Induction of Paralysis and Visual System Injury in Mice by T Cells Specific for Neuromyelitis Optica Autoantigen Aquaporin-4.

While it is recognized that aquaporin-4 (AQP4)-specific T cells and antibodies participate in the pathogenesis of neuromyelitis optica (NMO), a human central nervous system (CNS) autoimmune demyelinating disease, creation of an AQP4-targeted model with both clinical and histologic manifestations of CNS autoimmunity has proven challenging. Immunization of wild-type (WT) mice with AQP4 peptides elicited T cell proliferation, although those T cells could not transfer disease to naïve recipient mice. Recently, two novel AQP4 T cell epitopes, peptide (p) 135-153 and p201-220, were identified when studying immune responses to AQP4 in AQP4-deficient (AQP4-/-) mice, suggesting T cell reactivity to these epitopes is normally controlled by thymic negative selection. AQP4-/- Th17 polarized T cells primed to either p135-153 or p201-220 induced paralysis in recipient WT mice, that was associated with predominantly leptomeningeal inflammation of the spinal cord and optic nerves. Inflammation surrounding optic nerves and involvement of the inner retinal layers (IRL) were manifested by changes in serial optical coherence tomography (OCT). Here, we illustrate the approaches used to create this new in vivo model of AQP4-targeted CNS autoimmunity (ATCA), which can now be employed to study mechanisms that permit development of pathogenic AQP4-specific T cells and how they may cooperate with B cells in NMO pathogenesis

Timing of retinal neuronal and axonal loss in MS: a longitudinal OCT study

The objective of the study was to investigate the timing of central nervous system tissue atrophy in MS by evaluating longitudinal retinal volume changes in a broadly representative cohort with disease duration across the entire arc of disease. In this longitudinal study, 135 patients with MS and 16 healthy reference subjects underwent spectral-domain optical coherence tomography (OCT) at baseline and 2 years later. Following OCT quality control, automated segmentation of the peripapillary retinal nerve fiber layer (pRNFL), macular ganglion cell–inner plexiform layer (mGCIPL) and macular inner nuclear layer (mINL) was performed. Generalized estimation equations were used to analyze longitudinal changes and associations with disease duration and clinical measures. Participants had a median disease duration at baseline of 16.4 years (range 0.1–45.4). Nearly half (44 %) of the MS patients had previously experienced MS-related optic neuritis (MSON) more than 6 months prior. The MS patients demonstrated a significant decrease over 2 years of the pRNFL (−1.1 µm, 95 % CI 1.4–0.7, p < 0.001) and mGCIPL (−1.1 µm, 95 % CI −1.4 to −0.8, p < 0.001). This thinning was most pronounced early in the course of disease. These findings were irrespective of previous episodes of MSON. No consistent pattern of change was observed for the mINL (−0.03 µm, 95 % CI −0.2 to 0.2, p = 0.795). This longitudinal study demonstrated that injury of the innermost retinal layers is found in MS and that this damage occurs most rapidly during the early stages of disease. The attenuation of atrophy with longer disease duration is suggestive of a plateau effect. These findings emphasize the importance of early intervention to prevent such injury

On two superintegrable nonlinear oscillators in N dimensions

We consider the classical superintegrable Hamiltonian system given by $H=T+U={p^2}/{2(1+\lambda q^2)}+{{\omega}^2 q^2}/{2(1+\lambda q^2)}$, where U is known to be the "intrinsic" oscillator potential on the Darboux spaces of nonconstant curvature determined by the kinetic energy term T and parametrized by {\lambda}. We show that H is Stackel equivalent to the free Euclidean motion, a fact that directly provides a curved Fradkin tensor of constants of motion for H. Furthermore, we analyze in terms of {\lambda} the three different underlying manifolds whose geodesic motion is provided by T. As a consequence, we find that H comprises three different nonlinear physical models that, by constructing their radial effective potentials, are shown to be two different nonlinear oscillators and an infinite barrier potential. The quantization of these two oscillators and its connection with spherical confinement models is briefly discussed.Comment: 11 pages; based on the contribution to the Manolo Gadella Fest-60 years-in-pucelandia, "Recent advances in time-asymmetric quantum mechanics, quantization and related topics" hold in Valladolid (Spain), 14-16th july 201

The APOSTEL recommendations for reporting quantitative optical coherence tomography studies

OBJECTIVE: To develop consensus recommendations for reporting of quantitative optical coherence tomography (OCT) study results. METHODS: A panel of experienced OCT researchers (including 11 neurologists, 2 ophthalmologists, and 2 neuroscientists) discussed requirements for performing and reporting quantitative analyses of retinal morphology and developed a list of initial recommendations based on experience and previous studies. The list of recommendations was subsequently revised during several meetings of the coordinating group. RESULTS: We provide a 9-point checklist encompassing aspects deemed relevant when reporting quantitative OCT studies. The areas covered are study protocol, acquisition device, acquisition settings, scanning protocol, funduscopic imaging, postacquisition data selection, postacquisition data analysis, recommended nomenclature, and statistical analysis. CONCLUSIONS: The Advised Protocol for OCT Study Terminology and Elements recommendations include core items to standardize and improve quality of reporting in quantitative OCT studies. The recommendations will make reporting of quantitative OCT studies more consistent and in line with existing standards for reporting research in other biomedical areas. The recommendations originated from expert consensus and thus represent Class IV evidence. They will need to be regularly adjusted according to new insights and practices

Distinctive waves of innate immune response in the retina in experimental autoimmune encephalomyelitis

Neurodegeneration mediates neurological disability in inflammatory demyelinating diseases of the CNS. The role of innate immune cells in mediating this damage has remained controversial with evidence for destructive and protective effects. This has complicated efforts to develop treatment. The time sequence and dynamic evolution of the opposing functions are especially unclear. Given limits of in vivo monitoring in human diseases such as multiple sclerosis (MS), animal models are warranted to investigate the association and timing of innate immune activation with neurodegeneration. Using noninvasive in vivo retinal imaging of experimental autoimmune encephalitis (EAE) in CX3CR1GFP/+–knock-in mice followed by transcriptional profiling, we are able to show 2 distinct waves separated by a marked reduction in the number of innate immune cells and change in cell morphology. The first wave is characterized by an inflammatory phagocytic phenotype preceding the onset of EAE, whereas the second wave is characterized by a regulatory, antiinflammatory phenotype during the chronic stage. Additionally, the magnitude of the first wave is associated with neuronal loss. Two transcripts identified — growth arrest–specific protein 6 (GAS6) and suppressor of cytokine signaling 3 (SOCS3) — might be promising targets for enhancing protective effects of microglia in the chronic phase after initial injury

A multi-stakeholder multicriteria decision analysis for the reimbursement of orphan drugs (FinMHU-MCDA study)

Background: Patient access to orphan medicinal products (OMPs) is limited and varies between countries, reimbursement decisions on OMPs are complex, and there is a need for more transparent processes to know which criteria should be considered to inform these decisions. This study aimed to determine the most relevant criteria for the reimbursement of OMPs in Spain, from a multi-stakeholder perspective, and using multicriteria decision analysis (MCDA). Methods: An MCDA was developed in 3 phases and included 28 stakeholders closely related to the field of rare diseases (6 physicians, 5 hospital pharmacists, 7 health economists, 4 patient representatives and 6 members from national and regional health authorities). Initially [phase A], a bibliographic review was conducted to identify the potential reimbursement criteria. Then, a reduced advisory board (8 members) proposed, selected, and defined the final list of criteria that could be relevant for reimbursement. A discrete choice experiment (DCE) [phase B] was developed to determine the relevance and relative importance weight of such criteria according to the stakeholders’ preferences by choosing between pairs of hypothetical financing scenarios. A multinomial logit model was fitted to analyze the DCE responses. Finally [phase C], the advisory board review the results using a deliberative process. Results: Thirteen criteria were selected, related to 4 dimensions: patient population, disease, treatment, and economic evaluation. Nine criteria were deemed relevant for decision-making and associated with a higher relative importance: Health-related quality of life (HRQL) (23.53%), treatment efficacy (14.64%), availability of treatment alternatives (13.51%), disease severity (12.62%), avoided costs (11.21%), age of target population (7.75%), safety (seriousness of adverse events) (4.72%), quality of evidence (3.82%) and size of target population (3.12%). The remaining criteria had a < 3% relative importance: economic burden of disease (2.50%), cost of treatment (1.73%), cost-effectiveness (0.83%) and safety (frequency of adverse events) (0.03%). Conclusion: The reimbursement of OMPs in Spain should be determined by its effect on patient’s HRQL, the extent of its therapeutic benefit from efficacy and the availability of other therapeutic options. Furthermore, the severity of the rare disease should also influence the decision along with the potential of the treatment to avoid associated costs

Planck early results. V. The low frequency instrument data processing

We describe the processing of data from the Low Frequency Instrument (LFI) used in production of the Planck Early Release Compact Source Catalogue (ERCSC). In particular, we discuss the steps involved in reducing the data from telemetry packets to cleaned, calibrated, time-ordered data (TOD) and frequency maps. Data are continuously calibrated using the modulation of the temperature of the cosmic microwave background radiation induced by the motion of the spacecraft. Noise properties are estimated from TOD from which the sky signal has been removed using a generalized least square map-making algorithm. Measured 1/f noise knee-frequencies range from ~100 mHz at 30 GHz to a few tens of mHz at 70GHz. A destriping code (Madam) is employed to combine radiometric data and pointing information into sky maps, minimizing the variance of correlated noise. Noise covariance matrices required to compute statistical uncertainties on LFI and Planck products are also produced. Main beams are estimated down to the ??10dB level using Jupiter transits, which are also used for geometrical calibration of the focal plane.Planck is too large a project to allow full acknowledgement of all contributions by individuals, institutions, industries, and funding agencies. The main entities involved in the mission operations are as follows. The European Space Agency operates the satellite via its Mission Operations Centre located at ESOC (Darmstadt, Germany) and coordinates scientific operations via the Planck Science Office located at ESAC (Madrid, Spain). Two Consortia, comprising around 50 scientific institutes within Europe, the USA, and Canada, and funded by agencies from the participating countries, developed the scientific instruments LFI and HFI, and continue to operate them via Instrument Operations Teams located in Trieste (Italy) and Orsay (France). The Consortia are also responsible for scientific processing of the acquired data. The Consortia are led by the Principal Investigators: J.L. Puget in France for HFI (funded principally by CNES and CNRS/INSU-IN2P3) and N. Mandolesi in Italy for LFI(funded principally via ASI). NASA US Planck Project, based at J.P.L. and involving scientists at many US institutions, contributes significantly to the efforts of these two Consortia. The author list for this paper has been selected by the Planck Science Team, and is composed of individuals from all of the above entities who have made multi-year contributions to the development of the mission. It does not pretend to be inclusive of all contributions. The Planck-LFI project is developed by an International Consortium lead by Italy and involving Canada, Finland, Germany, Norway, Spain, Switzerland, UK, USA. The Italian contribution to Planck is supported by the Italian Space Agency (ASI) and INAF. This work was supported by the Academy of Finland grants 121703 and 121962. We thank the DEISA Consortium (http://www.deisa.eu), co-funded through the EU FP6 project RI-031513 and the FP7 project RI-222919, for support within the DEISA Virtual Community Support Initiative. We thank CSC – IT Center for Science Ltd (Finland) for computational resources. We acknowledge financial support provided by the Spanish Ministerio de Ciencia e Innovaciõn through the Plan Nacional del Espacio y Plan Nacional de Astronomia y Astrofisica. We acknowledge The Max Planck Institute for Astrophysics Planck Analysis Centre (MPAC) is funded by the Space Agency of the German Aerospace Center (DLR) under grant 50OP0901 with resources of the German Federal Ministry of Economics and Technology, and by the Max Planck Society. This work has made use of the Planck satellite simulation package (Level-S), which is assembled by the Max Planck Institute for Astrophysics Planck Analysis Centre (MPAC) Reinecke et al. (2006). We acknowledge financial support provided by the National Energy Research Scientific Computing Center, which is supported by the Office of Science of the U.S. Department of Energy under Contract No. DE-AC02-05CH11231. Some of the results in this paper have been derived using the HEALPix package Górski et al. (2005). A description of the Planck Collaboration and a list of its members, indicating which technical or scientific activities they have been involved in, can be found at http://www.rssd.esa.int/index.php?project=PLANCK&page=Planck_Collaboration

Distinctive waves of innate immune response in the retina in experimental autoimmune encephalomyelitis

Neurodegeneration mediates neurological disability in inflammatory demyelinating diseases of the CNS. The role of innate immune cells in mediating this damage has remained controversial with evidence for destructive and protective effects. This has complicated efforts to develop treatment. The time sequence and dynamic evolution of the opposing functions are especially unclear. Given limits of in vivo monitoring in human diseases such as multiple sclerosis (MS), animal models are warranted to investigate the association and timing of innate immune activation with neurodegeneration. Using noninvasive in vivo retinal imaging of experimental autoimmune encephalitis (EAE) in CX3CR1(GFP/+)-knock-in mice followed by transcriptional profiling, we are able to show 2 distinct waves separated by a marked reduction in the number of innate immune cells and change in cell morphology. The first wave is characterized by an inflammatory phagocytic phenotype preceding the onset of EAE, whereas the second wave is characterized by a regulatory, antiinflammatory phenotype during the chronic stage. Additionally, the magnitude of the first wave is associated with neuronal loss. Two transcripts identified - growth arrest-specific protein 6 (GAS6) and suppressor of cytokine signaling 3 (SOCS3) - might be promising targets for enhancing protective effects of microglia in the chronic phase after initial injury

Safety, pharmacokinetics and target engagement of novel RIPK1 inhibitor SAR443060 (DNL747) for neurodegenerative disorders:Randomized, placebo-controlled, double-blind phase I/Ib studies in healthy subjects and patients

RIPK1 is a master regulator of inflammatory signaling and cell death and increased RIPK1 activity is observed in human diseases, including Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). RIPK1 inhibition has been shown to protect against cell death in a range of preclinical cellular and animal models of diseases. SAR443060 (previously DNL747) is a selective, orally bioavailable, central nervous system (CNS)-penetrant, small-molecule, reversible inhibitor of RIPK1. In three early-stage clinical trials in healthy subjects and patients with AD or ALS (NCT03757325 and NCT03757351), SAR443060 distributed into the cerebrospinal fluid (CSF) after oral administration and demonstrated robust peripheral target engagement as measured by a reduction in phosphorylation of RIPK1 at serine 166 (pRIPK1) in human peripheral blood mononuclear cells compared to baseline. RIPK1 inhibition was generally safe and well-tolerated in healthy volunteers and patients with AD or ALS. Taken together, the distribution into the CSF after oral administration, the peripheral proof-of-mechanism, and the safety profile of RIPK1 inhibition to date, suggest that therapeutic modulation of RIPK1 in the CNS is possible, conferring potential therapeutic promise for AD and ALS, as well as other neurodegenerative conditions. However, SAR443060 development was discontinued due to long-term nonclinical toxicology findings, although these nonclinical toxicology signals were not observed in the short duration dosing in any of the three early-stage clinical trials. The dose-limiting toxicities observed for SAR443060 preclinically have not been reported for other RIPK1-inhibitors, suggesting that these toxicities are compound-specific (related to SAR443060) rather than RIPK1 pathway-specific