Objective:To evaluate (1) the frequency of aquaporin-4 antibody (AQP4-ab)-seropositive cases among patients treated with natalizumab (NAT) and previously diagnosed with MS (MSNAT) in a nationwide cohort, (2) the clinical course of NAT-treated AQP4-ab–seropositive neuromyelitis optica spectrum disorder (NMOSD) patients (NMONAT), (3) AQP4-ab titers in NMONAT and AQP4-ab–seropositive NMOSD treated with other immunotherapies (NMOIT), and (4) immune mechanisms influencing disease activity in NMONAT.Methods:MSNAT serum samples were retrospectively screened with a cell-based assay for AQP4-IgG and titers determined by ELISA. The annualized relapse rate (ARR) and disability progression were assessed. Serum levels of proinflammatory cytokines (interleukin [IL]-1β, IL-4, IL-6, IL-8, IL-10, IL-17, IL-21, and interferon [IFN]-γ) and the chemokine CXCL-10 of NMONAT patients identified in this (n = 4) and a previous study (n = 5) were measured by cytometric bead array and ELISA.Results:Of the 1,183 MSNAT patients (851 female, median 9 NAT infusions), only 4 (0.33%; 3 female, 1 male) had AQP4-IgG. Of these, 2 fulfilled the 2006 NMO criteria and all met the 2015 NMOSD criteria. The ARR was higher in NMONAT vs MSNAT (p = 0.0182). All 4 NMONAT patients had relapses and 2 had an increase of disability. AQP4-ab titers were higher in NMONAT (n = 9) vs NMOIT (n = 13; p = 0.0059). IL-8, IL-1β, and IFN-γ serum levels were significantly higher, and CXCL-10 was significantly lower in NMONAT vs NMOIT.Conclusions:Misdiagnosis of NMOSD with MS is rare. NAT was not able to control disease activity in NMONAT patients, who had higher serum levels of AQP4-IgG and proinflammatory cytokines than patients with NMOSD treated with other immunotherapies.

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In the present study we investigated in vivo the effects of pharmacological manipulation of retinal processing on the response properties of direction selective retinal slip cells in the nucleus of the optic tract and dorsal terminal nucleus (NOT-DTN), the key visuomotor interface in the pathway underlying the optokinetic reflex. Employing a moving visual stimulus consisting of either a large dark or light edge we could differentiate direction selective ON and OFF responses in retinal slip cells. To disclose the origin of the retinal slip cells' unexpected OFF response we selectively blocked the retinal ON channels and inactivated the visual cortex by cooling. Cortical cooling had no effect on the direction selectivity of the ON or the OFF response in NOT-DTN retinal slip cells. Blockade of the retinal ON channel with APB led to a loss of the ON and, to a lesser degree, of the OFF response and a reduction in direction selectivity. Subsequent blocking of GABA receptors in the retina with picrotoxin unmasked a vigorous albeit direction unselective OFF response in the NOT-DTN. Disturbing the retinal chloride homeostasis by intraocular injections of bumetanide or furosemide led to a loss of direction selectivity in both the NOT-DTN's ON and the OFF response due to a reduced response in the neuron's preferred direction under bumetanide as well as under furosemide and a slightly increased response in the null direction under bumetanide. Our results indicate that the direction specificity of retinal slip cells in the NOT-DTN of the rat strongly depends on direction selective retinal input which depends on intraretinal chloride homeostasis. On top of the well established input from ON center direction selective ganglion cells we could demonstrate an equally effective input from the retinal OFF system to the NOT-DTN.

BackgroundBetween 2013 to 2014 autochthonous cases ChikV virus were confirmed in the Americas and Mexico. The clinical and inflammatory profile and the prevalence of chronic disease were analyzed in Mexican patients.ObjectivesTo describe clinical profile, self reported-disability, inflammatory biomarkers and chronic articular (CA) disease during 10 month follow-up in ChikV Mexican patients.MethodsTen patients with ChikV confirmed by real-time PCR were included. Clinical manifestations, Disease Activity Index (DAS-28), self-reported disability by 32 item WHODAS-2 score and inflammatory biomarkers (C-reactive protein (CRP), eritrosedimentation rate (ESR), Rheumatoid Factor (RF), high sensivity Interleukin-6 (hsIL-6) were measured at onset and every month until 10 months of follow-up.ResultsTen patients (6 women and 4 men) with mean age 48.0 15.04 years-old were followed. Acute symptoms were: fever (100%), arthralgias (100%), myalgias (80%), rash (80%), synovitis (60%), nausea (50%), vomiting (20%) and back pain (20%); number of tender joints was 13.8 (SD 5.09) and number of articulations with synovitis was 7.1 (SD 3.78). At diagnosis biomarkers were: CRP 5.09 (SD 7.23) mg/dl, ESR: 32.6 (SD 17.5) mm/h, rF: 64 (SD 21.7) IU/ml and hsIL-6: 17 (SD 10.3) pg/ml. At diagnosis WHODAS-2 score was 74.5 (SD 7.59) % and DAS-28 was 4.37 (SD 0.78). Four cases resolved in acute phase, 5 developed subacute and CAand 1 patient died (with Systemic Lupus Erythematosus). During follow-up ESR, hsIL-6, DAS-28 index and WHODAS2 score were higher in patients with subacute or CA compared to solved cases (p<0.05). High levels of ESR and hs-IL6 at onset of ChikV infection were related with the development of CA (p<0.05). High DAS 28 index and WHODAS-II score were related to development of subacute or CA (p<0.05).ConclusionsFever, polyarthralgias, myalgias and rash were the main acute symptoms of ChikV fever and 50% of patients developed CA and a high disability. High levels of hsIL-6 and ESR could be used as a biomarkers to predict CA since acute phase. Inflammatory biomarkers, disability and DAS-28 remained high in subacute an CA compared to solved cases.ReferencesSchwartz O, Albert ML. Biology and pathogenesis of Chikungunya virus. Nature Rev Microbiol 2010; 8: 491500.Leparc-Goffart I, Nougairede A, Cassadou S, et al. Chikungunya in the Americas. Lancet 2014;383:514Kautz TF, Diaz-Gonzalez EE, Erasmus JH, et al. Chikungunya Virus as cause of Febrile Illness outbreak, Chiapas, Mexico, 2014. Emerg Infect Dis 2015;21(11):2070–2073.Disclosure of InterestNone declared

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