70 research outputs found
Latent cluster analysis of ALS phenotypes identifies prognostically differing groups
BACKGROUND
Amyotrophic lateral sclerosis (ALS) is a degenerative disease predominantly affecting motor neurons and manifesting as several different phenotypes. Whether these phenotypes correspond to different underlying disease processes is unknown. We used latent cluster analysis to identify groupings of clinical variables in an objective and unbiased way to improve phenotyping for clinical and research purposes.
METHODS
Latent class cluster analysis was applied to a large database consisting of 1467 records of people with ALS, using discrete variables which can be readily determined at the first clinic appointment. The model was tested for clinical relevance by survival analysis of the phenotypic groupings using the Kaplan-Meier method.
RESULTS
The best model generated five distinct phenotypic classes that strongly predicted survival (p<0.0001). Eight variables were used for the latent class analysis, but a good estimate of the classification could be obtained using just two variables: site of first symptoms (bulbar or limb) and time from symptom onset to diagnosis (p<0.00001).
CONCLUSION
The five phenotypic classes identified using latent cluster analysis can predict prognosis. They could be used to stratify patients recruited into clinical trials and generating more homogeneous disease groups for genetic, proteomic and risk factor research
In Vivo Imaging Reveals Distinct Inflammatory Activity of CNS Microglia versus PNS Macrophages in a Mouse Model for ALS
Mutations in the enzyme superoxide dismutase-1 (SOD1) cause hereditary variants
of the fatal motor neuronal disease Amyotrophic lateral sclerosis (ALS).
Pathophysiology of the disease is non-cell-autonomous: neurotoxicity is derived
not only from mutant motor neurons but also from mutant neighbouring
non-neuronal cells. In vivo imaging by two-photon
laser-scanning microscopy was used to compare the role of
microglia/macrophage-related neuroinflammation in the CNS and PNS using
ALS-linked transgenic SOD1G93A mice. These mice contained labeled
projection neurons and labeled microglia/macrophages. In the affected lateral
spinal cord (in contrast to non-affected dorsal columns), different phases of
microglia-mediated inflammation were observed: highly reactive microglial cells
in preclinical stages (in 60-day-old mice the reaction to axonal transection was
∼180% of control) and morphologically transformed microglia that have
lost their function of tissue surveillance and injury-directed response in
clinical stages (reaction to axonal transection was lower than 50% of
control). Furthermore, unlike CNS microglia, macrophages of the PNS lack any
substantial morphological reaction while preclinical degeneration of peripheral
motor axons and neuromuscular junctions was observed. We present in
vivo evidence for a different inflammatory activity of microglia
and macrophages: an aberrant neuroinflammatory response of microglia in the CNS
and an apparently mainly neurodegenerative process in the PNS
Benchmark thermochemistry of the C_nH_{2n+2} alkane isomers (n=2--8) and performance of DFT and composite ab initio methods for dispersion-driven isomeric equilibria
The thermochemistry of linear and branched alkanes with up to eight carbons
has been reexamined by means of W4, W3.2lite and W1h theories. `Quasi-W4'
atomization energies have been obtained via isodesmic and hypohomodesmotic
reactions. Our best atomization energies at 0 K (in kcal/mol) are: 1220.04
n-butane, 1497.01 n-pentane, 1774.15 n-hexane, 2051.17 n-heptane, 2328.30
n-octane, 1221.73 isobutane, 1498.27 isopentane, 1501.01 neopentane, 1775.22
isohexane, 1774.61 3-methylpentane, 1775.67 diisopropyl, 1777.27 neohexane,
2052.43 isoheptane, 2054.41 neoheptane, 2330.67 isooctane, and 2330.81
hexamethylethane. Our best estimates for are: -30.00
n-butane, -34.84 n-pentane, -39.84 n-hexane, -44.74 n-heptane, -49.71 n-octane,
-32.01 isobutane, -36.49 isopentane, -39.69 neopentane, -41.42 isohexane,
-40.72 3-methylpentane, -42.08 diisopropyl, -43.77 neohexane, -46.43
isoheptane, -48.84 neoheptane, -53.29 isooctane, and -53.68 hexamethylethane.
These are in excellent agreement (typically better than 1 kJ/mol) with the
experimental heats of formation at 298 K obtained from the CCCBDB and/or NIST
Chemistry WebBook databases. However, at 0 K a large discrepancy between theory
and experiment (1.1 kcal/mol) is observed for only neopentane. This deviation
is mainly due to the erroneous heat content function for neopentane used in
calculating the 0 K CCCBDB value. The thermochemistry of these systems,
especially of the larger alkanes, is an extremely difficult test for density
functional methods. A posteriori corrections for dispersion are essential.
Particularly for the atomization energies, the B2GP-PLYP and B2K-PLYP
double-hybrids, and the PW6B95 hybrid-meta GGA clearly outperform other DFT
functionals.Comment: (J. Phys. Chem. A, in press
Major histocompatibility complex class I molecules protect motor neurons from astrocyte-induced toxicity in amyotrophic lateral sclerosis
Astrocytes isolated from individuals with amyotrophic lateral sclerosis (ALS) are toxic to motor neurons (MNs) and play a non–cell autonomous role in disease pathogenesis. The mechanisms underlying the susceptibility of MNs to cell death remain unclear. Here we report that astrocytes derived from either mice bearing mutations in genes associated with ALS or human subjects with ALS reduce the expression of major histocompatibility complex class I (MHCI) molecules on MNs; reduced MHCI expression makes these MNs susceptible to astrocyte-induced cell death. Increasing MHCI expression on MNs increases survival and motor performance in a mouse model of ALS and protects MNs against astrocyte toxicity. Overexpression of a single MHCI molecule, HLA-F, protects human MNs from ALS astrocyte–mediated toxicity, whereas knockdown of its receptor, the killer cell immunoglobulin-like receptor KIR3DL2, on human astrocytes results in enhanced MN death. Thus, our data indicate that, in ALS, loss of MHCI expression on MNs renders them more vulnerable to astrocyte-mediated toxicity
Avaliação do impacto de uma exposição cientÃfica itinerante em uma região carente do Rio de Janeiro: um estudo de caso
Constitution of ethnozoological semantic domains: meaning and inclusiveness of the lexeme "insect" for the inhabitants of the county of Pedra Branca, Bahia State, Brazil
Efficiency of estimation of anisotropic texture orientation on the basis of a gradient structure tensor
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