FTY720 (fingolimod) modulates the severity of viral-induced encephalomyelitis and demyelination.

BackgroundFTY720 (fingolimod) is the first oral drug approved by the Food and Drug Administration for treatment of patients with the relapsing-remitting form of the human demyelinating disease multiple sclerosis. Evidence suggests that the therapeutic benefit of FTY720 occurs by preventing the egress of lymphocytes from lymph nodes thereby inhibiting the infiltration of disease-causing lymphocytes into the central nervous system (CNS). We hypothesized that FTY720 treatment would affect lymphocyte migration to the CNS and influence disease severity in a mouse model of viral-induced neurologic disease.MethodsMice were infected intracranially with the neurotropic JHM strain of mouse hepatitis virus. Infected animals were treated with increasing doses (1, 3 and 10 mg/kg) of FTY720 and morbidity and mortality recorded. Infiltration of inflammatory virus-specific T cells (tetramer staining) into the CNS of FTY720-treated mice was determined using flow cytometry. The effects of FTY720 treatment on virus-specific T cell proliferation, cytokine production and cytolytic activity were also determined. The severity of neuroinflammation and demyelination in FTY720-treated mice was examined by flow cytometry and histopathologically, respectively, in the spinal cords of the mice.ResultsAdministration of FTY720 to JHMV-infected mice resulted in increased clinical disease severity and mortality. These results correlated with impaired ability to control viral replication (P < 0.05) within the CNS at days 7 and 14 post-infection, which was associated with diminished accumulation of virus-specific CD4+ and CD8+ T cells (P < 0.05) into the CNS. Reduced neuroinflammation in FTY720-treated mice correlated with increased retention of T lymphocytes within draining cervical lymph nodes (P < 0.05). Treatment with FTY720 did not affect virus-specific T cell proliferation, expression of IFN-γ, TNF-α or cytolytic activity. FTY720-treated mice exhibited a reduction in the severity of demyelination associated with dampened neuroinflammation.ConclusionThese findings indicate that FTY720 mutes effective anti-viral immune responses through impacting migration and accumulation of virus-specific T cells within the CNS during acute viral-induced encephalomyelitis. FTY720 treatment reduces the severity of neuroinflammatory-mediated demyelination by restricting the access of disease-causing lymphocytes into the CNS but is not associated with viral recrudescence in this model

The Thousand Aviator Study - Smoking history correlates of selected physiological, biochemical, and anthropometric measures

Smoking history correlates of selected physiological, biochemical, and anthropometric measure

Origin of 21+2_1^+ Excitation Energy Dependence on Valence Nucleon Numbers

It has been shown recently that a simple formula in terms of the valence nucleon numbers and the mass number can describe the essential trends of excitation energies of the first $2^+$ states in even-even nuclei. By evaluating the first order energy shift due to the zero-range residual interaction, we find that the factor which reflects the effective particle number participating in the interaction from the Fermi orbit governs the main dependence of the first $2^+$ excitation energy on the valence nucleon numbers.Comment: 9 pages, 5 figure

Surrogate measures: A proposed alternative in human factors assessment of operational measures of performance

Surrogate measures are proposed as an alternative to direct assessment of operational performance for purposes of screening agents who may have to work under unusual stresses or in exotic environments. Such measures are particularly proposed when the surrogate can be empirically validated against the operational criterion. The focus is on cognitive (or throughput) performances in humans as opposed to sensory (input) or motor (output) measures, but the methods should be applicable for development of batteries which will tap input/output functions. A menu of performance tasks is under development for implementation on a battery-operated portable microcomputer, with 21 tests currently available. The tasks are reliable and become stable in minimum amounts of time; appear sensitive to some agents; comprise constructs related to actual job tasks; and are easily administered in most environments. Implications for human factors engineering studies in environmental stress are discussed

Trends in systolic blood pressure in the thousand aviator cohort over a 24-year period

Age, weight, and parental longevity effects on trends in systolic blood pressure in thousand aviator cohort over 24 year perio

Soluble CD40 ligand can replace the normal T cell-derived CD40 ligand signal to B cells in T cell-dependent activation

We have constructed a soluble chimeric fusion protein between the mouse CD8 alpha chain and the mouse CD40 T cell ligand. This protein binds to both human and mouse B cells. By itself it induced a modest degree of B cell proliferation, but together with anti-immunoglobulin (anti-Ig) antibody it greatly stimulated B cell proliferation, as determined by both [3H]thymidine uptake and increase in cell numbers. These data are evidence that the CD40 ligand on T cells provides a signal that drives B cell proliferation. This signal is synergistic with that delivered by anti-Ig antibody

Studies of finite element analysis of composite material structures

Research in the area of finite element analysis is summarized. Topics discussed include finite element analysis of a picture frame shear test, BANSAP (a bandwidth reduction program for SAP IV), FEMESH (a finite element mesh generation program based on isoparametric zones), and finite element analysis of a composite bolted joint specimens

A unique facility for V/STOL aircraft hover testing

The Langley Impact Dynamics Research Facility (IDRF) was modified to obtain static force and moment data and to allow assessment of aircraft handling qualities during dynamic tethered hover flight. Test probe procedures were also established. Static lift and control measurements obtained are presented along with results of limited dynamic tethered hover flight

Morphology-dependent trends of galaxy age with environment in Abell 901/902 seen with COMBO-17

We investigate correlations between galaxy age and environment in the Abell 901/2 supercluster for separate morphologies. Using COMBO-17 data, we define a sample of 530 galaxies, complete at $M_V -5\log h<-18$ on an area of $3.5\times 3.5$ (Mpc/$h$)$^2$. We explore several age indicators including an extinction-corrected residual from the colour-magnitude relation (CMR). As a result, we find a clear trend of age with density for galaxies of all morphologies that include a spheroidal component, in the sense that galaxies in denser environments are older. This trend is not seen among Scd/Irr galaxies since they all have young ages. However, the trend among the other types is stronger for fainter galaxies. While we also see an expected age-morphology relation, we find no evidence for a morphology-density relation at fixed age.Comment: Accepted for publication in MNRAS (Letters