Quantitative assessment of tear production: A review of methods and utility in dry eye drug discovery

The successful development of a therapeutic agent targeting treatment of dry eye syndrome necessitates the demonstration of drug efficacy for both sign and symptom endpoints. As numerous therapeutic strategies incorporate a secretagogue function into their overall mechanism of action, the quantitative assessment of tear production serves as a logical endpoint to anchor “sign” efficacy. Although several methods including the Schirmer, the phenol red thread and tear clearance tests exist, their utility in clinical evaluations of novel therapeutics is unclear. The purpose of this review is to summarize findings and conclusions describing the performance of each of these tests so as to gain insight into which, if any, is most applicable for use in discovering new dry eye therapeutics

Targeting BAFF and APRIL in systemic lupus erythematosus and other antibody-associated diseases.

The B cell-stimulating molecules, BAFF (B cell activating factor) and APRIL (a proliferation-inducing ligand), are critical factors in the maintenance of the B cell pool and humoral immunity. In addition, BAFF and APRIL are involved in the pathogenesis of a number of human autoimmune diseases, with elevated levels of these cytokines detected in the sera of patients with systemic lupus erythematosus (SLE), IgA nephropathy, Sjögren's syndrome, and rheumatoid arthritis. As such, both molecules are rational targets for new therapies in B cell-driven autoimmune diseases, and several inhibitors of BAFF or BAFF and APRIL together have been investigated in clinical trials. These include the BAFF/APRIL dual inhibitor, atacicept, and the BAFF inhibitor, belimumab, which is approved as an add-on therapy for patients with active SLE. Post hoc analyses of these trials indicate that baseline serum levels of BAFF and BAFF/APRIL correlate with treatment response to belimumab and atacicept, respectively, suggesting a role for the two molecules as predictive biomarkers. It will, however, be important to refine future testing to identify active forms of BAFF and APRIL in the circulation, as well as to distinguish between homotrimer and heteromer configurations. In this review, we discuss the rationale for dual BAFF/APRIL inhibition versus single BAFF inhibition in autoimmune disease, by focusing on the similarities and differences between the physiological and pathogenic roles of the two molecules. A summary of the preclinical and clinical data currently available is also presented

Application of remote sensing to state and regional problems

The author has identified the following significant results. The Lowndes County data base is essentially complete with 18 primary variables and 16 proximity variables encoded into the geo-information system. The single purpose, decision tree classifier is now operational. Signatures for the thematic extraction of strip mines from LANDSAT Digital data were obtained by employing both supervised and nonsupervised procedures. Dry, blowing sand areas of beach were also identified from the LANDSAT data. The primary procedure was the analysis of analog data on the I2S signal slicer

Submicron scale tissue multifractal anisotropy in polarized laser light scattering

The spatial fluctuations of the refractive index within biological tissues exhibit multifractal anisotropy, leaving its signature as a spectral linear diattenuation of scattered polarized light. The multifractal anisotropy has been quantitatively assessed by the processing of relevant Mueller matrix elements in the Fourier domain, utilizing the Born approximation and subsequent multifractal analysis. The differential scaling exponent and width of the singularity spectrum appear to be highly sensitive to the structural multifractal anisotropy at the micron/sub-micron length scales. An immediate practical use of these multifractal anisotropy parameters was explored for non-invasive screening of cervical precancerous alterations ex vivo, with the indication of a strong potential for clinical diagnostic purposes

The Excursion Set Theory of Halo Mass Functions, Halo Clustering, and Halo Growth

I review the excursion set theory (EST) of dark matter halo formation and clustering. I recount the Press-Schechter argument for the mass function of bound objects and review the derivation of the Press-Schechter mass function in EST. The EST formalism is powerful and can be applied to numerous problems. I review the EST of halo bias and the properties of void regions. I spend considerable time reviewing halo growth in the EST. This section culminates with descriptions of two Monte Carlo methods for generating halo mass accretion histories. In the final section, I emphasize that the standard EST approach is the result of several simplifying assumptions. Dropping these assumptions can lead to more faithful predictions and a more versatile formalism. One such assumption is the constant height of the barrier for nonlinear collapse. I review implementations of the excursion set approach with arbitrary barrier shapes. An application of this is the now well-known improvement to standard EST that follows from the ellipsoidal-collapse barrier. Additionally, I emphasize that the statement that halo accretion histories are independent of halo environments is a simplifying assumption, rather than a prediction of the theory. I review the method for constructing correlated random walks of the density field in more general cases. I construct a simple toy model with correlated walks and I show that excursion set theory makes a qualitatively simple and general prediction for the relation between halo accretion histories and halo environments: regions of high density preferentially contain late-forming halos and conversely for regions of low density. I conclude with a brief discussion of this prediction in the context of recent numerical studies of the environmental dependence of halo properties. (Abridged)Comment: 62 pages, 19 figures. Review article based on lectures given at the Sixth Summer School of the Helmholtz Institute for Supercomputational Physics. Accepted for Publication in IJMPD. Comments Welcom

Linear systems with adiabatic fluctuations

We consider a dynamical system subjected to weak but adiabatically slow fluctuations of external origin. Based on the ``adiabatic following'' approximation we carry out an expansion in \alpha/|\mu|, where \alpha is the strength of fluctuations and 1/|\mu| refers to the time scale of evolution of the unperturbed system to obtain a linear differential equation for the average solution. The theory is applied to the problems of a damped harmonic oscillator and diffusion in a turbulent fluid. The result is the realization of `renormalized' diffusion constant or damping constant for the respective problems. The applicability of the method has been critically analyzed.Comment: Plain Latex, no figure, 21 page

Brownian Simulations and Uni-Directional Flux in Diffusion

Brownian dynamics simulations require the connection of a small discrete simulation volume to large baths that are maintained at fixed concentrations and voltages. The continuum baths are connected to the simulation through interfaces, located in the baths sufficiently far from the channel. Average boundary concentrations have to be maintained at their values in the baths by injecting and removing particles at the interfaces. The particles injected into the simulation volume represent a unidirectional diffusion flux, while the outgoing particles represent the unidirectional flux in the opposite direction. The classical diffusion equation defines net diffusion flux, but not unidirectional fluxes. The stochastic formulation of classical diffusion in terms of the Wiener process leads to a Wiener path integral, which can split the net flux into unidirectional fluxes. These unidirectional fluxes are infinite, though the net flux is finite and agrees with classical theory. We find that the infinite unidirectional flux is an artifact caused by replacing the Langevin dynamics with its Smoluchowski approximation, which is classical diffusion. The Smoluchowski approximation fails on time scales shorter than the relaxation time $1/\gamma$ of the Langevin equation. We find the unidirectional flux (source strength) needed to maintain average boundary concentrations in a manner consistent with the physics of Brownian particles. This unidirectional flux is proportional to the concentration and inversely proportional to $\sqrt{\Delta t}$ to leading order. We develop a BD simulation that maintains fixed average boundary concentrations in a manner consistent with the actual physics of the interface and without creating spurious boundary layers