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[PMID]: 23582699 [Au] Autor: Haghikia A; Hohlfeld R; Gold R; Fugger L [Ad] Address: Nuffield Department of Clinical Neurosciences and MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK; Department of Neurology of the Ruhr-University Bochum at St Josef-Hospital, Bochum, Germany. [Ti] Title: Therapies for multiple sclerosis: translational achievements and outstanding needs. [So] Source: Trends Mol Med;19(5):309-19, 2013 May. [Is] ISSN: 1471-499X [Cp] Country of publication: England [La] Language: eng [Ab] Abstract: In recent years, multiple sclerosis (MS) research has progressed on several fronts, prompting numerous clinical trials, primarily for immunotherapeutics. Although several new therapies have been disappointing and some were revealed to have devastating side effects, others have shown benefits and all have generated valuable knowledge about the progression of MS, the key contributors to pathogenesis, and on natural surveillance mechanisms for brain infections. This makes now a useful time to take stock of recent advances in developing MS treatments and consider new approaches for adding information where the gaps are greatest - mainly in understanding the degenerative processes responsible for most of the long-term disability. Here, we summarize currently accepted therapeutic principles and the drugs in late stages of development, as well as spotlighting potential novel openings for future research. [Pt] Publication type: JOURNAL ARTICLE [Em] Entry month: 1305 [Js] Journal subset: IM [St] Status: In-Data-Review

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[PMID]: 23649812 [Au] Autor: Wang J; Xiang M [Ad] Address: Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Pharmacology, College of Medicine, Wuhan University of Science and Technology, Wuhan, China. [Ti] Title: Targeting Potassium Channels Kv1.3 and KC a 3.1: Routes to Selective Immunomodulators in Autoimmune Disorder Treatment? [So] Source: Pharmacotherapy;33(5):515-28, 2013 May. [Is] ISSN: 1875-9114 [Cp] Country of publication: United States [La] Language: eng [Ab] Abstract: The Kv1.3 and KC a 3.1 potassium channels are promising targets for the treatment of autoimmune disorders. Many Kv1.3 and KC a 3.1 blockers have a more favorable adverse event profiles than existing immunosuppressants, suggesting the selectivity of Kv1.3 and KC a 3.1 blockade. The Kv1.3 and KC a 3.1 blockers exert differential effects in different autoimmune diseases. The Kv1.3 inhibitors or gene deletion have been shown to have benefits in multiple sclerosis, type 1 diabetes, rheumatoid arthritis, psoriasis, and rapidly progressive glomerulonephritis. The KC a 3.1 blockers have demonstrated efficacy in human primary biliary cirrhosis and showed protective effects in animal models of severe colitis, allergic encephalomyelitis, inflammatory bowel disease, and multiple sclerosis. The KC a 3.1 blockers are not considered candidates for treatment of multiple sclerosis. The selective immunosuppressive effects of the Kv1.3 and KC a 3.1 blockers are due to the differences in their distribution on autoimmune-related immune cells and tissues and ß1 integrin (very late activating antigen)-Kv1.3 channel cross-talk. [Pt] Publication type: JOURNAL ARTICLE [Em] Entry month: 1305 [Js] Journal subset: IM [St] Status: In-Data-Review [do] DOI: 10.1002/phar.1236

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[PMID]: 23650566 [Au] Autor: Sabo JK; Aumann TD; Kilpatrick TJ; Cate HS [Ad] Address: Centre for Neuroscience Research, Department of Anatomy and Neuroscience, University of Melbourne, Melbourne, Australia ; Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Australia. [Ti] Title: Investigation of Sequential Growth Factor Delivery during Cuprizone Challenge in Mice Aimed to Enhance Oligodendrogliogenesis and Myelin Repair. [So] Source: PLoS One;8(5):e63415, 2013. [Is] ISSN: 1932-6203 [Cp] Country of publication: United States [La] Language: eng [Ab] Abstract: Repair in multiple sclerosis involves remyelination, a process in which axons are provided with a new myelin sheath by new oligodendrocytes. Bone morphogenic proteins (BMPs) are a family of growth factors that have been shown to influence the response of oligodendrocyte progenitor cells (OPCs) in vivo during demyelination and remyelination in the adult brain. We have previously shown that BMP4 infusion increases numbers of OPCs during cuprizone-induced demyelination, while infusion of Noggin, an endogenenous antagonist of BMP4 increases numbers of mature oligodendrocytes and remyelinated axons following recovery. Additional studies have shown that insulin-like growth factor-1 (IGF-1) promotes the survival of OPCs during cuprizone-induced demyelination. Based on these data, we investigated whether myelin repair could be further enhanced by sequential infusion of these agents firstly, BMP4 to increase OPC numbers, followed by either Noggin or IGF-1 to increase the differentiation and survival of the newly generated OPCs. We identified that sequential delivery of BMP4 and IGF-1 during cuprizone challenge increased the number of mature oligodendrocytes and decreased astrocyte numbers following recovery compared with vehicle infused mice, but did not alter remyelination. However, sequential delivery of BMP4 and Noggin during cuprizone challenge did not alter numbers of oligodendrocytes or astrocytes in the corpus callosum compared with vehicle infused mice. Furthermore, electron microscopy analysis revealed no change in average myelin thickness in the corpus callosum between vehicle infused and BMP4-Noggin infused mice. Our results suggest that while single delivery of Noggin or IGF-1 increased the production of mature oligodendrocytes in vivo in the context of demyelination, only Noggin infusion promoted remyelination. Thus, sequential delivery of BMP4 and Noggin or IGF-1 does not further enhance myelin repair above what occurs with delivery of Noggin alone. [Pt] Publication type: JOURNAL ARTICLE [Em] Entry month: 1305 [Js] Journal subset: IM [St] Status: In-Data-Review [do] DOI: 10.1371/journal.pone.0063415

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[PMID]: 23648659 [Au] Autor: Sato K; Iwasaki M; Uematsu M; Nakasato N; Tominaga T [Ad] Address: Department of Neurosurgery, Tohoku University Graduate School of Medicine. [Ti] Title: [A primary epileptogenic tuber revealed after corpus callosotomy in a patient with tuberous sclerosis complex and multiple tubers]. [So] Source: No Shinkei Geka;41(5):421-8, 2013 May. [Is] ISSN: 0301-2603 [Cp] Country of publication: Japan [La] Language: jpn [Ab] Abstract: Identification of primary epileptogenic tuber is often challenging in patients with bilateral multiple tubers in tuberous sclerosis complex. We report a 3 year old girl with tuberous sclerosis complex presenting with intractable epilepsy and multiple tubers, who was successfully treated by corpus callosotomy and subsequent resective surgery. She initially presented with West syndrome which was intractable to ACTH therapy and multiple antiepileptic medications. Her EEG was characterized by generalized and multifocal spikes, and by non-focal changes at seizure onset. Ictal single photon emission computed tomography(SPECT)showed no focal hyperperfusion. Total corpus callosotomy was performed to alleviate her drop attacks. Post-operatively, interictal spikes were completely lateralized to the right hemisphere. Since her seizures were still kept uncontrolled with medications, second pre-surgical evaluation was planned and ictal SPECT disclosed focal hyperperfusion at a tuber in the right frontal lobe. After complete resection of the right frontal tuber, she was completely seizure free on antiepileptic medications for 1 year with no additional neurological deficits. Generalized or multifocal electroencephalographic(EEG)spikes are occasionally lateralized to one hemisphere after corpus callosotomy, which may help identifying the primary epileptogenic focus. Repeat pre-surgical evaluation is important after corpus callosotomy in patients with generalized or multifocal epileptiforms in EEG. [Pt] Publication type: ENGLISH ABSTRACT; JOURNAL ARTICLE [Em] Entry month: 1305 [Js] Journal subset: IM [St] Status: In-Data-Review

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[PMID]: 23649115 [Au] Autor: Al-Araji AH; Al-Mahdawi AM; Mohammad AI [Ad] Address: Baghdad Multiple Sclerosis Clinic, PO Box 28595, Code 12631, Baghdad, Iraq. Tel. +964 (1) 5430091. E-mail: ahalaraji@uruklink.net. [Ti] Title: Autonomic dysfunction in multiple sclerosis. [So] Source: Neurosciences (Riyadh);8(3):177-83, 2003 Jul. [Is] ISSN: 1319-6138 [Cp] Country of publication: Saudi Arabia [La] Language: eng [Ab] Abstract: OBJECTIVE: Multiple sclerosis (MS) is a demyelinating disorder of the central nervous system. Autonomic dysfunction in MS patients may cause significant morbidity. The aim of this controlled cross sectional study was to investigate the prevalence, pattern and severity of autonomic dysfunction in Iraqi MS patients and to correlate them with patient`s age, disease course, duration and severity. METHODS: Fifty-five patients with clinically definite MS according to Poser`s criteria attending Baghdad MS clinic at Baghdad Teaching Hospital were studied between July 2000 and August 2001. Each patient was assessed according to a detailed protocol paper. Expanded disability status scale was used to assess the severity of the disease. The severity of autonomic symptoms was classified according to autonomic nervous system disability scale (ANSDS). Five standardized autonomic cardiovascular (Ewing) tests were performed for every patient which included: heart rate responses to deep breathing, Valsalva maneuver and standing, and blood pressure responses to standing and sustained hand grip. Forty matched healthy subjects were studied as a control group who were assessed with the same protocol paper, ANSDS and Ewing tests. RESULTS: Autonomic symptoms were significantly more prevalent in MS patients than in the controls. Cardiovascular, urinary and gastrointestinal symptoms were highly prevalent. The severity of the different autonomic symptoms as assessed by ANSDS, were higher in the patients than the controls. All 5 Ewing tests in the patients showed highly significant abnormal results as compared to those of the control. Definite parasympathetic derangement was found in 45.5% of the patients while combined sympathetic and parasympathetic derangements were found in 34.5% of the patients. There were significant correlations between the finding of definite autonomic dysfunctions and the age of the patients at the time of assessment and the duration of the disease. CONCLUSION: Autonomic dysfunctions as assessed by a formal interview, ANSDS and by Ewing tests were common in Iraqi MS patients. Careful attention to autonomic disturbances should be considered in the routine evaluation of MS patients which might help in improving their quality of life. [Pt] Publication type: JOURNAL ARTICLE [Em] Entry month: 1305 [St] Status: In-Data-Review

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[PMID]: 23648979 [Au] Autor: Kargwell H; Yaqub BA; Al-Deeb SM [Ad] Address: Department of Neurosciences, Armed Forces Hospital, PO Box 7897, Riyadh 11159, Kingdom of Saudi Arabia. Tel. +966 (1) 4777714 Ext. 5419. Fax. +966 (1) 4777194. E-mail: rkhnsksa@zajil.net or hkargwell@hotmail.com. [Ti] Title: Response to beta interferon 1b among Saudi patients with multiple sclerosis. [So] Source: Neurosciences (Riyadh);8(1):12-6, 2003 Jan. [Is] ISSN: 1319-6138 [Cp] Country of publication: Saudi Arabia [La] Language: eng [Ab] Abstract: OBJECTIVE: To determine the efficacy and tolerability of subcutaneous beta interferon 1b (B1F1b) among Saudi patients with remitting-relapsing multiple sclerosis (R-R MS). METHODS: An open label study held at the Neurology Division of the Armed Forces Hospital, Riyadh from March 1997 until December 2001. Thirty-two consecutive patients below the age of 50 years with clinically definite R-R MS according to Poser`s Criteria and expanded disability status scale below 5.5 were enrolled in treatment with subcutaneous B1F1b 8 million IU 3 times a week. The primary outcome measures used were: reduction in annual relapses, proportion of relapse-free patients, and the mean time to the first relapse after treatment was started. The secondary outcome measures used were the time to progression in disability, tolerability and safety of the beta interferon. RESULTS: Only 28 patients were analyzed to assess the outcome measures, the other 4 patients dropped out and were followed-up. Twenty were women and 8 were men (female:male ratio of 2.5:1). There was a significant reduction in relapse-rate in all patients, 32.5% were relapse-free, while 37.5% showed reduction in the number of relapses. None of our patients showed progression of disability (P<0.0249). Mild adverse reactions were seen in 38.5%, influenza-like illness occurred in 53.6%, and injection-site reaction in 35.7%. CONCLUSION: Subcutaneous B1F1b is effective in patients with R-R MS, especially in reducing relapse rate, probable disability, and it is well tolerated. However, longer follow-up is necessary to evaluate the role of B1F1b in preventing disability. [Pt] Publication type: JOURNAL ARTICLE [Em] Entry month: 1305 [St] Status: In-Data-Review

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[PMID]: 23650231 [Au] Autor: Langer-Gould A; Brara SM; Beaber BE; Zhang JL [Ad] Address: From the Department of Research and Evaluation (A.L.-G., J.L.Z.), Kaiser Permanente, Southern California, Pasadena; and Neurology Department (A.L.-G., S.M.B., B.E.B.), Kaiser Permanente, Southern California Los Angeles Medical Center, CA. [Ti] Title: Incidence of multiple sclerosis in multiple racial and ethnic groups. [So] Source: Neurology;80(19):1734-9, 2013 May 7. [Is] ISSN: 1526-632X [Cp] Country of publication: United States [La] Language: eng [Ab] Abstract: OBJECTIVE: To determine whether the incidence of multiple sclerosis (MS) varies by race/ethnicity in a multiethnic, population-based cohort. METHODS: We conducted a retrospective cohort study of more than 9 million person-years of observation from the multiethnic, community-dwelling members of Kaiser Permanente Southern California health plan from January 1, 2008 to December 31, 2010. Incidence of MS and risk ratios comparing incidence rates between racial/ethnic groups were calculated using Poisson regression. RESULTS: We identified 496 patients newly diagnosed with MS who met McDonald criteria. The average age at diagnosis was 41.6 years (range 8.6-78.3 years) and 70.2% were women. The female preponderance was more pronounced among black (79.3%) than white, Hispanic, and Asian individuals with MS (67.8%, 68.1%, and 69.2%, respectively; p = 0.03). The incidence of MS was higher in blacks (10.2, 95% confidence interval [CI] 8.4-12.4; p < 0.0001) and lower in Hispanics (2.9, 95% CI 2.4-3.5; p < 0.0001) and Asians (1.4, 95% CI 0.7-2.4; p < 0.0001) than whites (6.9, 95% CI 6.1-7.8). Black women had a higher risk of MS (risk ratio 1.59, 95% CI 1.27-1.99; p = 0.0005) whereas black men had a similar risk of MS (risk ratio 1.04, 95% CI = 0.67-1.57) compared with whites. CONCLUSIONS: Our findings do not support the widely accepted assertion that blacks have a lower risk of MS than whites. A possible explanation for our findings is that people with darker skin tones have lower vitamin D levels and thereby an increased risk of MS, but this would not explain why Hispanics and Asians have a lower risk of MS than whites or why the higher risk of MS among blacks was found only among women. [Pt] Publication type: JOURNAL ARTICLE [Em] Entry month: 1305 [Js] Journal subset: AIM; IM [St] Status: In-Data-Review [do] DOI: 10.1212/WNL.0b013e3182918cc2

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[PMID]: 23616161 [Au] Autor: Yeung J; Cauquil C; Saliou G; Nasser G; Rostomashvili S; Adams D; Théaudin M [Ad] Address: From AP-HP (J.Y., C.C., G.S., G.N., S.R., D.A., M.T.), Hôpital Bicêtre; UMR8081 CNRS (M.T.) and UMR788 INSERM (D.A.), Le Kremlin-Bicêtre, France. [Ti] Title: Varicella-zoster virus acute myelitis in a patient with MS treated with natalizumab. [So] Source: Neurology;80(19):1812-3, 2013 May 7. [Is] ISSN: 1526-632X [Cp] Country of publication: United States [La] Language: eng [Ab] Abstract: We report a case of varicella-zoster virus (VZV) myelitis in a woman with relapsing-remitting multiple sclerosis (RRMS) receiving natalizumab, a humanized monoclonal antibody that induces an immunosuppression localized to the CNS. [Pt] Publication type: JOURNAL ARTICLE [Em] Entry month: 1305 [Js] Journal subset: AIM; IM [St] Status: In-Data-Review [do] DOI: 10.1212/WNL.0b013e3182918d27

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[PMID]: 23596077 [Au] Autor: Cannon A; Fujioka S; Rutherford NJ; Ferman TJ; Broderick DF; Boylan KB; Graff-Radford NR; Uitti RJ; Rademakers R; Wszolek ZK; Dickson DW [Ad] Address: From the Departments of Neuroscience (A.C., S.F., N.J.R., R.R., D.W.D.), Neurology (S.F., K.B.B., N.R.G.-R., R.J.U., Z.K.W.), Psychiatry and Psychology (T.J.F.), and Radiology (D.F.B.), Mayo Clinic, Jacksonville, FL. [Ti] Title: Clinicopathologic variability of the GRN A9D mutation, including amyotrophic lateral sclerosis. [So] Source: Neurology;80(19):1771-7, 2013 May 7. [Is] ISSN: 1526-632X [Cp] Country of publication: United States [La] Language: eng [Ab] Abstract: OBJECTIVE: We examined the clinical and pathologic phenotypes of GRN mutation carriers with the pathogenic A9D (g.26C>A) missense mutation. METHODS: Three patients with GRN A9D mutations were evaluated clinically and came to autopsy with subsequent neuropathologic examination. RESULTS: The clinical diagnoses of patients with GRN A9D mutations were amyotrophic lateral sclerosis, atypical extrapyramidal disorder, and behavioral variant frontotemporal dementia. Immunohistochemistry for TAR DNA-binding protein 43 (TDP-43) revealed variability in morphology and distribution of pathology. One patient had notable involvement of motor neurons in the spinal cord as well as type B TDP-43, whereas 2 other patients had type A TDP-43. CONCLUSIONS: The clinical presentation of the GRN A9D missense mutation is not restricted to behavioral variant frontotemporal dementia and may include aphasia, extrapyramidal features, and, notably, amyotrophic lateral sclerosis. [Pt] Publication type: JOURNAL ARTICLE [Em] Entry month: 1305 [Js] Journal subset: AIM; IM [St] Status: In-Data-Review [do] DOI: 10.1212/WNL.0b013e3182919059

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[PMID]: 23576628 [Au] Autor: Arnett PA; Brochet B [Ad] Address: From the Department of Psychology (P.A.A.), Pennsylvania State University, State College; and the Department of Neurology (B.B.), CHU and Université de Bordeaux, Bordeaux, France. [Ti] Title: How can cognitive reserve in multiple sclerosis inform clinical care? [So] Source: Neurology;80(19):1724-5, 2013 May 7. [Is] ISSN: 1526-632X [Cp] Country of publication: United States [La] Language: eng [Ab] Abstract: The concept of cognitive reserve (CR) emerged from studies on Alzheimer disease (AD) that revealed that individuals with greater CR were less likely to show cognitive decline as AD pathology accumulated. Cognitive reserve has typically been defined as spare cognitive capacity available to buffer the effects of disease or trauma to the brain.(1,2) In more recent years, a number of studies have examined CR in persons with MS (PwMS),(3-6) with a recent study examining the extent to which CR might mitigate cognitive decline longitudinally.(7.) [Pt] Publication type: JOURNAL ARTICLE [Em] Entry month: 1305 [Js] Journal subset: AIM; IM [St] Status: In-Data-Review [do] DOI: 10.1212/WNL.0b013e3182919083

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