90 research outputs found
Characterization of Antiallodynic Actions of ALE-0540, a Novel Nerve Growth Factor Receptor Antagonist, in the Rat1
There is growing evidence that nerve growth factor (NGF) may
function as a mediator of persistent pain states. We have identified
a novel nonpeptidic molecule, ALE-0540, that inhibits the
binding of NGF to tyrosine kinase (Trk) A or both p75 and TrkA
(IC50 5.88 6 1.87 mM, 3.72 6 1.3 mM, respectively), as well as
signal transduction and biological responses mediated by TrkA
receptors. ALE-0540 was tested in models of neuropathic pain
and thermally-induced inflammatory pain, using two routes of
administration, a systemic i.p. and a spinal intrathecal (i.th.)
route. Morphine was also tested for comparison in the antiallodynia
model using mechanical stimuli. We show that either
i.p. or i.th. administration of ALE-0540 in rats produced antiallodynia
in the L5/L6 ligation model of neuropathic pain. The
calculated A50 values (and 95% confidence intervals) for ALE-
0540 administered i.p. and i.th. were 38 (17.5â 83) mg/kg and
34.6 (17.3â 69.4) mg, respectively. ALE-0540 given i.th., at
doses of 30 and 60 mg, also blocked tactile allodynia in the
thermal sensitization model. Although morphine displayed
greater potency [A50 value of 7.1 (5.6â8.8) mg/kg] than ALE-
0540 in anti-allodynic effect when given i.p. to L5/L6-ligated
rats, it was not active when administered i.th. These data
suggest that a blockade of NGF bioactivity using a NGF receptor
antagonist is capable of blocking neuropathic and inflammatory
pain and further support the hypothesis that NGF is
involved in signaling pathways associated with these pain
states. ALE-0540 represents a nonpeptidic small molecule
which can be used to examine mechanisms leading to the
development of agents for the treatment of pain
Smooth 2D Coordinate Systems on Discrete Surfaces
International audienceWe introduce a new method to compute conformal param- eterizations using a recent definition of discrete conformity, and estab- lish a discrete version of the Riemann mapping theorem. Our algorithm can parameterize triangular, quadrangular and digital meshes. It can be adapted to preserve metric properties. To demonstrate the efficiency of our method, many examples are shown in the experiment section
The geometry of a vorticity model equation
We provide rigorous evidence of the fact that the modified
Constantin-Lax-Majda equation modeling vortex and quasi-geostrophic dynamics
describes the geodesic flow on the subgroup of orientation-preserving
diffeomorphisms fixing one point, with respect to right-invariant metric
induced by the homogeneous Sobolev norm and show the local existence
of the geodesics in the extended group of diffeomorphisms of Sobolev class
with .Comment: 24 page
Recurrent intragenic rearrangements of EGFR and BRAF in soft tissue tumors of infants.
Soft tissue tumors of infancy encompass an overlapping spectrum of diseases that pose unique diagnostic and clinical challenges. We studied genomes and transcriptomes of cryptogenic congenital mesoblastic nephroma (CMN), and extended our findings to five anatomically or histologically related soft tissue tumors: infantile fibrosarcoma (IFS), nephroblastomatosis, Wilms tumor, malignant rhabdoid tumor, and clear cell sarcoma of the kidney. A key finding is recurrent mutation of EGFR in CMN by internal tandem duplication of the kinase domain, thus delineating CMN from other childhood renal tumors. Furthermore, we identify BRAF intragenic rearrangements in CMN and IFS. Collectively these findings reveal novel diagnostic markers and therapeutic strategies and highlight a prominent role of isolated intragenic rearrangements as drivers of infant tumors
The Astrocyte-Targeted Therapy by Bushi for the Neuropathic Pain in Mice
BACKGROUND: There is accumulating evidence that the activation of spinal glial cells, especially microglia, is a key event in the pathogenesis of neuropathic pain. However, the inhibition of microglial activation is often ineffective, especially for long-lasting persistent neuropathic pain. So far, neuropathic pain remains largely intractable and a new therapeutic strategy for the pain is still required. METHODS/PRINCIPAL FINDINGS: Using Seltzer model mice, we investigated the temporal aspect of two types of neuropathic pain behaviors, i.e., thermal hyperalgesia and mechanical allodynia, as well as that of morphological changes in spinal microglia and astrocytes by immunohistochemical studies. Firstly, we analyzed the pattern of progression in the pain behaviors, and found that the pain consisted of an "early induction phase" and subsequent "late maintenance phase". We next analyzed the temporal changes in spinal glial cells, and found that the induction and the maintenance phase of pain were associated with the activation of microglia and astrocytes, respectively. When Bushi, a Japanese herbal medicine often used for several types of persistent pain, was administered chronically, it inhibited the maintenance phase of pain without affecting the induction phase, which was in accordance with the inhibition of astrocytic activation in the spinal cord. These analgesic effects and the inhibition of astrocytic activation by Bushi were mimicked by the intrathecal injection of fluorocitrate, an inhibitor of astrocytic activation. Finally, we tested the direct effect of Bushi on astrocytic activation, and found that Bushi suppressed the IL-1ÎČ- or IL-18-evoked ERK1/2-phosphorylation in cultured astrocytes but not the ATP-evoked p38- and ERK1/2-phosphorylation in microglia in vitro. CONCLUSIONS: Our results indicated that the activation of spinal astrocytes was responsible for the late maintenance phase of neuropathic pain in the Seltzer model mice and, therefore, the inhibition of astrocytic activation by Bushi could be a useful therapeutic strategy for treating neuropathic pain
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