Effects of Repeated Intrathecal Triamcinolone-Acetonide Application on Cerebrospinal Fluid Biomarkers of Axonal Damage and Glial Activity in Multiple Sclerosis Patients

Multiple sclerosis (MS) is the most common inflammatory disease of the central nervous system in young adults. Over time, the disease progresses and, with accumulating disability, symptoms such as spasticity may occur. Although several treatment options are available, some patients may not respond to first-line therapeutics. However, some of these patients may benefit from intrathecally administered triamcinolone-acetonide (TCA), a derivative of glucocorticosteroids (GCS).GCSmay have neurotoxic effects, and cell apoptosis may occur. The aim of this study was to investigate the effects of TCA on biomarkers in the cerebrospinal fluid (CSF) suggestive of neurodegeneration

Local density of states and scanning tunneling currents in graphene

We present exact analytical calculations of scanning tunneling currents in locally disordered graphene using a multimode description of the microscope tip. Analytical expressions for the local density of states (LDOS) are given for energies beyond the Dirac cone approximation. We show that the LDOS at the $A$ and $B$ sublattices of graphene are out of phase by $\pi$ implying that the averaged LDOS, as one moves away from the impurity, shows no trace of the $2q_F$ (with $q_F$ the Fermi momentum) Friedel modulation. This means that a STM experiment lacking atomic resolution at the sublattice level will not be able of detecting the presence of the Friedel oscillations [this seems to be the case in the experiments reported in Phys. Rev. Lett. {\bf 101}, 206802 (2008)]. The momentum maps of the LDOS for different types of impurities are given. In the case of the vacancy, $2q_F$ features are seen in these maps. In all momentum space maps, $K$ and $K+K^\prime$ features are seen. The $K+K^\prime$ features are different from what is seen around zero momentum. An interpretation for these features is given. The calculations reported here are valid for chemical substitution impurities, such as boron and nitrogen atoms, as well as for vacancies. It is shown that the density of states close to the impurity is very sensitive to type of disorder: diagonal, non-diagonal, or vacancies. In the case of weakly coupled (to the carbon atoms) impurities, the local density of states presents strong resonances at finite energies, which leads to steps in the scanning tunneling currents and to suppression of the Fano factor.Comment: 21 pages. Figures 6 and 7 are correctly displayed in this new versio

Immunotherapies in neuromyelitis optica spectrum disorder: efficacy and predictors of response

OBJECTIVE: To analyse predictors for relapses and number of attacks under different immunotherapies in patients with neuromyelitis optica spectrum disorder (NMOSD). DESIGN: This is a retrospective cohort study conducted in neurology departments at 21 regional and university hospitals in Germany. Eligible participants were patients with aquaporin-4-antibody-positive or aquaporin-4-antibody-negative NMOSD. Main outcome measures were HRs from Cox proportional hazard regression models adjusted for centre effects, important prognostic factors and repeated treatment episodes. RESULTS: 265 treatment episodes with a mean duration of 442 days (total of 321 treatment years) in 144 patients (mean age at first attack: 40.9 years, 82.6% female, 86.1% aquaporin-4-antibody-positive) were analysed. 191 attacks occurred during any of the treatments (annual relapse rate=0.60). The most common treatments were rituximab (n=77, 111 patient-years), azathioprine (n=52, 68 patient-years), interferon-beta (n=32, 61 patient-years), mitoxantrone (n=34, 32.1 patient-years) and glatiramer acetate (n=17, 10 patient-years). Azathioprine (HR=0.4, 95% CI 0.3 to 0.7, p=0.001) and rituximab (HR=0.6, 95% CI 0.4 to 1.0, p=0.034) reduced the attack risk compared with interferon-beta, whereas mitoxantrone and glatiramer acetate did not. Patients who were aquaporin-4-antibody-positive had a higher risk of attacks (HR=2.5, 95% CI 1.3 to 5.1, p=0.009). Every decade of age was associated with a lower risk for attacks (HR=0.8, 95% CI 0.7 to 1.0, p=0.039). A previous attack under the same treatment tended to be predictive for further attacks (HR=1.5, 95% CI 1.0 to 2.4, p=0.065). CONCLUSIONS: Age, antibody status and possibly previous attacks predict further attacks in patients treated for NMOSD. Azathioprine and rituximab are superior to interferon-beta

Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation

We conducted a genome-wide association study (GWAS) on multiple sclerosis (MS) susceptibility in German cohorts with 4888 cases and 10,395 controls. In addition to associations within the major histocompatibility complex (MHC) region, 15 non-MHC loci reached genome-wide significance. Four of these loci are novel MS susceptibility loci. They map to the genes L3MBTL3, MAZ, ERG, and SHMT1. The lead variant at SHMT1 was replicated in an independent Sardinian cohort. Products of the genes L3MBTL3, MAZ, and ERG play important roles in immune cell regulation. SHMT1 encodes a serine hydroxymethyltransferase catalyzing the transfer of a carbon unit to the folate cycle. This reaction is required for regulation of methylation homeostasis, which is important for establishment and maintenance of epigenetic signatures. Our GWAS approach in a defined population with limited genetic substructure detected associations not found in larger, more heterogeneous cohorts, thus providing new clues regarding MS pathogenesis

DOGS: Reaction-Driven de novo Design of Bioactive Compounds

We present a computational method for the reaction-based de novo design of drug-like molecules. The software DOGS (Design of Genuine Structures) features a ligand-based strategy for automated ‘in silico’ assembly of potentially novel bioactive compounds. The quality of the designed compounds is assessed by a graph kernel method measuring their similarity to known bioactive reference ligands in terms of structural and pharmacophoric features. We implemented a deterministic compound construction procedure that explicitly considers compound synthesizability, based on a compilation of 25'144 readily available synthetic building blocks and 58 established reaction principles. This enables the software to suggest a synthesis route for each designed compound. Two prospective case studies are presented together with details on the algorithm and its implementation. De novo designed ligand candidates for the human histamine H4 receptor and γ-secretase were synthesized as suggested by the software. The computational approach proved to be suitable for scaffold-hopping from known ligands to novel chemotypes, and for generating bioactive molecules with drug-like properties

Altered grey matter networks in young patients with MS at genetic risk for Alzheimer's disease [Abstract]

Background: The Apolipoprotein E (APOE) ε4 is the major susceptibility factor for cognitive impairment and Alzheimer’s disease. Cognitive decline is also a concern in patients with multiple sclerosis (MS). Whether APOE ε4 exerts an effect on brain structure and grey matter (GM) networks in MS patients that could potentiate the long-term cognitive disabilities is unclear. Moreover the description of the exact link between genetic markers and MR driven measures of brain integrity are of essential importance to study cognition in patients with MS and for interventions to prevent longitudinal deterioration. Methods: MS Patients with no immunomodulatory treatment were enrolled in the “Krankheitsbezogene Kompetenznetz Multiple Sclerosis (KKNMS)”. From this multicenter dataset 37 heterozygous APOE ε4 carriers (i.e. having the genotype ε3/ε4) and 37 non-carriers (ε3/ε3) were matched for demographics (mean age: 38.4±9.2 yrs, mean EDSS 1.23±0.99) from one site. A replication study was performed in a cohort (n=46) from a second site. Cortical thickness (CT) was derived from 3T MRI using FreeSurfer. GM connectivity networks were reconstructed from the CT correlation between the 68 regions of the Desikan-Killiany atlas. Cortical integrity and network connectivity -derived from graph theoretical approaches- were compared between the groups in both cohorts. Results corrected for multiple comparisons were considered (p< 0.05 FDR). Results: No regional or global cortical atrophy differences were attested between the two groups in both cohorts. In the network connectivity analysis a decreased local connectivity pattern (reduced transitivity, t=-3.24 p=0.008) was evident in APOE ε4 carriers. Regions with decreased connectivity were consistently seen in the medial part of the left temporal lobe. APOE ε4 status was further associated with raised whole brain connectivity, reflected by increased global efficiency (t=4.34 p=0.005) and reduced modularity (t=-2.84 p=0.02). This network pattern was shown in the frontal, parietal and lateral temporal associative cortices. The results were entirely replicated in the second cohort. Conclusion: We found that MS patients at genetic risk for cognitive decline have significant abnormalities of local GM networks and possibly compensatory increased long-range connectivity patterns. Chronic or focal neuroinflammation could lead to behaviourally relevant memory impairments in these patients through a specific break-down of the long-range paths

White matter correlates of complex processing speed performance in relapsing-remitting multiple sclerosis

Background: Natalizumab (NTZ) exerts a positive impact on cognitive functions in Relapsing Multiple Sclerosis (RRMS). Little is known about the effect of Fingolimod (FIN) on these functions. Objectives: to compare the effect on cognitive functions of 1-year treatment with FIN or NTZ. Methods: All consecutive RRMS scheduled for treatment with NTZ or FIN underwent neuropsychological evaluations using the Brief Repeatable Battery, Stroop Test, Fatigue Severity Scale (FSS) and Beck Depression Inventory (BDI) at baseline and every 12 months. A test was considered failed if the corresponding z-score was 2 standard deviation (SD) below the mean Italian normative values. The Cognitive Impairment Index (CII) as a measure of global cognitive function was calculated for each patient. Patients were propensity score (PS)-matched on a 1-to-1 basis at the time of treatment start using the following covariates: sex, age, prior treatment exposure, relapses prior the treatment, school education, and BDI score. The relapse risk during the treatment was estimated through a Poisson regression model. A generalized linear mixed model for repeated measures with an autoregressive variance-covariance structure was applied to evaluate changes in CII, the mean number of cognitive tests failed and FSS score at 1 year of treatment. Results: the effect of treatment on cognitive functions was evaluated in 62 matched RRMS patients receiving NTZ(n=31) or FIN(n=31). The relapse incidence was not significant different between the treatments (FIN vs NTZ: Incidence rate ratio=0.71, p=0.6). The mean±SD number of cognitive tests failed was significantly reduced only in FIN treated patients (2.8±2.2 vs 1.7±1.8, p=0.0014). The CII significantly improved in both groups (NAT 18.5±6.1 vs 14.5±6.1, p=0.0075; FIN 14.0±7.3 vs 11.5±7.5, p&lt; 0.0001), but there was not a significant interaction between group X time. The FSS was unchanged in both groups. Conclusions: Our results indicates, for the first time, that both NAT and FIN treatments significantly ameliorate cognitive functions in RRMS. Moreover, the effect on the number of tests failed suggest that FIN could have a greater impact on cognition than NTZ. The effect on cognition of these two drugs goes in parallel with the reduction of the relapse rate. This latter finding support the hypothesis that in the short-term, NTZ and FIN, exert a positive impact on cognition likely by means of their anti-inflammatory properties

Recovery of release cloud from laser shock-loaded graphite and hydrocarbon targets: in search of diamonds

This work presents first insights into the dynamics of free-surface release clouds from dynamically compressed polystyrene and pyrolytic graphite at pressures up to 200 GPa, where they transform into diamond or lonsdaleite, respectively. These ejecta clouds are released into either vacuum or various types of catcher systems, and are monitored with high-speed recordings (frame rates up to 10 MHz). Molecular dynamics simulations are used to give insights to the rate of diamond preservation throughout the free expansion and the catcher impact process, highlighting the challenges of diamond retrieval. Raman spectroscopy data show graphitic signatures on a catcher plate confirming that the shock-compressed PS is transformed. First electron microscopy analyses of solid catcher plates yield an outstanding number of different spherical-like objects in the size range between ten(s) up to hundreds of nanometres, which are one type of two potential diamond candidates identified. The origin of some objects can unambiguously be assigned, while the history of others remains speculative

Diverse Hematological Malignancies Including Hodgkin-Like Lymphomas Develop in Chimeric MHC Class II Transgenic Mice

A chimeric HLA-DR4-H2-E (DR4) homozygous transgenic mouse line spontaneously develops diverse hematological malignancies with high frequency (70%). The majority of malignancies were distributed equally between T and B cell neoplasms and included lymphoblastic T cell lymphoma (LTCL), lymphoblastic B cell lymphoma (LBCL), diffuse large B cell lymphoma (DLBCL), the histiocyte/T cell rich variant of DLBCL (DLBCL-HA/T cell rich DLBCL), splenic marginal zone lymphoma (SMZL), follicular B cell lymphoma (FBL) and plasmacytoma (PCT). Most of these neoplasms were highly similar to human diseases. Also, some non-lymphoid malignancies such as acute myeloid leukemia (AML) and histiocytic sarcoma were found. Interestingly, composite lymphomas, including Hodgkin-like lymphomas, were also detected that had CD30+ Hodgkin/Reed-Sternberg (H/RS)-like cells, representing a tumor type not previously described in mice. Analysis of microdissected H/RS-like cells revealed their origin as germinal center B cells bearing somatic hypermutations and, in some instances, crippled mutations, as described for human Hodgkin lymphoma (HL). Transgene integration in an oncogene was excluded as an exclusive driving force of tumorigenesis and age-related lymphoma development suggests a multi-step process. Thus, this DR4 line is a useful model to investigate common molecular mechanisms that may contribute to important neoplastic diseases in man

Determination of nutrient salts by automatic methods both in seawater and brackish water: the phosphate blank

9 páginas, 2 tablas, 2 figurasThe main inconvenience in determining nutrients in seawater by automatic methods is simply solved: the preparation of a suitable blank which corrects the effect of the refractive index change on the recorded signal. Two procedures are proposed, one physical (a simple equation to estimate the effect) and the other chemical (removal of the dissolved phosphorus with ferric hydroxide).Support for this work came from CICYT (MAR88-0245 project) and Conselleria de Pesca de la Xunta de GaliciaPeer reviewe