source easily accessible for longitudinal studies.
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Biomarker report from the phase II lamotrigine trial in secondary progressive MS - neurofilament as a surrogate of disease progression.
PLoS ONE
PUBLISHED: 01-01-2013
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Lamotrigine trial in SPMS was a randomised control trial to assess whether partial blockade of sodium channels has a neuroprotective effect. The current study was an additional study to investigate the value of neurofilament (NfH) and other biomarkers in predicting prognosis and/or response to treatment.
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Assessing fracture risk in people with MS: a service development study comparing three fracture risk scoring systems.
BMJ Open
PUBLISHED: 01-01-2013
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Suboptimal bone health is increasingly recognised as an important cause of morbidity. Multiple sclerosis (MS) has been consistently associated with an increased risk of osteoporosis and fracture. Various fracture risk screening tools have been developed, two of which are in routine use and a further one is MS-specific. We set out to compare the results obtained by these in the MS clinic population.
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Vitamin D deficiency--do we follow our own advice?
Clin Med
PUBLISHED: 12-21-2011
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Over the last few years, vitamin D deficiency has emerged as a risk factor for many diseases. Public awareness of the importance of the sunshine vitamin is increasing, however deficiency remains an ongoing problem. Is an awareness of the importance of vitamin D enough to promote healthy people to take supplements or is a different approach required? In this article the importance of vitamin D is discussed and data showing that knowledge of this is not sufficient to encourage people to take supplements are presented.
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Long term lymphocyte reconstitution after alemtuzumab treatment of multiple sclerosis.
J. Neurol. Neurosurg. Psychiatr.
PUBLISHED: 11-05-2011
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Alemtuzumab is a lymphocyte depleting monoclonal antibody that has demonstrated superior efficacy over interferon ?-1a for relapsing-remitting multiple sclerosis (MS), and is currently under investigation in phase 3 trials. One unresolved issue is the duration and significance of the lymphopenia induced. The long term effects on lymphocyte reconstitution of a single course, and the consequences that this has on disability, morbidity, mortality and autoimmunity, were examined.
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The effect of gender in clinically isolated syndrome (CIS): a meta-analysis.
Mult. Scler.
PUBLISHED: 10-12-2011
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A clinically isolated syndrome compatible with demyelination (CIS) is the initial presentation for the majority of people that go on to develop multiple sclerosis (MS). There has previously been little work examining the effect of gender on the development and progression of CIS.
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Stiff person syndrome.
Pract Neurol
PUBLISHED: 09-17-2011
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Stiff person syndrome (SPS) is a rare disorder, characterised by fluctuating rigidity and stiffness of the axial and proximal lower limb muscles, with superimposed painful spasms and continuous motor unit activity on electromyography. Although rare in general neurology practice, once observed it is unforgettable. The general neurologist may see only one or two cases during his or her career and as such it remains underdiagnosed. Left untreated, SPS symptoms can progress to cause significant disability. Patients have a poor quality of life and an excess rate of comorbidity and mortality. The severity of symptoms and lack of public awareness of the condition create anxiety and uncertainty for people with the disease. This review aims to raise awareness of SPS and to improve the likelihood of its earlier diagnosis and treatment.
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More to come: humoral immune responses in MS.
J. Neuroimmunol.
PUBLISHED: 05-05-2011
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Interest in the role of B-cells in multiple sclerosis (MS) pathogenesis has increased, and a number of B-cell targeted therapies are currently in clinical trials. B-cells are key mediators of the humoral immune response, with roles including antibody production and acting as antigen presenting cells. Whilst previously, the presence of B-cells within MS plaques has been thought to be secondary to T-cell dysregulation, it is now becoming clear that B-cells play an independent role in disease. In this review we will discuss the potential role of B-cells in MS, how this influences our understanding of the disease, and potential therapeutic implications.
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Role of the HLA system in the association between multiple sclerosis and infectious mononucleosis.
Arch. Neurol.
PUBLISHED: 04-13-2011
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To determine whether multiple sclerosis (MS) and infectious mononucleosis (IM) share common HLA associations.
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Consensus Guidelines for CSF and Blood Biobanking for CNS Biomarker Studies.
Mult Scler Int
PUBLISHED: 04-05-2011
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There is a long history of research into body fluid biomarkers in neurodegenerative and neuroinflammatory diseases. However, only a few biomarkers in cerebrospinal fluid (CSF) are being used in clinical practice. Anti-aquaporin-4 antibodies in serum are currently useful for the diagnosis of neuromyelitis optica (NMO), but we could expect novel CSF biomarkers that help define prognosis and response to treatment for this disease. One of the most critical factors in biomarker research is the inadequate powering of studies performed by single centers. Collaboration between investigators is needed to establish large biobanks of well-defined samples. A key issue in collaboration is to establish standardized protocols for biobanking to ensure that the statistical power gained by increasing the numbers of CSF samples is not compromised by pre-analytical factors. Here, consensus guidelines for CSF collection and biobanking are presented, based on the guidelines that have been published by the BioMS-eu network for CSF biomarker research. We focussed on CSF collection procedures, pre-analytical factors and high quality clinical and paraclinical information. Importantly, the biobanking protocols are applicable for CSF biobanks for research targeting any neurological disease.
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Additional efficacy endpoints from pivotal natalizumab trials in relapsing-remitting MS.
J. Neurol.
PUBLISHED: 04-04-2011
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Standard clinical endpoints in multiple sclerosis (MS) studies, such as disability progression defined by the expanded disability status scale (EDSS) and annualized relapse rate, may not fully reflect all aspects of therapeutic benefit experienced by patients. Pivotal studies showed that natalizumab is effective both as monotherapy (AFFIRM study) and in combination with interferon beta-1a (IFN?-1a) (SENTINEL study) in patients with relapsing MS. We present AFFIRM and SENTINEL data demonstrating the efficacy of natalizumab on prespecified tertiary endpoints, including extent of confirmed change in EDSS score from baseline, time to sustained progression to EDSS milestone scores, hospitalizations, corticosteroid use, and time to confirmed progression of cognitive deficits. Natalizumab significantly reduced changes in EDSS scores (P < 0.001) and proportion of patients progressing to an EDSS score ?4.0 (P < 0.001) and ?6.0 (P = 0.002) compared with placebo. Natalizumab + IFN?-1a significantly reduced changes in EDSS scores compared with placebo + IFN?-1a (P = 0.011). Based on 0.5 standard deviation change in paced auditory serial addition test-3 score, natalizumab treatment reduced the risk of confirmed progression of cognitive deficits by 43% compared with placebo (HR 0.57 [95% CI 0.37, 0.89], P = 0.013); however, no significant difference between groups was seen in SENTINEL. Natalizumab, both as monotherapy and in combination with IFN?-1a, significantly reduced the annualized rate of MS-related hospitalizations (by 64 and 61%, respectively) and the annualized rate of relapses severe enough to require steroid treatment (by 69 and 61%, respectively) compared with placebo and placebo + IFN?-1a (P < 0.001). These analyses underline beneficial effects of natalizumab therapy in relapsing MS patients.
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Immunosuppression with FTY720 is insufficient to prevent secondary progressive neurodegeneration in experimental autoimmune encephalomyelitis.
Mult. Scler.
PUBLISHED: 04-01-2011
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There has been poor translation for the use of immunosuppressive agents from experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), into the treatment of MS. This may be due to the fact that most EAE studies examine prophylactic, pre-treatment regimes that prove to be therapeutically-ineffective in long-established, often progressive, MS. FTY720 (fingolimod/Gilenya) is a sphingosine-1-phosphate receptor modulator. This is a new oral agent that markedly reduces the number of relapses in people with MS, compared with currently licensed injectable agents such as the beta interferons. FTY720 has activity against lymphocytes but may also influence oligodendroglia and could therefore have the potential to influence progressive MS, by promoting remyelination.
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Promising emerging therapies for multiple sclerosis.
Neurol Clin
PUBLISHED: 03-29-2011
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Until recently, interferon beta and glatiramer acetate were the only licensed disease-modifying therapies for relapsing forms of multiple sclerosis. These agents have a modest effect on reducing relapse rates. The licensing of two more effective agents, mitoxantrone and natalizumab, provided alternatives. These agents are associated with potentially life-threatening or serious side effects. In addition, none of these licensed agents has been shown to be effective in primary progressive MS. There is a large unmet need, with several promising new therapies in the pipeline. This article reviews the proposed mechanisms of action of the anticipated treatments, their efficacy, and risks associated with their use.
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Surviving stiff-person syndrome: a case report.
J. Neurol.
PUBLISHED: 03-15-2011
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Stiff-person syndrome (SPS) is a rare condition of progressive muscular rigidity and spasm, frequently accompanied by other autoimmune conditions, an association which has been further strengthened by the discovery of anti-GAD antibodies and the response of SPS to immunotherapies. Intravenous immunoglobulin (IVIg) is the mainstay therapy. Because of the rarity of the GAD antibody associated conditions, most of the information regarding treatment is case series and individual case reports. Here we describe the 15 year long management of a subject with SPS who has had a favourable outcome.
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Sustained disease-activity-free status in patients with relapsing-remitting multiple sclerosis treated with cladribine tablets in the CLARITY study: a post-hoc and subgroup analysis.
Lancet Neurol
PUBLISHED: 03-15-2011
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On the basis of various clinical and MRI measurements, the phase 3 Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) study in patients with relapsing-remitting multiple sclerosis (RRMS) showed that short-course oral treatment with cladribine at cumulative doses of 3·5 and 5·25 mg/kg over 96 weeks was more effective than placebo. Achieving sustained freedom from disease activity is becoming a viable treatment goal in RRMS; we therefore aimed to assess the effects of cladribine on this composite outcome measure by doing a post-hoc analysis of data from the CLARITY study.
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Fingolimod modulates microglial activation to augment markers of remyelination.
J Neuroinflammation
PUBLISHED: 01-27-2011
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Microglial activation in multiple sclerosis has been postulated to contribute to long-term neurodegeneration during disease. Fingolimod has been shown to impact on the relapsing remitting phase of disease by modulating autoreactive T-cell egress from lymph organs. In addition, it is brain penetrant and has been shown to exert multiple effects on nervous system cells.
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Smoking and multiple sclerosis: an updated meta-analysis.
PLoS ONE
PUBLISHED: 01-13-2011
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Multiple sclerosis (MS) is a leading cause of disability in young adults. Susceptibility to MS is determined by environmental exposure on the background of genetic risk factors. A previous meta-analysis suggested that smoking was an important risk factor for MS but many other studies have been published since then.
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Therapies for multiple sclerosis: considerations in the pediatric patient.
Nat Rev Neurol
PUBLISHED: 01-11-2011
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Current and emerging therapies for multiple sclerosis (MS) offer promise for improved disease control and long-term clinical outcome. To date, these therapies have been evaluated solely in the context of adult MS. However, onset of MS in children is being increasingly recognized, and recent studies have identified a significant impact of MS onset during childhood on cognitive and physical functioning. Optimization of pediatric MS care requires that promising new therapies be made available to children and adolescents, but also that safety and tolerability and potential influence of therapies on the developing immune and neural networks of pediatric patients be closely considered. We propose care algorithms illustrating models for therapy that detail careful monitoring of pediatric patients with MS, provide definitions for inadequate treatment response and treatment escalation, and foster multinational collaboration in future therapeutic trials.
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Geography of hospital admissions for multiple sclerosis in England and comparison with the geography of hospital admissions for infectious mononucleosis: a descriptive study.
J. Neurol. Neurosurg. Psychiatr.
PUBLISHED: 01-06-2011
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It is well recognised that variation in the geographical distribution of multiple sclerosis (MS) exists. Early studies in England have shown the disease to have been more common in the North than the South. However, this could be an artefact of inaccurate diagnosis and ascertainment, and recent data on MS prevalence are lacking. In the present study, data were analysed to provide a more contemporary map of the distribution of MS in England and, as infectious mononucleosis (IM) has been shown to be associated with the risk of MS, the geographical distribution of IM with that of MS was compared.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.