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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]

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder with life-long consequences that affects up to 1 in 44 children. Treatment with leucovorin (folinic acid), a reduced form of folate, has been shown to improve symptoms in those with ASD and folate pathway abnormalities in controlled clinical trials. Although soluble folate binding proteins (sFBPs) have been observed in the serum of some patients with ASD, the significance of this finding has not been studied. Here, we present a cohort of ASD patients with sFBPs. These patients had severe ASD and were medically complex. Using baseline controlled open-label methodology and standardized assessments, these patients were found to improve in both core and associated ASD symptoms with leucovorin treatment. No adverse effects were related to leucovorin treatment. This is the first report of the sFBPs in ASD. This study complements ongoing controlled clinical trials and suggests that leucovorin may be effective for children with ASD who are positive for sFBPs. Further, sFBPs might be important biomarkers for treatment response to leucovorin in children with ASD. This study paves the way for further controlled studies for patients with sFBPs. [ABSTRACT FROM AUTHOR]

Dietary trimethylamines, such as choline, metabolized by intestinal microbiota to trimethylamine are absorbed by the gut and oxidized to trimethylamine N-oxide (TMAO). The objective of this study was to determine the effect of choline supplementation on atherosclerosis progression in Apoe−/− mice expressing human cholesterol ester transfer protein (hCETP) using the same diets as in previously reported studies. Mice expressing hCETP, after transfection with AAV2/8-hCETP, were fed an 18% protein diet with either 0.09% (standard chow), 0.5% or 1% choline for 16 weeks. Control mice not transfected with hCETP were fed 1% choline. Dietary choline supplementation increased plasma TMAO levels at 8 and 16 weeks. When atherosclerotic lesions were measured in the thoracic aorta and aortic root, there were no differences between any of the treatment groups in the amount of plaque development at either site. Throughout the study, no significant changes in plasma lipids or major classes of lipoproteins were observed in hCETP-expressing mice. Plasma-oxidized low density lipoprotein, myeloperoxidase and high density lipoprotein inflammatory index were measured at 16 weeks, with no significant changes in any of these inflammatory markers between the four treatment groups. Despite increasing plasma TMAO levels, dietary choline supplementation in Apoe−/− mice expressing hCETP did not promote atherosclerosis. [ABSTRACT FROM AUTHOR]

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]

A generalized Langevin equation framework for the treatment of liquid state influence on solute dynamics in molecular solvents, which generalizes an earlier framework restricted to monatomic solvents [S. A. Adelman, Adv. Chem. Phys. 53, 61 (1983)], is developed. This framework permits one to realistically treat energy exchange between the solute atoms and the solvent vibrational (V) degrees of freedom. This energy exchange can qualitatively influence the rates of liquid state processes when the solute frequencies relevant to the process of interest (e.g., a solute normal mode frequency if one is interested in the vibrational energy relaxation of that mode) substantially overlap the V bands of the frequency spectrum describing local solvent density fluctuations. The main result of the present analysis is an infinite set of equivalent chain equations governing the dynamics of the solute configuration point in molecular solvents. These are equations of motion for the solute configuration point and for the coordinates of an infinite set of abstract chain ‘‘molecules’’. Each molecule is composed of r+1 ‘‘atoms’’ where r is the number of normal modes of a real solvent molecule. The nearest neighbor chain of fictitious molecules may alternatively be regarded as a set of r+1 nearest neighbor cross-linked ‘‘atomic’’ chains. Atomic chain 1 executes low frequency‘‘acoustical’’ motions which simulate the influence of local solvent translational–rotational (TR) density fluctuations. Atomic chains 2,3,. . .,r+1 execute high frequency ‘‘optical’’ motions which simulate the influence of normal mode V local solvent density fluctuations. The coupling of the optical and acoustical branches of the chain by the crosslinks is the chain formalism equivalent of the physical coupling, due to liquid state effects, of the temporal development... [ABSTRACT FROM AUTHOR]

MTGLE and Langevin equation stochastic classical trajectory studies of the mobile silver cation channeling and activated barrier crossing processes which underly superionic conduction in α-AgI are presented. To interpret non-Kramers effects on the channeling kinetics, a new description of the condensed phase effect on activated barrier crossing is developed. This picture emphasizes the competition between ‘‘whipback’’ of the reaction coordinate, arising from instantaneous environmental restoring forces, and frequency-dependent dissipation of reaction coordinate energy due to environmental relaxation. The simulations show that while the roughest features of the channeling trajectories are determined by the cation friction coefficient the finer details are governed by short-time scale cation-cage correlations. Analogously, for α-AgI, the gross features of the kinetics, e.g., the rough extent of the breakdown of the transition state model, are described by a Kramers-like picture. The finer details of the kinetics, however, are governed by the competition between whipback, which makes realistic barrier crossing less efficient than Kramers model barrier crossing, and dissipation, which works in the opposite direction. [ABSTRACT FROM AUTHOR]

A liquid state analog of the gas phase harmonic oscillator-rigid top model is developed. This analog, which we call the harmonic mean field model, permits one to compute the equilibrium and dynamic properties of real, i.e., vibrating, molecular solvents from the structure and dynamics of the corresponding rigid solvents. The harmonic mean field model is based on: (i) A mean field harmonic model for the solvent vibrational (V) force field. (ii) A rigid solvent model treatment of translational–rotational (TR) fluctuations. (iii) Complete neglect of explicit coupling between V and TR fluctuations. (Implicit coupling is included in the vibrational force field.) The model is developed for statics via a sequence of physically motivated approximations to the exact canonical ensemble phase space distribution function of the solvent, fCA[S]. This yields a model distribution function f(0)CA[S] =f(0)CA[pyy]fCA[pww; v0], where f(0)CA[pyy] is an effective harmonic vibrational phase space distribution function which describes mean field harmonic V fluctuations and where f(0)CA[pww; v0] is the rigid solvent canonical ensemble distribution function. The nonequilibrium version of the model is defined as the solvent dynamics generated by a model Liouville operator L(0). This is defined via the model equilibrium Liouville equation L(0)f(0)CA [S]=0. Explicit results for equilibrium averages and time correlation functions of molecular solvents are obtained. The frequency spectra of the time correlation functions contain a low frequency ‘‘acoustic’’ branch arising from solvent TR motions and high frequency ‘‘optical’’ branches arising from collective solvent V motions. A detailed analysis of the frequency spectra of autocorrelation functions of diatomic solvents is presented. [ABSTRACT FROM AUTHOR]

Cholesterol efflux capacity (CEC) is an important measure of high-density lipoprotein (HDL) function and is used as a measure of the ability of HDL to promote cholesterol efflux from macrophages, the first step in reverse cholesterol transport. CEC is inversely related to incident cardiovascular (CV) events and is a predictor of CV disease. CSL112 (apoA-I [human]) is a novel therapy designed to reduce the risk of recurrent CV events following acute myocardial infarction (AMI). CSL112 infusion rapidly and robustly increases CEC when infused in patients post-AMI. It is unknown whether this effect on CEC translates to increased hepatocyte cholesterol uptake, the subsequent step in reverse cholesterol transport. To evaluate whether infusion of CSL112 increases cholesterol uptake by hepatocytes when administered to patients post-AMI. Patients from the AEGIS-I (ApoA-I Event Reducing in Ischemic Syndromes I) study received either placebo, 2 g or 6 g CSL112 post-AMI. Serum samples from a subset of individuals (n=15 per group) were studied ex vivo. Firstly, CEC was assessed using J774 macrophages loaded with labelled [3H] cholesterol tracer. Cholesterol uptake media (200 μL) was then collected and applied to Fu5AH hepatocytes for assessment of labelled cholesterol uptake. A dose-dependent increase in hepatocyte cholesterol uptake was observed following CSL112 infusion, with the 6 g dose inducing a 2.1-fold increase at the end of infusion (2 hours), and sustained elevation above baseline at 24 to 48 hours post-infusion. Hepatocyte cholesterol uptake across all dose groups and timepoints was strongly correlated with total CEC (r=0.949; p<0.001) and plasma apoA-I (r=0.746; p<0.001). A rapid and robust increase in CEC following CSL112 infusion is associated with increased cholesterol uptake into hepatocytes, an important subsequent step in reverse cholesterol transport which precedes cholesterol excretion in bile. The efficacy and safety of CSL112 is currently being investigated in an ongoing Phase 3 study (AEGIS-II; NCT03473223). Yes The study was sponsored by CSL Behring. [ABSTRACT FROM AUTHOR]

The article presents a reprint of the article "RUN, HIDE FIGHT" by Steven A. Adelman, which appeared in a 2016 issue of the journal "Protocol." The article discusses the requirement of active shooter response training and presents examples of tragedies like terrorist attack in Paris, Triangle Shirtwaist Fire in New York, and Beverly Hills Supper Club Fire in Southgate Kentucky. It also describes the needed action that should be taken during emergency situation and ensures public safety.

MDCO-216 is a complex of dimeric ApoA-IMilano and palmitoyl oleoyl phosphatidylcholine (POPC), previously shown to reduce atherosclerotic plaque burden. Here we studied the effect of incubation of human plasma or serum with MDCO-216 on cholesterol efflux capacity from J774 cells, on prebeta-1 high density lipoprotein (prebeta-1 HDL) and on HDL size assessed by proton nuclear magnetic resonance (1H-NMR). MDCO-216 incubated in buffer containing 4% human serum albumin stimulated both ABCA1-mediated efflux and ABCA1-independent cholesterol efflux from J774 macrophages. When incubated with human serum a dose- and time-dependent synergistic increase of the ABCA1-mediated efflux capacity were observed. Using a commercially available ELISA for prebeta-1 HDL, MDCO-216 as such was poorly detected (12-15% of nominal amount of protein). Prebeta-1 HDL was rapidly lost when human plasma alone is incubated at 37°C. In contrast, incubation of human plasma with MDCO-216 at 37°C produced a large amount of new prebeta-1 HDL. Native 2D electrophoresis followed by immunoblotting with an apoA-I antibody, which also detects ApoA-I Milano, confirmed the increase in prebeta-1 HDL upon incubation at 37°C. With the increase of prebeta-1 HDL, the concomitant disappearance of the small alpha-3 and alpha-4 HDL and MDCO-216 and an increase in the large alpha-1 and alpha-2 HDL were observed. Immunoblotting with Mab 17F3 specific for ApoA-I Milano showed the appearance of ApoA-I Milano in alpha-1 and alpha-2, but not in prebeta-1 HDL. 1H-NMR analysis of plasma incubated with MDCO-216 confirmed rapid disappearance of small-sized HDL particles and increase of medium- and large-sized HDL particles accompanied with a decrease in total HDL particle number. In conclusion, incubation of human plasma or serum with MDCO-216 strongly enhanced ABCA1-mediated cholesterol efflux, caused a strong increase of prebeta-1 HDL, and drastically changed the distribution of HDL subpopulations. Overall, the results are in line with the hypothesis that MDCO-216 fuses with small alpha-migrating HDL particles forming larger particles containing both apoA-I WT and ApoA-I Milano, meanwhile liberating the endogenous wild-type apoA-I which enriches prebeta-1 HDL subpopulation. [ABSTRACT FROM AUTHOR]

Endothelial lipase is a phospholipase with activity against high-density lipoprotein. Although a small number of mutations in LIPG have been described, the role of LIPG in protection against atherosclerosis is unclear.We identified 8 loss-of-function (LOF) mutations in LIPG in individuals with high-density lipoprotein cholesterol. Functional analysis confirmed that most rare mutations abolish lipase activity in vitro, indicating complete LOF, whereas 2 more common mutations N396S and R476W reduce activity by ≈50%, indicating partial LOF and implying ≈50% and ≈75% remaining endothelial lipase function in heterozygous complete LOF and partial LOF mutation carriers, respectively. complete LOF mutation carriers had significantly higher plasma high-density lipoprotein cholesterol levels compared with partial LOF mutation carriers. Apolipoprotein B-depleted serum from complete LOF carriers showed significantly enhanced cholesterol efflux acceptor capacity, whereas only trends were observed in partial LOF carriers. Carriers of LIPG mutations exhibited trends toward reduced coronary artery disease in 4 independent cohorts (meta-analysis odds ratio, 0.7; P=0.04).Our data suggest that the impact of LIPG mutations is directly related to their effect on endothelial lipase function and support that antagonism of endothelial lipase function improves cardioprotection. [ABSTRACT FROM AUTHOR]

Current alcohol treatment programs are comprised of a combination of diverse therapeutic modalities. The use of carefully prescribed psychotropic medications is an important treatment component for selected alcoholic patients. The prescription of medication to alcoholics sometimes raises psychodynamic issues which influence the treatment. Identifying these issues may enhance the treatment process for both patlent and doctor. Two case examples which illustrate these points are presented and discussed. [ABSTRACT FROM PUBLISHER]

Background: Potent cholesteryl ester transfer protein (CETP) inhibitors have been shown to substantially increase high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I levels as monotherapy and combined with statins. However, data on the effects of this class of drugs on macrophage cholesterol efflux capacity (CEC), a functional assay that characterizes a key step in the process of reverse cholesterol transport, are limited.Objectives: This study assessed the impact of evacetrapib, statins, or combination therapy on CEC.Methods: We analyzed samples from 377 subjects with elevated low-density lipoprotein cholesterol (LDL-C) or low HDL-C levels who were enrolled in a phase 2 trial of evacetrapib. Percent changes from baseline in CEC (total, non-ABCA1-, and ABCA1-specific) and HDL subpopulations were evaluated after 12 weeks of treatment with placebo, statin monotherapy, evacetrapib monotherapy, or evacetrapib combined with statins. Pre-beta-1 HDL levels were quantified by immunofixation and nondenaturing 2-dimensional gel electrophoresis (2DGE).Results: Relative to placebo, evacetrapib monotherapy increased dose-dependent total and non-ABCA1-specific CEC up to 34% and 47%, respectively. Evacetrapib monotherapy also increased ABCA1-specific CEC up to 26%. Relative to statin monotherapy, evacetrapib with statins also increased total, non-ABCA1-, and ABCA1-specific CEC by 21%, 27%, and 15%, respectively. In contrast, rosuvastatin and simvastatin significantly reduced total and ABCA1-specific CEC, whereas atorvastatin had no significant effect. Consistent with ABCA1-specific CEC, evacetrapib monotherapy and evacetrapib combined with statins significantly increased pre-beta-1 HDL levels as measured by either method.Conclusions: Evacetrapib, as monotherapy and combined with statins, not only increased total CEC, but also increased ABCA1-specific CEC and pre-beta-1 HDL. The mechanisms by which potent CETP inhibition increases ABCA1-specific CEC and pre-beta-1 HDL require further study. (A Study of LY2484595 in Patients With High LDL-C or Low HDL-C; NCT01105975). [ABSTRACT FROM AUTHOR]