250 results on '"Carroll, W.M."'
Search Results
2. Changes in serum neurofilament light chain levels following narrowband ultraviolet B phototherapy in clinically isolated syndrome
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Fabis‐Pedrini, M.J., Kuhle, J., Roberts, K.M.A., Trend, S., Jones, A.P., Maceski, A., Carroll, W.M., Lucas, R.M., Mastaglia, F.L., Hart, P.H., Kermode, A.G., Fabis‐Pedrini, M.J., Kuhle, J., Roberts, K.M.A., Trend, S., Jones, A.P., Maceski, A., Carroll, W.M., Lucas, R.M., Mastaglia, F.L., Hart, P.H., and Kermode, A.G. more...
- Abstract
Objective To determine whether serum neurofilament light chain (sNfL) levels are suppressed in patients with the clinically isolated syndrome (CIS) following narrowband ultraviolet B phototherapy (UVB-PT). Methods sNfL levels were measured using a sensitive single-molecule array assay at baseline and up to 12 months in 17 patients with CIS, 10 of whom received UVB-PT, and were compared with healthy control (HC) and early relapsing remitting multiple sclerosis (RRMS) group. sNfL levels were correlated with magnetic resonance imaging total lesion volume (LV) determined using icobrain version 4.4.1 and with clinical outcomes. Results Baseline median sNfL levels were significantly higher in the CIS (20.6 pg/mL, interquartile range [IQR] 13.7–161.4) and RRMS groups (36.6 pg/ml [IQR] 16.2–212.2) than in HC (10.7 pg/ml [IQR] 4.9–21.5) (p = .012 and p = .0002, respectively), and were strongly correlated with T2 and T1 LV at 12 months (r = .800; p = .014 and r = .833; p = .008, respectively) in the CIS group. Analysis of changes in sNfL levels over time in the CIS group showed a significant cumulative suppressive effect of UVB-PT in the first 3 months (UVB-PT −10.6% vs non-UVB-PT +58.3%; p = .04) following which the levels in the two groups converged and continued to fall. Conclusions Our findings provide the basis for further studies to determine the utility of sNfL levels as a marker of neuro-axonal damage in CIS and early MS and for assessing the efficacy of new therapeutic interventions such as UVB-PT. more...
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- 2022
Catalog
3. Longitudinally extensive myelopathy in Caucasians: a West Australian study of 26 cases from the Perth Demyelinating Diseases Database
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Qiu, W., Wu, J.-S., Zhang, M.-N., Matsushita, T., Kira, J.-i., Carroll, W.M., Mastaglia, F.L., and Kermode, A.G.
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Spinal muscular atrophy -- Genetic aspects ,Spinal muscular atrophy -- Research ,Demyelinating diseases -- Genetic aspects ,Demyelinating diseases -- Research ,Longitudinal method -- Reports ,Health ,Psychology and mental health - Published
- 2010
4. Characterisation of the spectrum of demyelinating disease in Western Australia
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Wu, J.-S., Zhang, M.-N., Carroll, W.M., and Kermode, A.G.
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Demyelinating diseases -- Research ,Demyelinating diseases -- Demographic aspects ,Multiple sclerosis -- Statistics ,Multiple sclerosis -- Demographic aspects ,Health ,Psychology and mental health - Published
- 2008
5. NMOSD and MS prevalence in the Indigenous populations of Australia and New Zealand
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Bukhari, W., Khalilidehkordi, E., Mason, D.F., Barnett, M.H., Taylor, B.V., Fabis-Pedrini, M., Kermode, A.G., Subramanian, S., Waters, P., Broadley, S.A., Abernethy, D., Bhuta, S., Blum, S., Boggild, M., Boundy, K., Brew, B.J., Brilot, F., Brownlee, W.J., Bundell, C.S., Butzkueven, H., Carroll, W.M., Chen, C., Clarke, L., Coulthard, A., Dale, R.C., Das, C., Dear, K., Fulcher, D., Gillis, D., Hawke, S., Heard, R., Henderson, A.P.D., Heshmat, S., Hodgkinson, S., Jimenez Sanchez, S., Kilpatrick, T.J., King, J., Kneebone, C., Kornberg, A.J., Lechner-Scott, J., Lin, M-W, Lynch, C., Macdonell, R.A.L., Marriott, M.P., McCombe, P.A., O’Gorman, C., Parratt, J.D.E., Pender, M.P., Pereira, J., Pollard, J.D., Prain, K.M., Ramanathan, S., Reddell, S.W., Shaw, C., Silvestrini, R.A., Slee, M., Spies, J., Stankovich, J., Sutton, I., Vincent, A., Vucic, S., Walsh, M., Willoughby, E., Wong, R.C., Woodhall, M., Yiu, E.M., Bukhari, W., Khalilidehkordi, E., Mason, D.F., Barnett, M.H., Taylor, B.V., Fabis-Pedrini, M., Kermode, A.G., Subramanian, S., Waters, P., Broadley, S.A., Abernethy, D., Bhuta, S., Blum, S., Boggild, M., Boundy, K., Brew, B.J., Brilot, F., Brownlee, W.J., Bundell, C.S., Butzkueven, H., Carroll, W.M., Chen, C., Clarke, L., Coulthard, A., Dale, R.C., Das, C., Dear, K., Fulcher, D., Gillis, D., Hawke, S., Heard, R., Henderson, A.P.D., Heshmat, S., Hodgkinson, S., Jimenez Sanchez, S., Kilpatrick, T.J., King, J., Kneebone, C., Kornberg, A.J., Lechner-Scott, J., Lin, M-W, Lynch, C., Macdonell, R.A.L., Marriott, M.P., McCombe, P.A., O’Gorman, C., Parratt, J.D.E., Pender, M.P., Pereira, J., Pollard, J.D., Prain, K.M., Ramanathan, S., Reddell, S.W., Shaw, C., Silvestrini, R.A., Slee, M., Spies, J., Stankovich, J., Sutton, I., Vincent, A., Vucic, S., Walsh, M., Willoughby, E., Wong, R.C., Woodhall, M., and Yiu, E.M. more...
- Abstract
Background We studied the prevalence of neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS) in Indigenous populations of Australia and New Zealand with the aim of assessing potential differences. Methods Cases of possible NMOSD and MS were collected from Australia and New Zealand. Clinical details, MR imaging, and serologic results were used to apply 2015 IPND diagnostic criteria for NMOSD and 2010 McDonald criteria for MS. Frequencies of self-determined ethnic ancestry were calculated for confirmed NMOSD, suspected NMOSD, and MS. Prevalence rates for NMOSD and MS according to ancestry were compared. Results There were 75 cases with NMOSD, 89 with suspected NMSOD, and 101 with MS. NMOSD cases were more likely to have Asian, Indigenous, or Other ancestry compared to suspected NMOSD or MS. There were no differences in the clinical phenotype of NMOSD seen in Indigenous compared to European ancestry populations. Per 100,000, the prevalence estimate for NMOSD in people with Māori ancestry was 1.50 (95% CI 0.52–2.49) which was similar to those with Asian ancestry 1.57 (95% CI 1.15–1.98). NMOSD prevalence in Australian Aboriginal and Torres Strait Islander populations was 0.38 (95% CI 0.00–0.80) per 100,000. Conclusion The prevalence of NMOSD in the Māori population is similar to South East Asian countries, reflecting their historical origins. The prevalence of MS in this group is intermediate between those with South East Asian and European ancestry living in New Zealand. Both NMOSD and particularly MS appear to be uncommon in the Indigenous populations of Australia. more...
- Published
- 2021
6. Narrowband UVB phototherapy alters peripheral blood immune cell frequencies in people with clinically isolated syndrome
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Trend, S., Jones, A.P., Fabis-Pedrini, M.J., Carroll, W.M., Booth, D.R., Lucas, R.M., French, M., Byrne, S.N., Kermode, A.G., Hart, P.H., Trend, S., Jones, A.P., Fabis-Pedrini, M.J., Carroll, W.M., Booth, D.R., Lucas, R.M., French, M., Byrne, S.N., Kermode, A.G., and Hart, P.H. more...
- Abstract
Background: UV radiation exposure has immunosuppressive effects in humans. Low environmental UV radiation exposure is associated with multiple sclerosis risk. Narrowband UVB phototherapy is an established treatment for psoriasis, and is under investigation in people with clinically isolated syndrome (CIS) at risk of developing MS. Objective: To determine whether systemic leukocyte phenotypes in blood are significantly altered by a short course of narrowband UVB phototherapy in people with CIS. Methods: 20 participants with CIS were recruited and half received narrowband UVB phototherapy in 24 sessions over 2 months. Peripheral blood mononuclear cells (PBMC) were collected at baseline, and 1, 2, 3, 6 and 12 months after enrolment. Multicolour flow cytometry was used to identify T cell, B cell, monocyte, dendritic cell, and natural killer cell subsets. The effects of phototherapy on the frequencies of PBMCs were examined using linear regression. Results: Significant differences in the frequencies of PBMC phenotypes were detected between treated and untreated individuals during phototherapy, including in subsets of B cells, monocytes and T cells. No effects were detected after phototherapy treatment ceased. The largest treatment effects were detected in B cell subsets, where phototherapy was associated with significantly higher naïve B cell frequency and significantly lower frequency of switched memory B cells. Conclusions: Narrowband UVB phototherapy may contribute to immune suppression through regulation of systemic leukocyte phenotypes in people with CIS. more...
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- 2020
7. A global role for the world federation of neurology
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Carroll, W.M., primary
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- 2019
- Full Text
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8. Progress in progressive MS
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Carroll, W.M., primary
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- 2019
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9. Passivation of nitinol wire for vascular implants—a demonstration of the benefits
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O’Brien, B, Carroll, W.M, and Kelly, M.J
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- 2002
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10. Short-term changes in frequencies of circulating leukocytes associated with narrowband UVB phototherapy in people with clinically isolated syndrome
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Trend, S., Jones, A.P., Cha, L., Cooper, M.N., Geldenhuys, S., Fabis-Pedrini, M.J., Carroll, W.M., Cole, J.M., Booth, D.R., Lucas, R.M., French, M.A., Byrne, S.N., Kermode, A.G., Hart, P.H., Trend, S., Jones, A.P., Cha, L., Cooper, M.N., Geldenhuys, S., Fabis-Pedrini, M.J., Carroll, W.M., Cole, J.M., Booth, D.R., Lucas, R.M., French, M.A., Byrne, S.N., Kermode, A.G., and Hart, P.H. more...
- Abstract
Clinically isolated syndrome (CIS) is the earliest clinical episode in multiple sclerosis (MS). Low environmental exposure to UV radiation is implicated in risk of developing MS, and therefore, narrowband UVB phototherapy might delay progression to MS in people with CIS. Twenty individuals with CIS were recruited, and half were randomised to receive 24 sessions of narrowband UVB phototherapy over a period of 8 weeks. Here, the effects of narrowband UVB phototherapy on the frequencies of circulating immune cells and immunoglobulin levels after phototherapy are reported. Peripheral blood samples for all participants were collected at baseline, and 1, 2, 3, 6 and 12 months after enrolment. An extensive panel of leukocyte populations, including subsets of T cells, B cells, monocytes, dendritic cells, and natural killer cells were examined in phototherapy-treated and control participants, and immunoglobulin levels measured in serum. There were significant short-term increases in the frequency of naïve B cells, intermediate monocytes, and fraction III FoxP3+ T regulatory cells, and decreases in switched memory B cells and classical monocytes in phototherapy-treated individuals. Since B cells are increasingly targeted by MS therapies, the effects of narrowband UVB phototherapy in people with MS should be investigated further. more...
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- 2019
11. Clean air for Brain Heath; ongoing agenda of 2018 World Brain Day
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Reis, J., primary, Spencer, P.S., additional, Wasay, M., additional, Grisold, W., additional, and Carroll, W.M., additional
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- 2019
- Full Text
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12. The origin of remyelinating oligodendrocytes in antiserum-mediated demyelinative optic neuropathy
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Carroll, W.M., Jennings, A.R., and Mastaglia, F.L.
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Myelin sheath -- Growth ,Oligodendroglia -- Research ,Health - Abstract
The ability of the brain and spinal cord to recover from damage is quite limited when compared with other parts of the body. Also limited is the ability of nerves to remyelinate after the insulating myelin sheath has been destroyed by a lesion or a demyelinating disease. However, evidence is now accumulating that remyelination does occur under some circumstances. Since remyelination is thought by some to be responsible for the periodic remissions which can occur in diseases such as multiple sclerosis, it is important to determine the factors which account for remyelination under experimental conditions. Although it is universally agreed that the myelin sheaths are built by cells called oligodendrocytes, it is uncertain how these cells cause the development of new myelin in demyelinating lesions. This question was examined using an experimental model of demyelination in the optic nerve of the cat. Antibodies were injected into the optic nerve; these antibodies, which react with galactocerebroside found only on oligodendrocytes, cause the destruction of the cells and the associated myelin. Since the cells, as well as the myelin, are destroyed, the remyelination must result from the action of some other cell. Using specific antibodies to chemically distinguish the new cells which appeared in the damaged area during the healing process, investigators were able to observe the appearance of small glial cells, which were clearly not astrocytes, the predominant form of glial cell. These small glial cells were seen to differentiate; that is, begin to take on the characteristics of adult oligodendrocytes. Over time, the newly differentiated oligodendrocytes were able to complete the remyelination of the nerve fibers. However, it is not yet known where these small glial cells come from. They may be the descendants of a small number of undifferentiated cells kept in reserve by the brain. Another explanation is that astrocytes may be somehow altered and develop into functional oligodendrocytes. (Consumer Summary produced by Reliance Medical Information, Inc.) more...
- Published
- 1990
13. Serum Anti-JCV antibody status in Western Australian patients with multiple sclerosis
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Fabis-Pedrini, M.J., Jeereddy, S., Carroll, W.M., Kermode, A.G., Fabis-Pedrini, M.J., Jeereddy, S., Carroll, W.M., and Kermode, A.G.
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Background: The presence of anti-JCV antibodies is one of the risk factors for the development of progressive multifocal leukoencephalopathy (PML) among patients with multiple sclerosis (MS) treated with natalizumab or other disease modifying therapies (DMTs). Objective: The aim of this study was to evaluate the anti-JCV antibody status and index among Western Australian MS patients before and during treatment with natalizumab. Methods: We performed a cross-sectional study in 221 Western Australian MS patients to evaluate their JCV status using the STRATIFY JCVTM Test, a two-step enzyme-linked immunosorbent assay (ELISA; Unilabs, Copenhagen, Denmark). Associations with demographic and clinical characteristics were also investigated. Results: From a total of 221 patients included, 49% (n=108) were seropositive for anti-JCV antibodies, among which 53% (n=57) had an anti-JCV index ⩾1.5. Among 221 subjects analysed, 111 (50%) underwent repeated testing and within this group 15 (14%) seroconverted. All patients had relapsing-remitting disease course. Patients with JCV positive serostatus were of older age (42 vs 40 years), however this difference was not statistically significant. From the total Western Australian MS population investigated 47% of females and 54% of males were anti-JCV antibody seropositive. Conclusions: Anti-JCV antibody prevalence in our population is lower than in other reported cohorts, however over 50% of JCV seropositive patients had high JCV antibody index. more...
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- 2018
14. Efficacy and safety of mitoxantrone use in aggressive Multiple Sclerosis (P3.414)
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Fabis-Pedrini, M.J., Carroll, W.M., Kermode, A.G., Fabis-Pedrini, M.J., Carroll, W.M., and Kermode, A.G.
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Objective: To evaluate the clinical and radiological outcome in patients with aggressive MS following treatment with mitoxantrone (MX). Background: Mitoxantrone is one of the treatment options for patients with aggressive or refractory multiple sclerosis. In most cases MX was used for relapsing –remitting MS (RRMS) with frequent and disabling relapses and for rapid secondary progressive MS (SPMS). Design/Methods: This retrospective study included mitoxantrone-treated patients (n=21) diagnosed with worsening RRMS, SPMS, or primary progressive MS. All received intravenous (IV) MX infusion every 3 months at a dose of 12mg/m2 body surface area per infusion plus 1g IV methylprednisolone. Patients regularly received cardiac monitoring before and during the treatment phase. Twenty-one MX-treated MS patients (14 females, 7 males) with mean age 43.5 years (range, 25–61 years), 4 had RRMS, 2 had PPMS, and 15 had SPMS. Mean disease duration to MX initiation was 11.7 years. Results: Ten years following MX treatment 3 of our patients had died, 3 developed cancer, 5 were clinically improved, 4 had little change, and 12 continued deterioration. Four out of 5 patients with improvement had RRMS with gadolinium positive MRI lesions. One patient had transient atrial fibrillation. Conclusions: Mitoxantrone was an effective and safe treatment in selected cases of rapidly progressive RRMS with active MRI lesions. Evidence for benefit in progressive forms of MS without MRI activity was lacking. more...
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- 2018
15. Prevalence of anti-aquaporin 4 antibody in a diagnostic cohort of patients being investigated for possible neuromyelitis optica spectrum disorder in Western Australia
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Fabis-Pedrini, M.J., Bundell, C., Wee, C-K, Lucas, M., McLean-Tooke, A., Mastaglia, F.L., Carroll, W.M., Kermode, A.G., Fabis-Pedrini, M.J., Bundell, C., Wee, C-K, Lucas, M., McLean-Tooke, A., Mastaglia, F.L., Carroll, W.M., and Kermode, A.G. more...
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Objective To evaluate the prevalence of anti-AQP4 antibody in serum and CSF samples from patients being investigated for possible neuromyelitis optica spectrum disorder (NMOSD) referred to the PathWest State reference laboratory using a sensitive cell-based assay (CBA). Background NMOSD is an inflammatory CNS disease distinct from MS, which is relatively rare in Western countries. A proportion of patients with NMOSD have detectable serum IgG antibodies that target the water channel aquaporin-4 (AQP4-IgG), but the frequency varies in different populations studied and according to the assay method employed. Methods Sera or CSF from a diagnostic cohort of 196 consecutive patients with possible NMOSD which had previously been screened by indirect immunofluorescence (IIF) on primate cerebellum were re-tested for AQP4-IgG reactivity to the M1 and M23 isoforms of AQP4using a commercial CBA. A control group of 205 patients with definite MS was also included in the study. Results Of the 196 patients, only 5 sera were AQP4-IgG positive, representing 2.6% of patients in the diagnostic cohort. All 5 AQP4-IgG positive patients fulfilled the 2015 revised diagnostic criteria for NMOSD and were females of varied ethnic origins, 4 of whom had longitudinally extensive transverse myelitis. The CBA confirmed AQP4-IgG positivity in the four patients previously reported as positive by IIF, and an additional patient with NMOSD who had previously been diagnosed as MS was also identified. None of the 205 MS sera were AQP4-IgG positive. Conclusions Our study confirms the utility and greater reliability of the M1/M23 CBA for detecting AQP4-IgG in patients with possible NMOSD, and indicates a prevalence of seropositive NMOSD in the Western Australian population similar to that in other Western populations. more...
- Published
- 2018
16. Higher serum immunoglobulin G3 levels may predict the development of multiple sclerosis in individuals with Clinically Isolated Syndrome
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Trend, S., Jones, A.P., Cha, L., Byrne, S.N., Geldenhuys, S., Fabis-Pedrini, M.J., Carroll, W.M., Cole, J.M., Booth, D.R., Lucas, R.M., Kermode, A.G., French, M.A., Hart, P.H., Trend, S., Jones, A.P., Cha, L., Byrne, S.N., Geldenhuys, S., Fabis-Pedrini, M.J., Carroll, W.M., Cole, J.M., Booth, D.R., Lucas, R.M., Kermode, A.G., French, M.A., and Hart, P.H. more...
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Clinically isolated syndrome (CIS) is a first episode of neurological symptoms that may precede a diagnosis of multiple sclerosis (MS). Therefore, studying individuals with CIS may lead to breakthroughs in understanding the development and pathogenesis of MS. In this study, serum levels of immunoglobulin (Ig)G, IgA, IgM, and IgG1–4 were measured in 20 people with CIS and compared with those in 10 healthy controls (HC) and 8 people with MS. Serum Ig levels in individuals with CIS were compared with (a) the time to their conversion from CIS to MS, (b) serum levels of antibodies to Epstein–Barr virus, (c) frequencies of T regulatory (Treg), T follicular regulatory (Tfr), and B cell subsets, and (d) Treg/Tfr expression of Helios. Serum IgG, IgM, and IgG2 levels were significantly lower in people with CIS than HC, and IgG, IgM, and IgG1 levels were significantly lower in people with CIS than MS. After adjusting for age, sex, and serum 25(OH) vitamin D3 [25(OH)D] levels, CIS was associated with lower serum levels of IgG and IgG2 compared with HC (p = 0.001 and p < 0.001, respectively). People with MS had lower IgG2 levels (p < 0.001) and IgG2 proportions (%IgG; p = 0.007) compared with HC. After adjusting for age, sex, and 25(OH)D, these outcomes remained, in addition to lower serum IgA levels (p = 0.01) and increased IgG3 levels (p = 0.053) in people with MS compared with HC. Furthermore, serum from people with MS had increased proportions of IgG1 and IgG3 (p = 0.03 and p = 0.02, respectively), decreased proportions of IgG2 (p = 0.007), and greater ratios of “upstream” to “downstream” IgG subclasses (p = 0.001) compared with HC. Serum IgG3 proportions (%IgG) from people with CIS correlated with the frequency of plasmablasts in peripheral blood (p = 0.02). Expression of Helios by Treg and Tfr cell subsets from individuals with CIS correlated with levels of serum IgG2 and IgG4. IgG3 levels and proportions of IgG3 (%IgG) in serum at CIS diagnosis were inversely correlated w more...
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- 2018
17. Tryptophan and arginine catabolic enzymes and regulatory cytokines in clinically isolated syndrome and multiple sclerosis
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Cha, L., Jones, A.P., Trend, S., Byrne, S.N., Fabis-Pedrini, M.J., Carroll, W.M., Lucas, R.M., Cole, J.M., Booth, D.R., Kermode, A.G., Hart, P.H., Cha, L., Jones, A.P., Trend, S., Byrne, S.N., Fabis-Pedrini, M.J., Carroll, W.M., Lucas, R.M., Cole, J.M., Booth, D.R., Kermode, A.G., and Hart, P.H. more...
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Objectives Clinically isolated syndrome (CIS) is the earliest clinical episode in multiple sclerosis (MS). A study of circulating cells from patients with CIS may help us understand the transition to, and processes associated with, the development of MS. Methods As immune cell activity can be determined by flux through metabolic pathways, the mRNA expression of l‐tryptophan‐ and l‐arginine‐catabolising enzymes, indoleamine 2,3‐dioxygenase (IDO) 1 and IDO2 and arginase (ARG) 1 and ARG2, respectively, was compared between peripheral blood mononuclear cells (PBMCs) from healthy controls, and patients with CIS and definite MS. As one measure of cell function, cytokine mRNA levels were analysed directly ex vivo and in cells after culture for 4 h in the absence of regulatory factors in autologous serum. Results When measured directly ex vivo, the expression of IDO and ARG was greater in cells from patients with CIS and MS than cells from healthy controls. Although not linked to IDO and ARG expression, PBMCs from the CIS patients were characterised by low IL‐10 and TGFB mRNA levels and not by greater expression of proinflammatory cytokines. When the cells were cultured for 4 h without autologous serum, pro‐ and anti‐inflammatory cytokine mRNA levels positively correlated with IDO1 expression, and TGFB mRNA levels correlated with ARG1 expression. Conclusion Higher IDO and ARG expression in CIS and MS provides one sustained homeostatic mechanism to control MS‐associated inflammation. However, potent extrinsic mediators in serum may regulate immune cell function in CIS and associations between IDO, ARG and cytokine expression. more...
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- 2018
18. A randomised, controlled clinical trial of narrowband UVB phototherapy for clinically isolated syndrome: The PhoCIS study
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Hart, P.H., Jones, A.P., Trend, S., Cha, L., Fabis-Pedrini, M.J., Cooper, M.N., d’Este, C., Geldenhuys, S., Carroll, W.M., Byrne, S.N., Booth, D.R., Cole, J.M., Lucas, R.M., Kermode, A.G., Hart, P.H., Jones, A.P., Trend, S., Cha, L., Fabis-Pedrini, M.J., Cooper, M.N., d’Este, C., Geldenhuys, S., Carroll, W.M., Byrne, S.N., Booth, D.R., Cole, J.M., Lucas, R.M., and Kermode, A.G. more...
- Abstract
Background The natural history of multiple sclerosis (MS) typically presents with the clinically isolated syndrome (CIS), an episode of neurological symptoms caused by central nervous system inflammation or demyelination that does not fulfil the diagnostic criteria for MS. Objective As preclinical studies have suggested that exposure to ultraviolet radiation (UVR) could regulate the development of MS, the Phototherapy for CIS (PhoCIS trial) was established to examine the effects of narrowband UVB phototherapy on patients with CIS, and their conversion to MS. Methods Of the 20 participants, half received 24 sessions of narrowband UVB exposure over eight weeks; participants in both arms were followed for 12 months. All participants were supplemented to 25-hydroxyvitamin D3 levels of >80 nmol/l. Results By 12 months, 100% of those in the no phototherapy arm and 70% in the phototherapy arm had converted to MS, although this difference was not statistically significant. Conclusion This study provides a basis for further studies to determine if there are any benefits of the therapeutic effects of narrowband UVB radiation on MS progression. more...
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- 2018
19. Narrowband UVB Phototherapy for Clinically Isolated Syndrome: Delivering the Benefits of All UVB-Induced Molecules
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Kermode, A.G., Hart, P.H., Fabis-Pedrini, M.J., Lucas, R.M., Booth, D.R., Carroll, W.M., Nolan, D., Cole, J.M., Jones, A.P., Trend, S., Kermode, A.G., Hart, P.H., Fabis-Pedrini, M.J., Lucas, R.M., Booth, D.R., Carroll, W.M., Nolan, D., Cole, J.M., Jones, A.P., and Trend, S. more...
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Background: Trials of vitamin D supplementation have to date lacked definitive outcomes in MS patients. Narrowband UVB can induce vitamin D production, but also other important immune-regulatory molecules in skin. Objective: The PhoCIS trial (Phototherapy for Clinically Isolated Syndrome) was established in Perth, Australia (32 degrees S), to investigate the clinical, radiological and immunological effects of narrowband UVB phototherapy on MS development in CIS. Patients and Methods: Nineteen individuals with CIS have been recruited with 53% of them given narrowband UVB phototherapy of 3 sessions per week for 8 weeks. All 19 participants were supplemented when necessary with vitamin D to 25(OH)-vitamin D levels of approximately 80 nmol/L. MRI was performed after 3, 6 and 12 months, and extensive blood cell phenotyping at 1 week, 1, 2, 3, 6 and 12 months after recruitment. No participant was taking any disease modifying drugs at recruitment. Results: After 6 months, 7 of 9 participants (78%) without phototherapy converted to MS (McDonald criteria). Only 5 of 10 participants (50%) who received phototherapy converted to MS (P=0.22). UVB therapy prevented the increase in memory B cells in the blood of non-phototherapy CIS participants, and produced a significant increase in immunoprotective IgG4. Conclusion: These interim results demonstrate UVB effects slowing the progression of individuals with CIS to MS. The PhoCIS trial provides a fresh approach to re-defining the reported associations of 25(OH)-vitamin D levels with MS development and progression. The outcomes suggest that UVB-irradiation of skin is immunomodulatory independent of Vitamin D, and can regulate CIS to MS progression. more...
- Published
- 2018
20. Low Prevalence of Anti Aquaporin 4 Antibody in Neuromyelitis Optica Spectrum Disorder and Multiple Sclerosis in Western Australia
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Fabis-Pedrini, M.J., Bundell, C., Wee, C.K., Qui, W., Lucas, M., Carroll, W.M., Kermode, A.G., Fabis-Pedrini, M.J., Bundell, C., Wee, C.K., Qui, W., Lucas, M., Carroll, W.M., and Kermode, A.G.
- Abstract
Background: NMOSD is an inflammatory disease of the CNS distinct from MS, and relatively rare in Western countries. Many patients with NMOSD have detectable serum antibodies that target the water channel aquaporin-4 (AQP4-immunoglobulin G [IgG]). Objective: To evaluate the prevalence of anti-AQP4 antibody in neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS) patients from the Western Australian cohort using highly sensitive test. Methods: 420 sera of patients with NMOSD, MS and suspicious demyelinating diseases were assessed for the presence of AQP4 antibody using a cell-based assay in cells transfected with 2 isoforms of AQP4 (M1 and M23) and in primate cerebellum tissue (Euroimmun, Luebeck, Germany). The anti-AQP4 antibody test was performed at PathWest Laboratory Medicine, QEII Medical Centre. Results: Only 6 out of 420 patient sera were AQP4 antibody-positive. Our study showed a low frequency of anti-AQP4 antibody in this predominantly Anglo-Celtic Western Australian population. All of the 6 AQP4 antibody-positive patients had a final diagnosis of NMOSD; four out of six AQP-4 positive patients had longitudinally extensive myelitis (LEM). Prevalence of AQP4 antibody positivity in Western Australia was as low as 0.25 (0.05-0.43) per 100,000. We did not find any statistical difference in age between AQP4 antibody-positive and negative patients. All AQP4 antibody-positive patients were females. Conclusions: Testing AQP4 antibody positivity on cerebellar tissue is less sensitive than the cell-based assay. Our study confirmed the low anti-AQP4 antibody prevalence in the Western Australian idiopathic inflammatory CNS disease population. Our results are comparable with data from other Western populations. more...
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- 2018
21. Natural history of benign multiple sclerosis: Clinical and HLA correlates in a Western Australian cohort
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Fabis-Pedrini, M.J., James, I., Seewann, A., Yau, W.Y., van de Bovenkamp, A.A., Sanders, F.R.K., Qiu, W., Burton, J., Mastaglia, F.L., Carroll, W.M., Kermode, A.G., Fabis-Pedrini, M.J., James, I., Seewann, A., Yau, W.Y., van de Bovenkamp, A.A., Sanders, F.R.K., Qiu, W., Burton, J., Mastaglia, F.L., Carroll, W.M., and Kermode, A.G. more...
- Abstract
Background Benign multiple sclerosis (BMS) is a controversial term that has been used for MS patients with minimal disability decades after disease onset. Herein, we evaluated disease status after 20 years in a Western Australian cohort defined as BMS based on an Expanded Disability Status Scale (EDSS) score ≤ 3.0 at 10 years from onset. Methods MS patients with an EDSS score ≤ 3.0 at 10 years from onset and minimum of 20 years follow up were included in the study. The 20-year EDSS score was considered the primary outcome. Associations with demographic and clinical characteristics and HLA-DRB1 genotype were investigated. Results Among 120 patients with a benign course at 10 years, 78 (65%) remained benign at the 20-year follow up, but patients with an EDSS ≥ 2.5 were more likely to go on to develop more severe disability in the next decade. When considering factors associated with an increase in EDSS score ≤ 1 from 10 to 20 years, indicating limited progression, apart from the EDSS score at 10 years, poly-symptomatic presentation (p = 0.004) and cerebellar/brainstem mono-symptomatic presentation (p = 0.016) were independently associated with more rapid progression compared with other mono-symptomatic presentations. Carriage of the high risk HLA-DRB1*1501 allele was marginally associated with slower progression. Conclusions In this geographically isolated MS cohort of predominantly Anglo-Celtic origin clinical progression in the benign MS group was similar to that in other published series from Western countries. These results are in keeping with the view that patients labeled as benign MS are part of a heterogeneous continuum of disease progression and do not possess unique clinical characteristics. Possible genetic determinants of a benign course warrant further investigation. more...
- Published
- 2018
22. Incidence and prevalence of NMOSD in Australia and New Zealand
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Bukhari, W., Prain, K.M., Waters, P., Woodhall, M., O‘Gorman, C.M., Clarke, L., Silvestrini, R.A., Bundell, C.S., Abernethy, D., Bhuta, S., Blum, S., Boggild, M., Boundy, K., Brew, B.J., Brown, M., Brownlee, W.J., Butzkueven, H., Carroll, W.M., Chen, C., Coulthard, A., Dale, R.C., Das, C., Dear, K., Fabis-Pedrini, M.J., Fulcher, D., Gillis, D., Hawke, S., Heard, R., Henderson, A.P.D., Heshmat, S., Hodgkinson, S., Jimenez-Sanchez, S., Killpatrick, T., King, J., Kneebone, C., Kornberg, A.J., Lechner-Scott, J., Lin, M., Lynch, C., Macdonell, R., Mason, D.F., McCombe, P.A., Pender, M.P., Pereira, J.A., Pollard, J.D., Reddel, S.W., Shaw, C., Spies, J., Stankovich, J., Sutton, I., Vucic, S., Walsh, M., Wong, R.C., Yiu, E.M., Barnett, M.H., Kermode, A.G., Marriott, M.P., Parratt, J.D.E., Slee, M., Taylor, B.V., Willoughby, E., Wilson, R.J., Vincent, A., Broadley, S.A., Bukhari, W., Prain, K.M., Waters, P., Woodhall, M., O‘Gorman, C.M., Clarke, L., Silvestrini, R.A., Bundell, C.S., Abernethy, D., Bhuta, S., Blum, S., Boggild, M., Boundy, K., Brew, B.J., Brown, M., Brownlee, W.J., Butzkueven, H., Carroll, W.M., Chen, C., Coulthard, A., Dale, R.C., Das, C., Dear, K., Fabis-Pedrini, M.J., Fulcher, D., Gillis, D., Hawke, S., Heard, R., Henderson, A.P.D., Heshmat, S., Hodgkinson, S., Jimenez-Sanchez, S., Killpatrick, T., King, J., Kneebone, C., Kornberg, A.J., Lechner-Scott, J., Lin, M., Lynch, C., Macdonell, R., Mason, D.F., McCombe, P.A., Pender, M.P., Pereira, J.A., Pollard, J.D., Reddel, S.W., Shaw, C., Spies, J., Stankovich, J., Sutton, I., Vucic, S., Walsh, M., Wong, R.C., Yiu, E.M., Barnett, M.H., Kermode, A.G., Marriott, M.P., Parratt, J.D.E., Slee, M., Taylor, B.V., Willoughby, E., Wilson, R.J., Vincent, A., and Broadley, S.A. more...
- Abstract
OBJECTIVES: We have undertaken a clinic-based survey of neuromyelitis optica spectrum disorders (NMOSDs) in Australia and New Zealand to establish incidence and prevalence across the region and in populations of differing ancestry. BACKGROUND: NMOSD is a recently defined demyelinating disease of the central nervous system (CNS). The incidence and prevalence of NMOSD in Australia and New Zealand has not been established. METHODS: Centres managing patients with demyelinating disease of the CNS across Australia and New Zealand reported patients with clinical and laboratory features that were suspicious for NMOSD. Testing for aquaporin 4 antibodies was undertaken in all suspected cases. From this group, cases were identified who fulfilled the 2015 Wingerchuk diagnostic criteria for NMOSD. A capture-recapture methodology was used to estimate incidence and prevalence, based on additional laboratory identified cases. RESULTS: NMOSD was confirmed in 81/170 (48%) cases referred. Capture-recapture analysis gave an adjusted incidence estimate of 0.37 (95% CI 0.35 to 0.39) per million per year and a prevalence estimate for NMOSD of 0.70 (95% CI 0.61 to 0.78) per 100 000. NMOSD was three times more common in the Asian population (1.57 (95% CI 1.15 to 1.98) per 100 000) compared with the remainder of the population (0.57 (95% CI 0.50 to 0.65) per 100 000). The latitudinal gradient evident in multiple sclerosis was not seen in NMOSD. CONCLUSIONS: NMOSD incidence and prevalence in Australia and New Zealand are comparable with figures from other populations of largely European ancestry. We found NMOSD to be more common in the population with Asian ancestry. more...
- Published
- 2017
23. Altered regulatory T-cell fractions and Helios expression in clinically isolated syndrome: Clues to the development of multiple sclerosis
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Jones, A.P., Trend, S., Byrne, S.N., Fabis-Pedrini, M.J., Geldenhuys, S., Nolan, D., Booth, D.R., Carroll, W.M., Lucas, R.M., Kermode, A.G., Hart, P.H., Jones, A.P., Trend, S., Byrne, S.N., Fabis-Pedrini, M.J., Geldenhuys, S., Nolan, D., Booth, D.R., Carroll, W.M., Lucas, R.M., Kermode, A.G., and Hart, P.H. more...
- Abstract
Development of multiple sclerosis (MS) is frequently preceded by an acute or subacute neurological disturbance referred to as clinically isolated syndrome (CIS). The specific immunological disturbances present in CIS remain underexamined. This study analysed peripheral blood mononuclear cells from n=18 treatment-naive individuals with recently diagnosed CIS (<120 days) for disturbances in the phenotype of T regulatory (Treg), follicular T regulatory (Tfr), T helper (Th), follicular T helper (Tfh) and B cells. Relative to healthy controls (n=19), CIS was associated with lower proportions of suppressive CD45RA+FoxP3lo Treg and Tfr cells and greater proportions of non-suppressive CD45RA−FoxP3lo and Th17-like Treg and Tfr. Lower Helios expression (maen fluorescent intensity) was measured across all Treg and Tfr fractions in the CIS group, suggesting less potent regulatory function. Greater frequencies of activated, efficient B-cell helper Tfh subsets and a trend for a higher proportion of IgD−CD27− B cells was also detected in the CIS group, characteristics that were positively correlated with Treg and Tfr Helios expression. These results indicate that Treg and Tfr impairment is an early feature in MS. more...
- Published
- 2017
24. Lymphocyte reconstitution following autologous stem cell transplantation for progressive MS
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Cull, G., Hall, D., Fabis-Pedrini, M.J., Carroll, W.M., Forster, L., Robins, F., Ghassemifar, R., Crosbie, C., Walters, S., James, I., Augustson, B., Kermode, A.G., Cull, G., Hall, D., Fabis-Pedrini, M.J., Carroll, W.M., Forster, L., Robins, F., Ghassemifar, R., Crosbie, C., Walters, S., James, I., Augustson, B., and Kermode, A.G. more...
- Abstract
BACKGROUND: Autologous stem cell transplantation (ASCT) for progressive multiple sclerosis (MS) may reset the immune repertoire. OBJECTIVE: The objective of this paper is to analyse lymphocyte recovery in patients with progressive MS treated with ASCT. METHODS: Patients with progressive MS not responding to conventional treatment underwent ASCT following conditioning with high-dose cyclophosphamide and antithymocyte globulin. Lymphocyte subset analysis was performed before ASCT and for two years following ASCT. Neurological function was assessed by the EDSS before ASCT and for three years post-ASCT. RESULTS: CD4+ T-cells fell significantly post-transplant and did not return to baseline levels. Recent thymic emigrants and naïve T-cells fell sharply post-transplant but returned to baseline by nine months and twelve months, respectively. T-regulatory cells declined post-transplant and did not return to baseline levels. Th1 and Th2 cells did not change significantly while Th17 cells fell post-transplant but recovered to baseline by six months. Neurological function remained stable in the majority of patients. Progression-free survival was 69% at three years. CONCLUSION: This study demonstrates major changes in the composition of lymphocyte subsets following ASCT for progressive MS. In particular, ablation and subsequent recovery of thymic output is consistent with the concept that ASCT can reset the immune repertoire in MS patients. more...
- Published
- 2017
25. Narrowband UVB phototherapy for clinically isolated syndrome: A trial to deliver the benefits of Vitamin D and other UVB-Induced molecules
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Hart, P.H., Lucas, R.M., Booth, D.R., Carroll, W.M., Nolan, D., Cole, J.M., Jones, A.P., Kermode, A.G., Hart, P.H., Lucas, R.M., Booth, D.R., Carroll, W.M., Nolan, D., Cole, J.M., Jones, A.P., and Kermode, A.G. more...
- Abstract
Low vitamin D and insufficient sun exposure are additive independent risk factors for the development of multiple sclerosis (MS). The usual measure of vitamin D status, serum 25-hydroxy vitamin D [25(OH)D], is also a marker of recent exposure to the UVB rays of sunshine. The main evidence for a protective effect for MS development of higher 25(OH)D comes from observational studies, but this study design cannot separate out whether 25(OH)D is acting as a marker of vitamin D status, sun exposure, or both. In light of a lack of definitive outcomes in MS patients after trials of vitamin D supplementation and the ability of narrowband UVB to induce vitamin D, as well as other immune-regulatory molecules in skin, the Phototherapy for Clinically Isolated Syndrome (PhoCIS) trial was established to investigate the benefits of narrowband UVB, in addition to supplemented vitamin D, on MS development in individuals with Clinically Isolated Syndrome. We propose that the PhoCIS trial provides a fresh approach to re-defining the reported associations of 25(OH)D levels with MS development and progression. more...
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- 2017
26. Circulating immune cells in multiple sclerosis
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Jones, A.P., Kermode, A.G., Lucas, R.M., Carroll, W.M., Nolan, D., Hart, P.H., Jones, A.P., Kermode, A.G., Lucas, R.M., Carroll, W.M., Nolan, D., and Hart, P.H.
- Abstract
Circulating T and B lymphocytes contribute to the pathogenesis of the neuroinflammatory autoimmune disease, multiple sclerosis (MS). Further progress in the development of MS treatments is dependent upon a greater understanding of the immunological disturbances that underlie the disease. Analyses of circulating immune cells by flow cytometry have revealed MS-associated alterations in the composition and function of T and B cell subsets, including temporal changes associated with disease activity. Disturbances in circulating immune populations reflect those observed in the central nervous system and include skewing towards proinflammatory CD4+ and CD8+ T cells and B cells, greater proportions of follicular T helper cells and functional defects in the corresponding T and B regulatory subsets. Utilizing the analytical power of modern flow cytometers, researchers are now well positioned to monitor immunological changes associated with disease activity or intervention, describe immunological signatures with predictive value and identify targets for therapeutic drug development. This review discusses the contribution of various T and B lymphocyte subsets to MS pathogenesis, provides current and relevant phenotypical descriptions to assist in experimental design and highlights areas of future research. more...
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- 2016
27. Asymptomatic progressive multifocal leukoencephalopathy during natalizumab therapy with treatment
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Fabis-Pedrini, M.J., Xu, W., Burton, J., Carroll, W.M., Kermode, A.G., Fabis-Pedrini, M.J., Xu, W., Burton, J., Carroll, W.M., and Kermode, A.G.
- Abstract
We report a case of asymptomatic progressive multifocal leukoencephalopathy (PML) detected on regular MRI screening in a 40-year-old patient with subsequent benign course with 12 months follow-up. The patient had a history of aggressive inflammatory multiple sclerosis, prior mitoxantrone therapy, Stratify John Cunningham Virus test positivity (Quest Diagnostics, Madison, NJ, USA), and 5 years of natalizumab monotherapy. The initial MRI detection of PML was both atypical and subtle. Early diagnosis and intervention, and pre-emptive treatment for immune reconstitution inflammatory syndrome with high dose steroids, as well as empirical mirtazapine and mefloquine, were associated with a benign PML disease course and outcome. more...
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- 2016
28. Identifying Patient-Specific Epstein-Barr nuclear antigen-1 genetic variation and potential autoreactive targets relevant to multiple sclerosis pathogenesis
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Tschochner, M., Leary, S., Cooper, D., Strautins, K., Chopra, A., Clark, H., Choo, L., Dunn, D., James, I., Carroll, W.M., Kermode, A.G., Nolan, D., Tschochner, M., Leary, S., Cooper, D., Strautins, K., Chopra, A., Clark, H., Choo, L., Dunn, D., James, I., Carroll, W.M., Kermode, A.G., and Nolan, D. more...
- Abstract
Background Epstein-Barr virus (EBV) infection represents a major environmental risk factor for multiple sclerosis (MS), with evidence of selective expansion of Epstein-Barr Nuclear Antigen-1 (EBNA1)-specific CD4+ T cells that cross-recognize MS-associated myelin antigens in MS patients. HLA-DRB1*15-restricted antigen presentation also appears to determine susceptibility given its role as a dominant risk allele. In this study, we have utilised standard and next-generation sequencing techniques to investigate EBNA-1 sequence variation and its relationship to HLA-DR15 binding affinity, as well as examining potential cross-reactive immune targets within the central nervous system proteome. Methods Sanger sequencing was performed on DNA isolated from peripheral blood samples from 73 Western Australian MS cases, without requirement for primary culture, with additional FLX 454 Roche sequencing in 23 samples to identify low-frequency variants. Patient-derived viral sequences were used to predict HLA-DRB1*1501 epitopes (NetMHCII, NetMHCIIpan) and candidates were evaluated for cross recognition with human brain proteins. Results EBNA-1 sequence variation was limited, with no evidence of multiple viral strains and only low levels of variation identified by FLX technology (8.3% nucleotide positions at a 1% cut-off). In silico epitope mapping revealed two known HLA-DRB1*1501-restricted epitopes (‘AEG’: aa 481–496 and ‘MVF’: aa 562–577), and two putative epitopes between positions 502–543. We identified potential cross-reactive targets involving a number of major myelin antigens including experimentally confirmed HLA-DRB1*15-restricted epitopes as well as novel candidate antigens within myelin and paranodal assembly proteins that may be relevant to MS pathogenesis. Conclusions This study demonstrates the feasibility of obtaining autologous EBNA-1 sequences directly from buffy coat samples, and confirms divergence of these sequences from standard laboratory strains. This approach more...
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- 2016
29. A new era in the treatment of multiple sclerosis
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Broadley, S.A., Barnett, M.H., Boggild, M., Brew, B.J., Butzkueven, H., Heard, R., Hodgkinson, S., Kermode, A.G., Lechner-Scott, J., Macdonell, R.A.L., Marriott, M., Mason, D.F., Parratt, J., Reddel, S.W., Shaw, C.P., Slee, M., Spies, J.M., Taylor, B.V., Carroll, W.M., Kilpatrick, T.J., King, J., McCombe, P.A., Pollard, J.D., Willoughby, E., Broadley, S.A., Barnett, M.H., Boggild, M., Brew, B.J., Butzkueven, H., Heard, R., Hodgkinson, S., Kermode, A.G., Lechner-Scott, J., Macdonell, R.A.L., Marriott, M., Mason, D.F., Parratt, J., Reddel, S.W., Shaw, C.P., Slee, M., Spies, J.M., Taylor, B.V., Carroll, W.M., Kilpatrick, T.J., King, J., McCombe, P.A., Pollard, J.D., and Willoughby, E. more...
- Abstract
• Multiple sclerosis (MS) is an autoimmune disease of the central nervous system with a multifactorial aetiology and highly variable natural history. • A growing understanding of the immunopathogenesis of the condition has led to an expanding array of therapies for this previously untreatable disease. • While a cure for MS remains elusive, the potential to reduce inflammatory disease activity by preventing relapses and minimising disease progression is achievable. • The importance of early treatment in minimising long-term disability is increasingly recognised. • Most of the newer, more effective therapies are associated with risks and practical problems that necessitate an active management strategy and continuous vigilance. • While the initiation of these therapies is likely to remain the responsibility of neurologists, other specialist physicians and general practitioners will be involved in the identification and management of adverse effects. more...
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- 2015
30. Helicobacter pylori infection as a protective factor against multiple sclerosis risk in females
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Pedrini, M.J.F., Seewann, A., Bennett, K.A., Wood, A.J.T., James, I., Burton, J., Marshall, B.J., Carroll, W.M., Kermode, A.G., Pedrini, M.J.F., Seewann, A., Bennett, K.A., Wood, A.J.T., James, I., Burton, J., Marshall, B.J., Carroll, W.M., and Kermode, A.G. more...
- Abstract
BACKGROUND: In recent years, a relationship between Helicobacter pylori and many disease conditions has been reported, however, studies in its relationship with multiple sclerosis (MS) have had contradictory results. OBJECTIVE: To determine the association between the H. pylori infection and MS. METHODS: 550 patients with MS were included in the study and were matched by gender and year of birth to 299 controls. Patients were assessed for clinical and demographic parameters. An enzyme immunoassay was used to detect the presence of specific IgG antibodies against H. pylori in the serum sample of both groups. RESULTS: H. pylori seropositivity was found to be lower in the patients with MS than in controls (16% vs 21%) with the decrease pertaining to females (14% vs 22%, p=0.027) but not males (19% vs 20%, p=1.0). When adjusted for age at onset, year of birth and disease duration, H. pylori seropositive females presented with a lower disability score than seronegative females (p=0.049), while among males the reverse was true (p=0.025). There was no significant association between H. pylori seropositivity and relapse rate. CONCLUSIONS: Our results could reflect a protective role of H. pylori in the disease development. However, it may be that H. pylori infection is a surrogate marker for the 'hygiene hypothesis', a theory which postulates that early life infections are essential to prime the immune system and thus prevent allergic and autoimmune conditions later in life. The fact that the association between H. pylori seropositivity and MS risk was seen almost exclusively in females requires further investigation. more...
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- 2015
31. Autologous stem cell transplantation in multiple sclerosis: Results from a single centre
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Pedrini, M.J., Cull, G., Augustson, B.M., Walters, S., Crosbie, C., Carroll, W.M., Kermode, A.G., Pedrini, M.J., Cull, G., Augustson, B.M., Walters, S., Crosbie, C., Carroll, W.M., and Kermode, A.G.
- Abstract
Background: In the last 2 decades, intensive immunosuppression followed by autologous stem cell transplantation (ASCT) has been proposed as a possible strategy for treatment of severe immune-mediated disorders, including multiple sclerosis (MS). Objective: To review the outcome of ASCT for MS in Western Australia. Methods: Eligibility criteria for ASCT were (1) progression of sustained disability with expanded disability status scale (EDSS) score increase of more than 1/10 over a 12 month period, (2) advanced MS with threatened loss of ambulation and (3) rapidly progressive disease not adequately assessed by EDSS. Stem cell mobilization was with cyclophosphamide (CY) 2g/m 2 and granu - locyte-colony stimulating factor 5ug/kg bd. conditioning chemo - therapy was with CY 50mg/kg and rabbit antithymocyte globulin 1mg/kg days -5 to -2. Patients were assessed at 3, 6, 12 and 24 months post-transplant. Results: Fourteen patients underwent ASCT. Median age was 47 years; median time from diagnosis to transplant was 12 years. Diagnosis at transplant was secondary progressive MS (12), pri - mary progressive MS (1) and neuromyelitis optica (1). About half the cohorts were neurologically stable at 24 months while the remainder had clinically relevant neurological deterioration. Two patients had meaningful improvement in bladder function. Follow-up MRI showed no Gd-enhancing lesions, but two patients developed new cerebral lesions on T2 weighted imaging. Conclusion: In this group of patients with advanced MS, neuro - logical function 24 months post-ASCT was essentially stable in half the cohort while the remainder experienced clinical progres - sion. It is not possible to conclude whether ASCT altered the natu - ral history of the disease. more...
- Published
- 2015
32. Therapeutic approaches to disease modifying therapy for multiple sclerosis in adults: An Australian and New Zealand perspective Part 2 New and emerging therapies and their efficacy
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Broadley, S.A., Barnett, M.H., Boggild, M., Brew, B.J., Butzkueven, H., Heard, R., Hodgkinson, S., Kermode, A.G., Lechner-Scott, J., Macdonell, R.A.L., Marriott, M., Mason, D.F., Parratt, J., Reddel, S.W., Shaw, C.P., Slee, M., Spies, J., Taylor, B.V., Carroll, W.M., Kilpatrick, T.J., King, J., McCombe, P.A., Pollard, J.D., Willoughby, E., Broadley, S.A., Barnett, M.H., Boggild, M., Brew, B.J., Butzkueven, H., Heard, R., Hodgkinson, S., Kermode, A.G., Lechner-Scott, J., Macdonell, R.A.L., Marriott, M., Mason, D.F., Parratt, J., Reddel, S.W., Shaw, C.P., Slee, M., Spies, J., Taylor, B.V., Carroll, W.M., Kilpatrick, T.J., King, J., McCombe, P.A., Pollard, J.D., and Willoughby, E. more...
- Abstract
In Part 2 of this three part review of multiple sclerosis (MS) treatment with a particular focus on the Australian and New Zealand perspective, we review the newer therapies that have recently become available and emerging therapies that have now completed phase III clinical trial programs. We go on to compare the relative efficacies of these newer and emerging therapies alongside the existing therapies. The effectiveness of β-interferon in the treatment of different stages and the different disease courses of MS is critically reviewed with the conclusion that the absolute level of response in term of annualised relapse rates (where relapses occur) and MRI activity are similar, but are disappointing in terms of sustained disability progression for progressive forms of the disease. Finally we review the controversial area of combination therapy for MS. Whilst it remains the case that we have no cure or means of preventing MS, we do have a range of effective therapies that when used appropriately and early in the disease course can have a significant impact on short term and longer term outcomes. more...
- Published
- 2014
33. Therapeutic approaches to disease modifying therapy for multiple sclerosis in adults: An Australian and New Zealand perspective Part 3 Treatment practicalities and recommendations
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Broadley, S.A., Barnett, M.H., Boggild, M., Brew, B.J., Butzkueven, H., Heard, R., Hodgkinson, S., Kermode, A.G., Lechner-Scott, J., Macdonell, R.A.L., Marriott, M., Mason, D.F., Parratt, J., Reddel, S.W., Shaw, C.P., Slee, M., Spies, J., Taylor, B.V., Carroll, W.M., Kilpatrick, T.J., King, J., McCombe, P.A., Pollard, J.D., Willoughby, E., Broadley, S.A., Barnett, M.H., Boggild, M., Brew, B.J., Butzkueven, H., Heard, R., Hodgkinson, S., Kermode, A.G., Lechner-Scott, J., Macdonell, R.A.L., Marriott, M., Mason, D.F., Parratt, J., Reddel, S.W., Shaw, C.P., Slee, M., Spies, J., Taylor, B.V., Carroll, W.M., Kilpatrick, T.J., King, J., McCombe, P.A., Pollard, J.D., and Willoughby, E. more...
- Abstract
In this third and final part of our review of multiple sclerosis (MS) treatment we look at the practical day-to-day management issues that are likely to influence individual treatment decisions. Whilst efficacy is clearly of considerable importance, tolerability and the potential for adverse effects often play a significant role in informing individual patient decisions. Here we review the issues surrounding switching between therapies, and the evidence to assist guiding the choice of therapy to change to and when to change. We review the current level of evidence with regards to the management of women in their child-bearing years with regards to recommendations about treatment during pregnancy and whilst breast feeding. We provide a summary of recommended pre- and post-treatment monitoring for the available therapies and review the evidence with regards to the value of testing for antibodies which are known to be neutralising for some therapies. We review the occurrence of adverse events, both the more common and troublesome effects and those that are less common but have potentially much more serious outcomes. Ways of mitigating these risks and managing the more troublesome adverse effects are also reviewed. Finally, we make specific recommendations with regards to the treatment of MS. It is an exciting time in the world of MS neurology and the prospects for further advances in coming years are high. more...
- Published
- 2014
34. Therapeutic approaches to disease modifying therapy for multiple sclerosis in adults: An Australian and New Zealand perspective Part 1 Historical and established therapies
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Broadley, S.A., Barnett, M.H., Boggild, M., Brew, B.J., Butzkueven, H., Heard, R., Hodgkinson, S., Kermode, A.G., Lechner-Scott, J., Macdonell, R.A.L., Marriott, M., Mason, D.F., Parratt, J., Reddel, S.W., Shaw, C.P., Slee, M., Spies, J., Taylor, B.V., Carroll, W.M., Kilpatrick, T.J., King, J., McCombe, P.A., Pollard, J.D., Willoughby, E., Broadley, S.A., Barnett, M.H., Boggild, M., Brew, B.J., Butzkueven, H., Heard, R., Hodgkinson, S., Kermode, A.G., Lechner-Scott, J., Macdonell, R.A.L., Marriott, M., Mason, D.F., Parratt, J., Reddel, S.W., Shaw, C.P., Slee, M., Spies, J., Taylor, B.V., Carroll, W.M., Kilpatrick, T.J., King, J., McCombe, P.A., Pollard, J.D., and Willoughby, E. more...
- Abstract
Multiple sclerosis (MS) is a potentially life-changing immune mediated disease of the central nervous system. Until recently, treatment has been largely confined to acute treatment of relapses, symptomatic therapies and rehabilitation. Through persistent efforts of dedicated physicians and scientists around the globe for 160 years, a number of therapies that have an impact on the long term outcome of the disease have emerged over the past 20 years. In this three part series we review the practicalities, benefits and potential hazards of each of the currently available and emerging treatment options for MS. We pay particular attention to ways of abrogating the risks of these therapies and provide advice on the most appropriate indications for using individual therapies. In Part 1 we review the history of the development of MS therapies and its connection with the underlying immunobiology of the disease. The established therapies for MS are reviewed in detail and their current availability and indications in Australia and New Zealand are summarised. We examine the evidence to support their use in the treatment of MS. more...
- Published
- 2014
35. Resequencing and fine-mapping of the chromosome 12q13-14 locus associated with multiple sclerosis refines the number of implicated genes
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Cortes, A., Field, J., Glazov, E.A., Hadler, J., Stankovich, J., Brown, M.A., Baxter, A., Kermode, A.G., Taylor, B., Booth, D.R., Mason, D., Stewart, G.J., Butzkueven, H., Charlesworth, J., Wiley, J., Lechner-Scott, J., Tajouri, L., Griffiths, L., Slee, M., Moscato, P., Scott, R.J., Broadley, S., Vucic, S., Kilpatrick, T.J., Carroll, W.M., Cortes, A., Field, J., Glazov, E.A., Hadler, J., Stankovich, J., Brown, M.A., Baxter, A., Kermode, A.G., Taylor, B., Booth, D.R., Mason, D., Stewart, G.J., Butzkueven, H., Charlesworth, J., Wiley, J., Lechner-Scott, J., Tajouri, L., Griffiths, L., Slee, M., Moscato, P., Scott, R.J., Broadley, S., Vucic, S., Kilpatrick, T.J., and Carroll, W.M. more...
- Abstract
Multiple sclerosis (MS) is a common chronic inflammatory disease of the central nervous system. Susceptibility to the disease is affected by both environmental and genetic factors. Genetic factors include haplotypes in the histocompatibility complex (MHC) and over 50 non-MHC loci reported by genome-wide association studies. Amongst these, we previously reported polymorphisms in chromosome 12q13-14 with a protective effect in individuals of European descent. This locus spans 288 kb and contains 17 genes, including several candidate genes which have potentially significant pathogenic and therapeutic implications. In this study, we aimed to fine-map this locus. We have implemented a two-phase study: a variant discovery phase where we have used next-generation sequencing and two target-enrichment strategies [long-range polymerase chain reaction (PCR) and Nimblegen's solution phase hybridization capture] in pools of 25 samples; and a genotyping phase where we genotyped 712 variants in 3577 healthy controls and 3269 MS patients. This study confirmed the association (rs2069502, P = 9.9 × 10(-11), OR = 0.787) and narrowed down the locus of association to an 86.5 kb region. Although the study was unable to pinpoint the key-associated variant, we have identified a 42 (genotyped and imputed) single-nucleotide polymorphism haplotype block likely to harbour the causal variant. No evidence of association at previously reported low-frequency variants in CYP27B1 was observed. As part of the study we compared variant discovery performance using two target-enrichment strategies. We concluded that our pools enriched with Nimblegen's solution phase hybridization capture had better sensitivity to detect true variants than the pools enriched with long-range PCR, whilst specificity was better in the long-range PCR-enriched pools compared with solution phase hybridization capture enriched pools; this result has important implications for the design of future fine-mapping studies. more...
- Published
- 2013
36. The influence of non-HLA gene polymorphisms and interactions on disease risk in a Western Australian multiple sclerosis cohort
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Qiu, W., Pham, K., James, I., Nolan, D., Castley, A., Christiansen, F.T., Czarniak, P., Luo, Y., Wu, J., Garlepp, M., Wilton, S., Carroll, W.M., Mastaglia, F.L., Kermode, A.G., Qiu, W., Pham, K., James, I., Nolan, D., Castley, A., Christiansen, F.T., Czarniak, P., Luo, Y., Wu, J., Garlepp, M., Wilton, S., Carroll, W.M., Mastaglia, F.L., and Kermode, A.G. more...
- Abstract
Non-Human Leukocyte Antigen (HLA) genes have concomitant, although modest, effects on multiple sclerosis (MS) susceptibility; however findings have varied in different populations. Here we present the results of an association study of 16 single nucleotide polymorphisms (SNPs) in 10 non-HLA genes (IL7R, IL2RA, CLEC-16A, TYK2, CD58, IRF5, STAT3, CTLA-4, APOE, ICAM-1) in a Western Australian cohort of 350 MS patients and 498 population control subjects. Our results indicate that in this population, SNPs in IL7R, TYK2, IRF5 and APOE have modifying effects on MS susceptibility. We also found evidence of interactive protective effects between polymorphisms in the IL7R/CD58, CLEC-16A/CTLA-4, and TYK2/IRF5 genes, which in some instances are restricted within HLA- or gender-defined groups. more...
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- 2013
37. Benign multiple sclerosis: A longitudinal follow-up study of large Western Australian cohort
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Pedrini, M.J., Xu, W., Xu, Z., Seewann, A., Burton, J., Carroll, W.M., Kermode, A.G., Pedrini, M.J., Xu, W., Xu, Z., Seewann, A., Burton, J., Carroll, W.M., and Kermode, A.G.
- Abstract
Background: The majority of multiple sclerosis (MS) cases are characterized by clinical onset with relapses and remissions (RRMS). However, years after the first disease manifestation most patients experience secondary progression (SPMS). The second principal group of MS patients is primary progressive MS (PPMS). In a minority of MS patients, however, disease never leads to substantial disability and shows little or no progression years after the first symptoms, termed benign MS (BMS). The aim of our study was to evaluate disease status after 15, 20, 25, 30 and 35 years in a well characterized Western Australian longitudinal cohort defined as BMS based on Expanded Disability Status Scale (EDSS) <= 3.5 at 10 years from onset. Methods: The cohort comprises a total of 1415 cases, with followup as long as 50 years. Patients with EDSS <= 3.5 at 10 years from disease onset were selected from the Perth Demyelinating Disease Database. EDSS score at the 15, 20, 25, 30 and 35 year epochs was evaluated. Potential modifying factors influencing prognosis including gender, age at onset, first symptoms, initial MRI, CSF, HLA and disease course were also studied. Results: 417 patients had 10 or more years of detailed followup, of whom 210 patients had EDSS of <= 3.5 10 years (50.3%). Female/male ratio was 5.4 : 1. Average onset age in females was 33 years and in males 36 years. RRMS was the dominant disease course at onset (93 %). Fifteen, 20, 25, 30 and 35 year EDSS scores <= 3.5 were obtained for 122, 64, 33, 17 and 8 of 210, which corresponded to 58.1%, 30.5%, 15.7%, 8.1% and 3.8% of benign outcome, respectively. At 10 years from onset 50% of MS patients were found as benign cases. Every 5 years the group of patients with EDSS <= 3.5 (“benign”) was reduced by approximately 50%. Conclusions: In this large well characterized, geographically isolated, predominantly Anglo-Celtic Western Australian cohort clinical progression was similar to other published series from Western countri more...
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- 2013
38. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis
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Sawcer, S., Hellenthal, G., Pirinen, M., Spencer, C.C.A., Patsopoulos, N.A., Moutsianas, L., Dilthey, A., Su, Z., Freeman, C., Hunt, S.E., Edkins, S., Gray, E., Booth, D.R., Potter, S.C., Goris, A., Band, G., Bang Oturai, A., Strange, A., Saarela, J., Bellenguez, C., Fontaine, B., Gillman, M., Hemmer, B., Gwilliam, R., Zipp, F., Jayakumar, A., Martin, R., Leslie, S., Hawkins, S., Giannoulatou, E., D’alfonso, S., Blackburn, H., Martinelli Boneschi, F., Liddle, J., Harbo, H.F., Perez, M.L., Spurkland, A., Waller, M.J., Mycko, M.P., Ricketts, M., Comabella, M., Hammond, N., Kockum, I., McCann, O.T., Ban, M., Whittaker, P., Kemppinen, A., Weston, P., Hawkins, C., Widaa, S., Zajicek, J., Dronov, S., Robertson, N., Bumpstead, S.J., Barcellos, L.F., Ravindrarajah, R., Abraham, R., Alfredsson, L., Ardlie, K., Aubin, C., Baker, A., Baker, K., Baranzini, S.E., Bergamaschi, L., Bergamaschi, R., Bernstein, A., Berthele, A., Boggild, M., Bradfield, J.P., Brassat, D., Broadley, S.A., Buck, D., Butzkueven, H., Capra, R., Carroll, W.M., Cavalla, P., Celius, E.G., Cepok, S., Chiavacci, R., Clerget-Darpoux, F., Clysters, K., Comi, G., Cossburn, M., Cournu-Rebeix, I., Cox, M.B., Cozen, W., Cree, B.A.C., Cross, A.H., Cusi, D., Daly, M.J., Davis, E., de Bakker, P.I.W., Debouverie, M., D’hooghe, M.B., Dixon, K., Dobosi, R., Dubois, B., Ellinghaus, D., Elovaara, I., Esposito, F., Fontenille, C., Foote, S., Franke, A., Galimberti, D., Ghezzi, A., Glessner, J., Gomez, R., Gout, O., Graham, C., Grant, S.F.A., Rosa Guerini, F., Hakonarson, H., Hall, P., Hamsten, A., Hartung, H-P, Heard, R.N., Heath, S., Hobart, J., Hoshi, M., Infante-Duarte, C., Ingram, G., Ingram, W., Islam, T., Jagodic, M., Kabesch, M., Kermode, A.G., Kilpatrick, T.J., Kim, C., Klopp, N., Koivisto, K., Larsson, M., Lathrop, M., Lechner-Scott, J.S., Leone, M.A., Leppä, V., Liljedahl, U., Lima Bomfim, I., Lincoln, R.R., Link, J., Liu, J., Lorentzen, Å.R., Lupoli, S., Macciardi, F., Mack, T., Marriott, M., Martinelli, V., Mason, D., McCauley, J.L., Mentch, F., Mero, I-L, Mihalova, T., Montalban, X., Mottershead, J., Myhr, K-M, Naldi, P., Ollier, W., Page, A., Palotie, A., Pelletier, J., Piccio, L., Pickersgill, T., Piehl, F., Pobywajlo, S., Quach, H.L., Ramsay, P.P., Reunanen, M., Reynolds, R., Rioux, J.D., Rodegher, M., Roesner, S., Rubio, J.P., Rückert, I-M, Salvetti, M., Salvi, E., Santaniello, A., Schaefer, C.A., Schreiber, S., Schulze, C., Scott, R.J., Sellebjerg, F., Selmaj, K.W., Sexton, D., Shen, L., Simms-Acuna, B., Skidmore, S., Sleiman, P.M.A., Smestad, C., Sørensen, P.S., Søndergaard, H.B., Stankovich, J., Strange, R.C., Sulonen, A-M, Sundqvist, E., Syvänen, A-C, Taddeo, F., Taylor, B., Blackwell, J.M., Tienari, P., Bramon, E., Tourbah, A., Brown, M.A., Tronczynska, E., Casas, J.P., Tubridy, N., Corvin, A., Vickery, J., Jankowski, J., Villoslada, P., Markus, H.S., Wang, K., Mathew, C.G., Wason, J., Palmer, C.N.A., Wichmann, H-E, Plomin, R., Willoughby, E., Rautanen, A., Winkelmann, J., Wittig, M., Trembath, R.C., Yaouanq, J., Viswanathan, A.C., Zhang, H., Wood, N.W., Zuvich, R., Deloukas, P., Langford, C., Duncanson, A., Oksenberg, J.R., Pericak-Vance, M.A., Haines, J.L., Olsson, T., Hillert, J., Ivinson, A.J., De Jager, P.L., Peltonen, L., Stewart, G.J., Hafler, D.A., Hauser, S.L., McVean, G., Donnelly, P., Compston, A., Sawcer, S., Hellenthal, G., Pirinen, M., Spencer, C.C.A., Patsopoulos, N.A., Moutsianas, L., Dilthey, A., Su, Z., Freeman, C., Hunt, S.E., Edkins, S., Gray, E., Booth, D.R., Potter, S.C., Goris, A., Band, G., Bang Oturai, A., Strange, A., Saarela, J., Bellenguez, C., Fontaine, B., Gillman, M., Hemmer, B., Gwilliam, R., Zipp, F., Jayakumar, A., Martin, R., Leslie, S., Hawkins, S., Giannoulatou, E., D’alfonso, S., Blackburn, H., Martinelli Boneschi, F., Liddle, J., Harbo, H.F., Perez, M.L., Spurkland, A., Waller, M.J., Mycko, M.P., Ricketts, M., Comabella, M., Hammond, N., Kockum, I., McCann, O.T., Ban, M., Whittaker, P., Kemppinen, A., Weston, P., Hawkins, C., Widaa, S., Zajicek, J., Dronov, S., Robertson, N., Bumpstead, S.J., Barcellos, L.F., Ravindrarajah, R., Abraham, R., Alfredsson, L., Ardlie, K., Aubin, C., Baker, A., Baker, K., Baranzini, S.E., Bergamaschi, L., Bergamaschi, R., Bernstein, A., Berthele, A., Boggild, M., Bradfield, J.P., Brassat, D., Broadley, S.A., Buck, D., Butzkueven, H., Capra, R., Carroll, W.M., Cavalla, P., Celius, E.G., Cepok, S., Chiavacci, R., Clerget-Darpoux, F., Clysters, K., Comi, G., Cossburn, M., Cournu-Rebeix, I., Cox, M.B., Cozen, W., Cree, B.A.C., Cross, A.H., Cusi, D., Daly, M.J., Davis, E., de Bakker, P.I.W., Debouverie, M., D’hooghe, M.B., Dixon, K., Dobosi, R., Dubois, B., Ellinghaus, D., Elovaara, I., Esposito, F., Fontenille, C., Foote, S., Franke, A., Galimberti, D., Ghezzi, A., Glessner, J., Gomez, R., Gout, O., Graham, C., Grant, S.F.A., Rosa Guerini, F., Hakonarson, H., Hall, P., Hamsten, A., Hartung, H-P, Heard, R.N., Heath, S., Hobart, J., Hoshi, M., Infante-Duarte, C., Ingram, G., Ingram, W., Islam, T., Jagodic, M., Kabesch, M., Kermode, A.G., Kilpatrick, T.J., Kim, C., Klopp, N., Koivisto, K., Larsson, M., Lathrop, M., Lechner-Scott, J.S., Leone, M.A., Leppä, V., Liljedahl, U., Lima Bomfim, I., Lincoln, R.R., Link, J., Liu, J., Lorentzen, Å.R., Lupoli, S., Macciardi, F., Mack, T., Marriott, M., Martinelli, V., Mason, D., McCauley, J.L., Mentch, F., Mero, I-L, Mihalova, T., Montalban, X., Mottershead, J., Myhr, K-M, Naldi, P., Ollier, W., Page, A., Palotie, A., Pelletier, J., Piccio, L., Pickersgill, T., Piehl, F., Pobywajlo, S., Quach, H.L., Ramsay, P.P., Reunanen, M., Reynolds, R., Rioux, J.D., Rodegher, M., Roesner, S., Rubio, J.P., Rückert, I-M, Salvetti, M., Salvi, E., Santaniello, A., Schaefer, C.A., Schreiber, S., Schulze, C., Scott, R.J., Sellebjerg, F., Selmaj, K.W., Sexton, D., Shen, L., Simms-Acuna, B., Skidmore, S., Sleiman, P.M.A., Smestad, C., Sørensen, P.S., Søndergaard, H.B., Stankovich, J., Strange, R.C., Sulonen, A-M, Sundqvist, E., Syvänen, A-C, Taddeo, F., Taylor, B., Blackwell, J.M., Tienari, P., Bramon, E., Tourbah, A., Brown, M.A., Tronczynska, E., Casas, J.P., Tubridy, N., Corvin, A., Vickery, J., Jankowski, J., Villoslada, P., Markus, H.S., Wang, K., Mathew, C.G., Wason, J., Palmer, C.N.A., Wichmann, H-E, Plomin, R., Willoughby, E., Rautanen, A., Winkelmann, J., Wittig, M., Trembath, R.C., Yaouanq, J., Viswanathan, A.C., Zhang, H., Wood, N.W., Zuvich, R., Deloukas, P., Langford, C., Duncanson, A., Oksenberg, J.R., Pericak-Vance, M.A., Haines, J.L., Olsson, T., Hillert, J., Ivinson, A.J., De Jager, P.L., Peltonen, L., Stewart, G.J., Hafler, D.A., Hauser, S.L., McVean, G., Donnelly, P., and Compston, A. more...
- Abstract
Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability1. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals2, 3, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk4. Modestly powered genome-wide association studies (GWAS)5, 6, 7, 8, 9, 10 have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility11. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis. more...
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- 2011
39. Hypothalamic lesions in multiple sclerosis
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Qiu, W., Raven, S., Wu, J-S, Bundell, C., Hollingsworth, P., Carroll, W.M., Mastaglia, F.L., Kermode, A.G., Qiu, W., Raven, S., Wu, J-S, Bundell, C., Hollingsworth, P., Carroll, W.M., Mastaglia, F.L., and Kermode, A.G. more...
- Abstract
Objectives To determine the frequency of hypothalamic lesions in patients with multiple sclerosis (MS) using conventional MRI (cMRI) protocols. Methods Brain cMRI (1.5 Tesla) scans of 105 Caucasian patients with classical MS (50 with stable and 55 with more active disease) and 12 patients with longitudinal extensive myelopathy (LEM) were reviewed retrospectively. NMO-IgG antibody was assayed in patients with hypothalamic lesions. Results Hypothalamic lesions were found in 13.3% of MS patients and in none of the LEM patients. A higher frequency of hypothalamic lesions was found in patients with active MS (18.2%) than in the stable group (8.0%), but this did not reach statistical significance (p=0.13). Patients with hypothalamic lesions also had more lesions in other cerebral structures. None of the LEM patients had hypothalamic lesions. No patients with hypothalamic lesions were positive for NMO-IgG. Conclusions Hypothalamic lesions in MS are more frequent than previously reported and are not associated with NMO-IgG antibody. more...
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- 2011
40. HLA-DR allele polymorphism and multiple sclerosis in Chinese populations: a meta-analysis
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Qiu, W., James, I., Carroll, W.M., Mastaglia, F.L., Kermode, A.G., Qiu, W., James, I., Carroll, W.M., Mastaglia, F.L., and Kermode, A.G.
- Abstract
Background: The association of human leukocyte antigen (HLA) genes and multiple sclerosis (MS) has been extensively investigated in Caucasians, but less so in Oriental races such as Chinese. Objectives: To review studies on association of HLA class II alleles with MS in the Chinese population. Methods: An extensive search for published studies up to June 2010 was performed in the electronic databases. The meta-analysis facilities in the NCSS statistical package were utilized to analyze the findings in these studies. The odds ratios (ORs) of HLA-DR allele distributions in MS were analyzed against controls. Results: Eleven case-control studies were identified: nine genotyping and two serotyping studies. Six genotyping studies were suitable for HLA-DRB1 allele meta-analysis, which showed that HLA-DRB1*15 was associated with risk of MS in the combined group (308 cases and 407 controls; OR 1.39) while the HLA-DRB1*09 and HLA-DRB1*0901 alleles were protective. When the equivalent serotypes in these six studies were combined with the results from the two serotyping studies (431 cases and 652 controls) for a meta-analysis of HLA-DR serotypes, HLA-DR2 was a risk factor (OR 1.63) and HLA-DR9 was strongly protective in the combined group (OR 0.64). Conclusions: Although limited data are available, our meta-analysis suggests that HLA-DR2/DRB1*15 are also associated with risk of MS in the Chinese population but less strongly so than in Western MS populations, whereas HLA-DR9 alleles appear to confer resistance in this population. more...
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- 2011
41. Spinal cord involvement in multiple sclerosis: A correlative MRI and high-resolution HLA-DRB1 genotyping study
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Qiu, W., Raven, S., James, I., Luo, Y., Wu, J., Castley, A., Christiansen, F.T., Carroll, W.M., Mastaglia, F.L., Kermode, A.G., Qiu, W., Raven, S., James, I., Luo, Y., Wu, J., Castley, A., Christiansen, F.T., Carroll, W.M., Mastaglia, F.L., and Kermode, A.G. more...
- Abstract
Background: There have been few magnetic resonance imaging (MRI) studies of the spinal cord in large multiple sclerosis (MS) patient cohorts and little is known about correlations between cord lesions and human leukocyte antigen (HLA) alleles. Objective: To investigate the spectrum of MRI changes in the spinal cord in MS and associations with the HLA-DRB1 genotype. Methods: Two hundred and fifty two consecutive MS patients from the Perth Demyelinating Diseases Database had MRI of the spinal cord and brain and high-resolution HLA-DRB1 genotyping. The numbers, locations, shape and segmental extent of cord lesions were analysed and were correlated with carriage of individual HLA-DRB1 alleles and diplotypes. Results: Focal cord lesions were present in 82.9% of cases, with numbers being maximal in the cervical cord and increasing with disease duration. Focal lesions were usually round or oval in shape but in 35% of cases subpial wedge-shaped lesions were present. Diffuse cord involvement was present in 10% of cases and correlated with carriage of HLA-DRB1*1501 and with higher disability. Carriage of the minor allele HLA-DRB1*0701 was significantly associated with numbers of wedge-shaped lesions and lesions in the cervical cord, while HLA-DRB1*1104 and DRB1*0103 were significantly associated respectively with higher and lower numbers of thoracic cord lesions. HLA-DRB1*1501 and the HLA-DRB1*11 sub-alleles DRB1*1101 and DRB1*1104 were significantly associated with the segmental length of cord lesions. Conclusions: Our study is the first to investigate the frequency of subpial wedge-shaped lesions in the cord in vivo and has provided preliminary evidence that HLA-DRB1 alleles may play a role in determining the severity and extent of spinal cord involvement in MS. more...
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- 2011
42. Wedge-shaped medullary lesions in multiple sclerosis
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Qiu, W., Raven, S., Wu, J-S, Carroll, W.M., Mastaglia, F.L., Kermode, A.G., Qiu, W., Raven, S., Wu, J-S, Carroll, W.M., Mastaglia, F.L., and Kermode, A.G.
- Abstract
Multiple sclerosis (MS) is a heterogeneous disease with variable clinical features and magnetic resonance imaging (MRI) findings. We report four MS cases with unusual wedge-shaped lesions in the paramedian ventral medulla oblongata demonstrated on MRI. The clinical features and MRI characteristics of the medullary lesions suggest an impairment of venous drainage. We propose that the formation of these wedge-shaped lesions may be related to the pattern of venous drainage in the ventral medulla and raised venous pressure due to chronic cerebrospinal venous insufficiency which has recently been described in MS. more...
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- 2010
43. HLA-DRB1 allele heterogeneity influences multiple sclerosis severity as well as risk in Western Australia
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Wu, J-S, James, I., Qiu, W., Castley, A., Christiansen, F.T., Carroll, W.M., Mastaglia, F.L., Kermode, A.G., Wu, J-S, James, I., Qiu, W., Castley, A., Christiansen, F.T., Carroll, W.M., Mastaglia, F.L., and Kermode, A.G. more...
- Abstract
Susceptibility to multiple sclerosis (MS) has been consistently associated with the Human Leukocyte Antigen (HLA)-DRB1*1501 genotype, however effects on disease severity and clinical outcome have varied in different populations. We present the results of a high-resolution HLA-DRB1 genotyping and genotype-phenotype correlation study in a large West Australian MS cohort. Our findings indicate that in this population, which is of largely Anglo-Celtic and Northern European origin, HLA-DRB1*1501 is not only a strong determinant of disease risk but may also be associated with disease severity as measured by the Multiple Sclerosis Severity Score (MSSS), with the MSSS increasing by an estimated 0.51 per DRB1*1501 allele. We also found evidence that the HLA-DRB1*1201 allele is associated with less severe disease. more...
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- 2010
44. Modifying effects of HLA-DRB1 allele interactions on age at onset of multiple sclerosis in Western Australia
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Wu, J-S, Qiu, W., Castley, A., James, I., Mastaglia, F.L., Christiansen, F.T, Carroll, W.M, Joseph, J., Kermode, A.G., Wu, J-S, Qiu, W., Castley, A., James, I., Mastaglia, F.L., Christiansen, F.T, Carroll, W.M, Joseph, J., and Kermode, A.G. more...
- Abstract
The contribution of genetic factors to the age at onset in multiple sclerosis is poorly understood. Our objective was to investigate the disease modifying effects of HLA-DRB1 alleles and allele interactions on age at onset of multiple sclerosis. High-resolution four-digit HLA-DRB1 genotyping was performed in a cohort of 461 multiple sclerosis patients from the Perth Demyelinating Diseases Database. Carriage of the HLA-DRB1*1501 risk allele was not significantly associated with age at onset but HLA-DRB1*0801 was associated with a later onset of the disease. The HLA-DRB1*0401 allele was associated with a reduced age at onset when combined with DRB1*1501 but may delay age at onset when combined with DRB1*0801. These findings indicate that epistatic interactions at the HLA-DRB1 locus have significant modifying effects on age at onset of multiple sclerosis and demonstrate the value of high-resolution genotyping in detecting such associations. more...
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- 2010
45. Low level of systemic autoimmunity in Western Australian multiple sclerosis patients
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Qiu, W., Bundell, C., Wu, J.-S., Castley, A., James, I., Hollingsworth, P., Christiansen, F., Carroll, W.M., Mastaglia, F.L., Kermode, A.G., Qiu, W., Bundell, C., Wu, J.-S., Castley, A., James, I., Hollingsworth, P., Christiansen, F., Carroll, W.M., Mastaglia, F.L., and Kermode, A.G. more...
- Abstract
Previous autoantibody (AAb) studies in multiple sclerosis MS have produced conflicting results. The objective of this study was to determine AAb frequency and association with the HLA-DRB1 genotype. Antinuclear antibody, antithyroid peroxidase and anti-aquaporin-4 assays and HLA-DRB1 genotyping were performed in 198 MS patients and 188 controls. There were no significant differences in AAb frequency or titres between MS and control subjects. AQP4-IgG was not found in any MS patients. There was no correlation between AAbs and HLA-DRB1 alleles. In conclusion, this study failed to confirm previous reports of increased AAbs in MS or to show an association between HLA-DRB1 genotype and the presence of AAbs. more...
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- 2010
46. Influence of HLA-DRB1 allele heterogeneity on disease risk and clinical course in a West Australian MS cohort: a high-resolution genotyping study
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Wu, J.S., James, I., Wei, Q., Castley, A., Christiansen, F.T., Carroll, W.M., Mastaglia, F.L., Kermode, A.G., Wu, J.S., James, I., Wei, Q., Castley, A., Christiansen, F.T., Carroll, W.M., Mastaglia, F.L., and Kermode, A.G. more...
- Abstract
Background: Previous studies on the influence of HLA-DRB1 alleles on multiple sclerosis (MS) susceptibility and clinical course have mostly employed the 2-point genotyping method. Objective: To assess the influence of HLA-DRB1 alleles and allele interactions on disease risk and clinical course in a large West Australian MS patient cohort using high-resolution genotyping. Methods: Four digit HLA-DRB1 genotyping was performed on a group of 466 clinically definite or probable MS patients from the Perth Demyelinating Diseases Database and 189 healthy Caucasian controls from the Busselton Community Health Study. Results: In addition to the known risk allele HLA-DRB1*1501, evidence of increased susceptibility to MS was found for three additional alleles, DRB1*0405, DRB1*1104 and DRB1*1303, though the power was insufficient to sustain significance for these when crudely Bonferroni corrected over all alleles considered. DRB1*0701 was found to be protective even after correction for multiple comparisons. In addition we found evidence that the DRB1*04 sub-allele HLA-DRB1*0407 and HLA-DRB1*0901 may be protective. Among the diplotypes, the highest estimated risk was in HLA-DRB1*1501/*0801 heterozygotes and DRB1*1501 homozygotes and the lowest in HLA-DRB1*0701/*0101 heterozygotes. There was no significant gender association with HLA-DRB1*1501 overall, but the HLA-DRB1*1501/*1104 risk genotype was significantly associated with female gender. HLA-DRB1*1501 was the strongest risk allele in both primary progressive MS and relapsing-remitting MS. Conclusion: Our results demonstrate the advantages of high-resolution HLA genotyping in recognizing risk-modifying alleles and allele combinations in this patient cohort and in recognizing the differential effects of HLA-DRB1*04 and DRB1*11 sub-alleles. more...
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- 2010
47. Clinical profile and HLA-DRB1 genotype of late onset multiple sclerosis in Western Australia
- Author
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Qiu, W., Wu, J-S, Castley, A., James, I., Joseph, J., Christiansen, F.T., Carroll, W.M., Mastaglia, F.L., Kermode, A.G., Qiu, W., Wu, J-S, Castley, A., James, I., Joseph, J., Christiansen, F.T., Carroll, W.M., Mastaglia, F.L., and Kermode, A.G. more...
- Abstract
We aimed to characterize the clinical profile and human leukocyte antigen (HLA)-DRB1 genotype of patients with late onset multiple sclerosis (LOMS) in Western Australia. The clinical features, laboratory studies and HLA-DRB1 alleles were analysed in patients with multiple sclerosis (MS) with onset over 50 years of age and compared with 100 patients with early onset MS (EOMS). Of a cohort of 829 patients with MS, 73 (8.8%) presented at over 50 years of age, including 14 (1.7%) over 60 years. Patients with LOMS had a lower female to male ratio, more frequent initial motor dysfunction, less frequent sensory symptoms and optic neuritis, a more frequent primary-progressive course and shorter time to reach Extended Disability Status Scale (EDSS) scores of 3.0 and 6.0. More LOMS patients were initially misdiagnosed compared to patients with EOMS. HLA-DRB1*1501 was strongly associated with both LOMS and EOMS compared to the Control subjects, while HLA-DRB1*0801 was over-represented in patients with LOMS. We concluded that patients with LOMS have a different clinical profile when compared to those with EOMS. Carriers of HLA-DRB1*0801 may be more prone to develop MS at a later age. more...
- Published
- 2010
48. Presence of CSF oligoclonal bands (OCB) is associated with the HLA-DRB1 genotype in a West Australian multiple sclerosis cohort
- Author
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Wu, J-S, Qiu, W., Castley, A., James, I., Joseph, J., Christiansen, F.T., Carroll, W.M., Mastaglia, F.L., Kermode, A.G., Wu, J-S, Qiu, W., Castley, A., James, I., Joseph, J., Christiansen, F.T., Carroll, W.M., Mastaglia, F.L., and Kermode, A.G. more...
- Abstract
High-resolution HLA-DRB1 genotyping was performed in 97 OCB-positive and 68 OCB-negative cases with demyelinating disease to determine the influence of HLA-DRB1 alleles on the presence of OCB in a West Australian multiple sclerosis (MS) cohort. Carriage of the HLA-DRB1*1501 allele was associated with both OCB-positive and OCB-negative MS compared with controls, but more strongly with the OCB-positive group, and increased the likelihood of having OCB 2.1-fold with evidence of a dominant dose-effect. The HLA-DRB1*0301 allele was negatively correlated with OCB, with all homozygotes OCB-negative, suggesting a possible recessive protective effect of HLA-DRB1*0301. There was no significant correlation between OCB and the DRB1*04 alleles which have been associated with OCB-negative MS in previous Swedish and Japanese studies. Evidence of allelic interactions was found with HLA-DRB1*1501/*1301 heterozygotes having a reduced frequency of OCB and HLA-DRB1*0301/*0401 heterozygotes all being OCB-negative. These findings confirm the strong association between HLA-DRB1*1501 and OCB which has been found in other populations but indicate that the influence of other HLA-DRB1 alleles varies in different populations. Our study is the first to show that HLA-DRB1 allele interactions and dose-effects influence the frequency of OCB. more...
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- 2010
49. Genome-wide association study identifies new multiple sclerosis susceptibility loci on chromosomes 12 and 20
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Bahlo, M., Booth, D.R., Broadley, S.A., Brown, M.A., Foote, S.J., Griffiths, L.R., Kilpatrick, T.J., Lechner-Scott, J., Moscato, P., Perreau, V.M., Rubio, J.P., Scott, R.J., Stankovich, J., Stewart, G.J., Taylor, B.V., Wiley, J., Clarke, G., Cox, M.B., Csurhes, P.A., Danoy, P., Drysdale, K., Field, J., Greer, J.M., Guru, P., Hadler, J., McMorran, B.J., Jensen, C.J., Johnson, L.J., McCallum, R., Merriman, M., Merriman, T., Pryce, K., Tajouri, L., Wilkins, E.J., Browning, B.L., Browning, S.R., Perera, D., Broadley, S., Butzkueven, H., Carroll, W.M., Chapman, C., Kermode, A.G., Marriott, M., Mason, D., Heard, R.N., Pender, M.P., Slee, M., Tubridy, N., Willoughby, E., Bahlo, M., Booth, D.R., Broadley, S.A., Brown, M.A., Foote, S.J., Griffiths, L.R., Kilpatrick, T.J., Lechner-Scott, J., Moscato, P., Perreau, V.M., Rubio, J.P., Scott, R.J., Stankovich, J., Stewart, G.J., Taylor, B.V., Wiley, J., Clarke, G., Cox, M.B., Csurhes, P.A., Danoy, P., Drysdale, K., Field, J., Greer, J.M., Guru, P., Hadler, J., McMorran, B.J., Jensen, C.J., Johnson, L.J., McCallum, R., Merriman, M., Merriman, T., Pryce, K., Tajouri, L., Wilkins, E.J., Browning, B.L., Browning, S.R., Perera, D., Broadley, S., Butzkueven, H., Carroll, W.M., Chapman, C., Kermode, A.G., Marriott, M., Mason, D., Heard, R.N., Pender, M.P., Slee, M., Tubridy, N., and Willoughby, E. more...
- Abstract
To identify multiple sclerosis (MS) susceptibility loci, we conducted a genome-wide association study (GWAS) in 1,618 cases and used shared data for 3,413 controls. We performed replication in an independent set of 2,256 cases and 2,310 controls, for a total of 3,874 cases and 5,723 controls. We identified risk-associated SNPs on chromosome 12q13–14 (rs703842, P = 5.4 times 10-11; rs10876994, P = 2.7 times 10-10; rs12368653, P = 1.0 times 10-7) and upstream of CD40 on chromosome 20q13 (rs6074022, P = 1.3 times 10-7; rs1569723, P = 2.9 times 10-7). Both loci are also associated with other autoimmune diseases1, 2, 3, 4, 5. We also replicated several known MS associations (HLA-DR15, P = 7.0 times 10-184; CD58, P = 9.6 times 10-8; EVI5-RPL5, P = 2.5 times 10-6; IL2RA, P = 7.4 times 10-6; CLEC16A, P = 1.1 times 10-4; IL7R, P = 1.3 times 10-3; TYK2, P = 3.5 times 10-3) and observed a statistical interaction between SNPs in EVI5-RPL5 and HLA-DR15 (P = 0.001). more...
- Published
- 2009
50. Wallenberg syndrome caused by multiple sclerosis mimicking stroke
- Author
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Qiu, W., Wu, J-S, Carroll, W.M., Mastaglia, F.L., Kermode, A.G., Qiu, W., Wu, J-S, Carroll, W.M., Mastaglia, F.L., and Kermode, A.G.
- Abstract
We describe a patient presenting with the rapid onset of incomplete Wallenberg syndrome (WS) as the initial clinical manifestation of multiple sclerosis (MS). This patient was initially diagnosed with acute ischaemic lateral medullary syndrome, but further assessment led to the diagnosis of definite MS. Our report aims to highlight the importance of awareness of MS as a cause of WS, as well as the potential misdiagnosis of MS as stroke. more...
- Published
- 2009
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