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Autism spectrum disorder (ASD) affects up to 1 in 36 children in the United States. It is a heterogeneous neurodevelopmental disorder with life-long consequences. Patients with ASD and folate pathway abnormalities have demonstrated improved symptoms after treatment with leucovorin (folinic acid), a reduced form of folate. However, biomarkers for treatment response have not been well investigated and clinical trials are lacking. In this retrospective analysis, a cohort of prospectively collected data from 110 consecutive ASD clinic patients [mean (SD) age: 10.5 (6.2) years; 74% male] was examined. These patients all underwent testing for folate receptor alpha autoantibodies (FRAAs) and soluble folate binding proteins (sFBPs) biomarkers and were treated with leucovorin, if appropriate. Analyses examined whether these biomarkers could predict response to leucovorin treatment as well as the severity of ASD characteristics at baseline. The social responsiveness scale (SRS), a measure of core ASD symptoms, and the aberrant behavior checklist (ABC), a measure of disruptive behavior, were collected at each clinic visit. Those positive for sFBPs had more severe ASD symptoms, and higher binding FRAA titers were associated with greater ABC irritability. Treatment with leucovorin improved most SRS subscales with higher binding FRAA titers associated with greater response. Leucovorin treatment also improved ABC irritability. These results confirm and expand on previous studies, underscore the need for biomarkers to guide treatment of folate pathways in ASD, and suggest that leucovorin may be effective for children with ASD. [ABSTRACT FROM AUTHOR]

Inflammation is now recognized as a key component in a number of diseases such as atherosclerosis, rheumatoid arthritis, and inflammatory bowel disease. The transcription factor NF-[kappa]B has been shown to be involved in both the early and late stages of the inflammatory-proliferative process. In this report, we describe the identification of the pathway-selective estrogen receptor (ER) ligand, WAY-169916, that inhibits NF-[kappa]B transcriptional activity but is devoid of conventional estrogenic activity. This pathway-selective ligand does not promote the classic actions of estrogens such as stimulation of uterine proliferation or ER-mediated gene expression, but is a potent antiinflammatory agent, as demonstrated in the HLA-B27 transgenic rat model of inflammatory bowel disease. Our results indicate the potential utility of pathway-selective ER ligands such as WAY-169916 in the treatment of chronic inflammatory diseases. inflammation | therapy

Research into etiology of marital aggression has focused primarily on psychosocial, political, and cultural factors, to the exclusion of physiological influences. Fifty-three partner abusive men, 45 maritally satisfied, and 32 maritally discordant, nonviolent men were evaluated for past history of head injury, by a physician who was not informed of group membership and aggression history. Logistic regressions confirmed that head injury was a significant predictor of being a batterer. The implications of these findings for both marital aggression and post-head injury rehabilitation are discussed.

In order to determine psychiatrists' strategies for managing the pharmacotherapy and treatment of mentally ill substance abusers, the authors constructed a series of standardized clinical vignettes, each with five multiple-choice treatment interventions. The vignettes, based on clinical experience, depict difficult dilemmas involving the use of medication in the treatment of a variety of dually diagnosed patients. The authors surveyed a heterogeneous reference group of 112 psychiatrists with these vignettes. The psychometric properties of the resultant Scale for Treatment Integration of the Dually Diagnosed (STIDD) are briefly described. The ten vignettes and the treatment interventions chosen by the reference group are described in detail. The results indicate that most clinicians favor an integrated treatment approach which attempts to address both diagnoses.

A molecular theory of liquid phase vibrational energy relaxation (VER) [S. A. Adelman et al., Adv. Chem. Phys. 84, 73 (1993)] is applied to study the temperature T and density p dependencies of the VER rate constant k(T,ρ)=T[sup -1, sub 1], where T[sub 1] is the energy relaxation time, of model Lennard-Jones systems that roughly simulate solutions of high-mass, low-frequency dihalogen solutes in rare gas solvents; specifically the I[sub 2]/Xe, I[sub 2]/Ar, and ICI/Xe solutions. For selected states of these systems, the theory's assumptions are tested against molecular dynamics (MD) results. The theory is based on the expression T[sub 1]=β[sup -1](ω[sub l]), where β(ω) and β(ω) are, respectively, the solute's liquid phase vibrational frequency and vibrational coordinate friction kernel. The friction kernel is evaluated as a cosine transform of the fluctuating force autocorrelation function of the solute vibrational coordinate, conditional that this coordinate is fixed at equilibrium. Additionally, the early-time decay of the force autocorrelation function is approximated by a Gaussian function which is exact to order t². This Gaussian approximation permits evaluation of T[sub 1] in terms of integrals over equilibrium solute-solvent pair correlation functions. The pair correlation function formulas yield T[sub 1]'s in semiquantitative agreement with those found by MD evaluations of the Gaussian approximation, but with three orders of magnitude less computational effort. For the isothermal ρ dependencies of k(T, ρ), the theory predicts for all systems that the Gaussian decay time r is nearly independent of ρ. This in turn implies that k(T,ρ) factorizes into a liquid phase structural contribution and a gas phase dynamical contribution, yielding a first-principles form for k(T, ρ) similar to that postulated by the isolated binary collision model. Also, the theory predicts both "classical" superlinear rate... [ABSTRACT FROM AUTHOR]

The theoretical treatment in Paper I [D. W. Miller and S. A. Adelman, J. Chem. Phys. 117, 2672, (2002), preceding paper] of the vibrational energy relaxation (VER) of low-frequency, large mass dihalogen solutes is extended to the VER of the high-frequency, small mass molecular hydrogen solutes H[sub 2] and D[sub 2] in a Lennard-Jones argon-like solvent. As in Paper I, values of the relaxation times T[sub 1] predicted by the theory are tested against molecular dynamics (MD) results and are found to be of semiquantitative accuracy. To start, it is noted that standard Lennard-Jones site-site potentials derived from macroscopic data can be very inaccurate in the steep repulsive slope region crucial for T[sub 1]. Thus, the H-Ar Lennard-Jones diameter σ[sub uv] is not taken from literature values but rather is chosen as σ[sub UV] = 1.39 Å, the value needed to make the theory reproduce the experimental H[sub 2]/Ar gas phase VER rate constant. Next, by MD simulation it is shown that the vibrational coordinate fluctuating force autocorrelation function 〈&Ftilde;(t)&Ftilde;〉[sub 0] of Paper I decays roughly an order of magnitude more rapidly for the molecular hydrogen solutions than for the dihalogen solutions. This result implies a relatively slow decay for the molecular hydrogen friction kernels β(ω) = (k[sub B]T)[sup -1] ∫[sup ∞, sub 0] 〈&Ftilde;(t)&Ftilde;〉[sub 0] cos ω tdt, yielding for the H[sub 2]/Ar and D[sub 2]/Ar systems at T= 150 K physical millisecond values for T[sub 1] =beta;[sup -1](ω) despite the high liquid phase vibrational frequencies ω[sub 1] of H[sub 2] and D[sub 2]. The rapid decay of 〈&Ftilde;(t)&Ftilde;&ran;[sub 0] is due to both the steepness of the repulsive slope of the H-Ar potential and the small masses of H and D. Thus, the small value chosen for σ[sub UV] is needed to avoid unphysically long T[sub 1]'s. Next, an analytical treatment of the H[sub 2]/D[sub... [ABSTRACT FROM AUTHOR]

This paper gives a theoretical treatment of liquid-phase activated barrier crossing that is valid for chemical reactions which occur on typical (e.g., high activation barrier) potential-energy surfaces. This treatment is based on our general approach [S. A. Adelman, Adv. Chem. Phys. 53, 61 (1983)] to problems in liquid-phase chemical dynamics. We focus on the early-time regime [times short compared to the relaxation time of 0, the fluctuating force autocorrelation function of the reaction coordinate] in which the solvent is nearly ‘‘frozen.’’ This regime has been shown to be important for the determination of the rate constant in the molecular-dynamics simulations of model aqueous SN2 reactions due to Wilson and co-workers. Our treatment is based on a generalized Langevin equation of motion which naturally represents the physics of the early-time regime.In this regime the main features of the reaction dynamics are governed by the instantaneous potential WIP[y,F], which accounts for the cage confinement forces which dominate the liquid-phase effects at early times, rather than by the familiar potential of mean force. The instantaneous potential is derived from the t→0 limit of the equation of motion and its properties are developed for both symmetric and nonsymmetric reactions. The potential is then shown to account for both the early-time barrier recrossing processes found to determine the transmission coefficient κ in the SN2 simulations and the dependence of these processes on environmental fluctuations modeled by F. Making the parabolic approximation for the gas-phase part of WIP[y,F] yields the following result for the transmission coefficient: κ=ω-1PMFx+=ω-1PMFωMIP[1+ω-2 MIPΘ(x+)]1/2≠ ω-1PMFω MIP[1+ (1)/(2) ω-2MIPΘ(ωMIP)], where ωMIP and ωPMF are, respectively, the barrier frequencies of WIP[y,F=0] and of the potential of mean force, and... [ABSTRACT FROM AUTHOR]

Algorithms which permit the explicit, albeit approximate, construction of a physically realistic generalized Langevin equation of motion for the energy relaxation dynamics of a specified solute normal mode coordinate y in a monatomic solvent are developed. These algorithms permit the construction, from equilibrium solute–solvent pair correlation functions, of the liquid state frequency ωl of the normal mode and of the Gaussian model approximation to the autocorrelation function 〈F(t)F〉0 of the fluctuating generalized force exerted by the solvent on the normal mode. From these quantities one may compute, from equilibrium solute–solvent pair correlation functions, the vibrational energy relaxation time T1 of the solute normal mode and also related quantities which permit one to assess the relative importance of direct [y coordinate→solvent] and indirect [y coordinate→solute translation–rotational coordinates→solvent] energy flow pathways in solute vibrational energy relaxation. The basis of the construction of T1 is the formula T1=β-1(ωl) where β(ω)=∫∞0 β(t)cos ω dt and where β(t)=[kBT]-1 〈F(t)F〉0 is the friction kernel of the solute normal mode. This formula is valid if T1>T2=vibrational phase relaxation time. The approximate formulas for T1 are worked out in detail for diatomic solutes. The approximations are tested for this diatomic solute case by comparing with molecular dynamics results. [ABSTRACT FROM AUTHOR]

A numerical study of the solute, solvent, and energy flow pathway dependence of the vibrational energy relaxation (VER) time T1 of a harmonic solute vibrational mode is presented for the prototype case of diatomic solutes in monatomic solvents. This study is based on formulas for T1 developed in the preceding paper, especially the relationship T1=β-1(ωl) where β(ω) is the frequency-dependent friction kernel of the solute normal mode and where ωl is its liquid state frequency. These formulas permit evaluation of T1 and its energy flow pathway dependence from equilibrium solute–solvent pair correlation functions. Applications are made to VER of ground electronic state molecular iodine and bromine in the fluids xenon and argon and in model Lennard-Jones solvents designed to simulate ethane and carbon tetrachloride. Satisfactory agreement between the present treatment and experimental and computer simulation results for 15 thermodynamic states is found. The VER rates (∼T-11) were found to increase with increase in the degree of resonance overlap between ωl and the solvent frequency spectrum ρF(ω)∼β(ω). Moreover indirect energy flow pathways, i.e., those which involve solute vibration ↔ solute translation–rotation ↔ solvent energy transfer, are found to play a qualitatively essential role for many of the systems studied here. Finally a study of the temperature and density dependence of T1 for iodine in xenon in the experimentally accessible range is presented. [ABSTRACT FROM AUTHOR]