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Amyotrophic lateral sclerosis (ALS) is a clinical diagnosis used to define a neurodegenerative process that involves progressive loss of voluntary muscle function and leads to death within 2-5 years after diagnosis, in most cases because of respiratory function failure. Respiratory vital capacity (VC) measurements are reproducible and strong predictors of survival. To understand the role of the innate immune response in progressive VC loss we evaluated ALS clinical trial and biomarker results from a 6-month phase 2 study of NP001, a regulator of innate immune function. All ALS baseline values were similar between treated and controls except for those > 65 years old who were excluded from analysis. Treated patients with plasma CRP ≥ 1.13 mg/L (high CRP) showed a 64% slower rate of VC decline compared with placebo and those with plasma CRP < 1.13 mg/L (low CRP) who showed no response. High CRP patients showed no age associated loss of VC whereas low CRP patients showed an age dependent loss of VC function. Plasma levels of serum amyloid A (SAA) were similarly elevated in high CRP patients consistent with ongoing innate immune activation. Plasma TGFB1 in high CRP treated patients was 95% higher than placebo at 6-months, confirming the activation and release of this anti-inflammatory factor by the innate immune alpha 2 macroglobulin (A2M) system. This report is the first to link a biomarker confirmed regulation of the innate immune system with a therapeutic approach for controlling VC loss in ALS patients.

Amyotrophic lateral sclerosis (ALS) is a heterogeneous, progressive, and universally fatal neurodegenerative disease. A subset of ALS patients has measurable plasma levels of lipopolysaccharide (LPS) and C-reactive protein (CRP) consistent with low-grade microbial translocation (MT). Unless interrupted, MT sets up a self-perpetuating loop of inflammation associated with systemic macrophage activation. To test whether MT contributed to ALS progression, blood specimens from a phase 2 study of NP001 in ALS patients were evaluated for changes in activity in treated patients as compared to controls over the 6-month study. In this post hoc analysis, plasma specimens from baseline and six-month timepoints were analyzed. Compared with baseline values, biomarkers related to MT were significantly decreased (LPS, LPS binding protein (LBP), IL-18, Hepatocyte growth factor (HGF), soluble CD163 (sCD163)) in NP001-treated patients as compared to controls, whereas wound healing and immunoregulatory factors were increased (IL-10, Epidermal growth factor (EGF), neopterin) by the end of study. These biomarker results linked to the positive clinical trial outcome confirm that regulation of macrophage activation may be an effective approach for the treatment of ALS and, potentially, other neuroinflammatory diseases related to MT.

OBJECTIVE. The goal was to evaluate the safety, tolerability, and efficacy of an investigational, refrigerator-stable formulation of live attenuated influenza vaccine (cold-adapted influenza vaccine-trivalent) against culture-confirmed influenza, acute otitis media, and effectiveness outcomes in young children in day care over 2 consecutive influenza seasons. METHODS. Children 6 to RESULTS. A total of 1616 subjects (vaccine: 951 subjects; placebo: 665 subjects) in year 1 and 1090 subjects (vaccine: 640 subjects; placebo: 450 subjects) in year 2 were able to be evaluated for efficacy. The mean age at first vaccination was 23.4 [+ or -] 7.9 months. In year 1, the overall efficacy of the vaccine against influenza subtypes similar to the vaccine was 85.4%; efficacy was 91.8% against A/H1N1 and 72.6% against B. In year 2, the overall efficacy was 88.7%; efficacy was 90.0% against H1N1, 90.3% against A/H3N2, and 81.7% against B. Efficacy against all episodes of acute otitis media associated with culture-confirmed influenza was 90.6% in year 1 and 97.0% in year 2. Runny nose or nasal discharge after dose 1 in year 1 was the only reactogenicity event that was significantly more frequent with cold-adapted influenza vaccine-trivalent (82.3%) than placebo (75.4%). Key Words influenza, cold-adapted influenza vaccine-trivalent, children CONCLUSIONS. Cold-adapted influenza vaccine-trivalent was well tolerated and effective in preventing culture-confirmed influenza illness in children as young as 6 months of age who attended day care., INFLUENZA IS A major cause of serious respiratory illness and acute otitis media (AOM) in young children and is associated with significant public health and socioeconomic burdens through excess hospitalizations, [...]

An exercise to stimulate students to consider the problems faced by organisms inhabiting different environments and the solutions that have arisen through natural selection is presented. Many aspects of biology and ecology outlining the way organisms adapt to the environment are discussed.

We examine the vibrational density of states of atomistic models of polypropylene glasses containing a single impurity molecule of s-tetrazine. We discuss existing methods and develop new ones to achieve significant data reduction and navigate through the complex spectrum of the normal modes of the glass. By calculating the participation ratio, the distribution of the kinetic energy of each mode on the atomic coordinates, and a mode-proximity index to the solute it is possible to identify impurity-related, polymer-related, and mixed modes and assess their relative contributions to the vibrational density of states. Activation of specific modes using molecular dynamics allows the observation of anharmonicities in the doped glass, even at very low temperatures. © 1996 American Institute of Physics. [ABSTRACT FROM AUTHOR]

An effective-potential approach is presented for improving sampling efficiency in simulations of atomistically detailed models of dense long-chain liquids. The motion of atoms on short-time scales is described as rapid fluctuations about the slowly moving mean conformations of the chain molecules. The distribution of these fluctuations is approximated by that of isotropic elastic motion. The interactions between nonbonded pairs of atoms are preaveraged over this distribution and a much softer, effective interaction is obtained, allowing a correspondingly faster exploration of configuration space. The approximate sampling scheme is then tested on two model systems of united-atom liquid hydrocarbons—a melt of twenty C24 chains and one of ten C71 chains. In the C24 melt, where a comparison with fully equilibrated samples from rigorous algorithms is possible, the preaveraging is shown to produce an improvement in sampling efficiency of up to an order of magnitude at the expense of only a moderate loss in accuracy. The method is then applied to the C71 melt, where currently available, rigorous sampling algorithms fail to produce thorough equilibration. Also in this case, the preaveraging method proves to significantly enhance the sampling speed while producing satisfactory distributions of observables. © 1995 American Institute of Physics. [ABSTRACT FROM AUTHOR]