187 research outputs found
Revealing the therapeutic potential of botulinum neurotoxin type a in counteracting paralysis and neuropathic pain in spinally injured mice
Botulinum neurotoxin type A (BoNT/A) is a major therapeutic agent that has been proven to be a successful treatment for different neurological disorders, with emerging novel therapeutic indications each year. BoNT/A exerts its action by blocking SNARE complex formation and vesicle release through the specific cleavage of SNAP-25 protein; the toxin is able to block the release of pro-inflammatory molecules for months after its administration. Here we demonstrate the extraordinary capacity of BoNT/A to neutralize the complete paralysis and pain insensitivity induced in a murine model of severe spinal cord injury (SCI). We show that the toxin, spinally administered within one hour from spinal trauma, exerts a long-lasting proteolytic action, up to 60 days after its administration, and induces a complete recovery of muscle and motor function. BoNT/A modulates SCI-induced neuroglia hyperreactivity, facilitating axonal restoration, and preventing secondary cells death and damage. Moreover, we demonstrate that BoNT/A affects SCI-induced neuropathic pain after moderate spinal contusion, confirming its anti-nociceptive action in this kind of pain, as well. Our results provide the intriguing and real possibility to identify in BoNT/A a therapeutic tool in counteracting SCI-induced detrimental effects. Because of the well-documented BoNT/A pharmacology, safety, and toxicity, these findings strongly encourage clinical translation
Sphincter preservation in patients with low rectal cancer: striking the right oncological balance
Background:
The surgical treatment options for low rectal cancer patients include the Abdominoperineal Resection and the sphincter saving Low Anterior Resection. There is growing evidence towards better outcomes for patients being treated with a Low Anterior Resection compared to an Abdominoperineal Resection.
Objective:
The aim of this study was to evaluate the short term and oncological outcomes in low rectal cancer treatment.
Design:
This is a retrospective cohort study of prospectively collected data.
Setting:
Rectal cancer patients from a single center in the United Kingdom.
Patients:
Patients included all low rectal cancer patients (≤ 6 cm from the anal verge) undergoing Low Anterior Resection or Abdominoperineal Resection between 2006 and 2016.
Outcome measures:
To identify differences in postoperative complications and disease free and overall survival.
Results:
A total of 262 patients were included for analysis (Low Anterior Resection n = 170, Abdominoperineal Resection n = 92). Abdominoperineal Resection patients were significantly older (69 versus 66 years), had lower tumours (3 versus 5 cm), received more neo-adjuvant radiation, had longer hospital stay and more complications (wound infections and wound dehiscence). Low Anterior Resections had a significantly higher number of harvested lymph nodes (17 versus 12) however there was no difference in nodal involvement and R0 resection rate. No significant difference was found for recurrence, overall survival and disease free survival.
Limitation:
Retrospective review of cancer database and single center data.
Conclusion:
In the treatment of low rectal cancer Abdominoperineal Resection is associated with higher rates of postoperative complications and longer hospital stay compared to the Low Anterior Resection, with similar oncological outcomes
Tyr682 in the Aβ-precursor protein intracellular domain regulates synaptic connectivity, cholinergic function, and cognitive performance.
Processing of Aβ-precursor protein (APP) plays an important role in Alzheimer's disease (AD) pathogenesis. The APP intracellular domain contains residues important in regulating APP function and processing, in particular the 682YENPTY687 motif. To dissect the functions of this sequence in vivo, we created an APP knock-in allele mutating Y682 to Gly (APP(YG/YG) mice). This mutation alters the processing of APP and TrkA signaling and leads to postnatal lethality and neuromuscular synapse defects when expressed on an APP-like protein 2 KO background. This evidence prompted us to characterize further the APP(YG/YG) mice. Here, we show that APP(YG/YG) mice develop aging-dependent decline in cognitive and neuromuscular functions, a progressive reduction in dendritic spines, cholinergic tone, and TrkA levels in brain regions governing cognitive and motor functions. These data are consistent with our previous findings linking NGF and APP signaling and suggest a causal relationship between altered synaptic connectivity, cholinergic tone depression and TrkA signaling deficit, and cognitive and neuromuscular decline in APP(YG/YG) mice. The profound deficits caused by the Y682 mutation underscore the biological importance of APP and indicate that APP(YG/YG) are a valuable mouse model to study APP functions in physiological and pathological processes
Study of single muons with the Large Volume Detector at Gran Sasso Laboratory
The present study is based on the sample of about 3 mln single muons observed
by LVD at underground Gran Sasso Laboratory during 36500 live hours from June
1992 to February 1998. We have measured the muon intensity at slant depths from
3 km w.e. to 20 km w.e. Most events are high energy downward muons produced by
meson decay in the atmosphere. The analysis of these muons has revealed the
power index of pion and kaon spectrum: 2.76 \pm 0.05. The reminders are
horizontal muons produced by the neutrino interactions in the rock surrounding
LVD. The value of this flux is obtained. The results are compared with Monte
Carlo simulations and the world data.Comment: 13 pages, 2 figures, accepted for publication in "Physics of Atomic
Nuclei
Muon `Depth -- Intensity' Relation Measured by LVD Underground Experiment and Cosmic-Ray Muon Spectrum at Sea Level
We present the analysis of the muon events with all muon multiplicities
collected during 21804 hours of operation of the first LVD tower. The measured
angular distribution of muon intensity has been converted to the `depth --
vertical intensity' relation in the depth range from 3 to 12 km w.e.. The
analysis of this relation allowed to derive the power index, , of the
primary all-nucleon spectrum: . The `depth -- vertical
intensity' relation has been converted to standard rock and the comparison with
the data of other experiments has been done. We present also the derived
vertical muon spectrum at sea level.Comment: 7 pages, 3 figures, to be published on Phys. Rev.
Upper Limit on the Prompt Muon Flux Derived from the LVD Underground Experiment
We present the analysis of the muon events with all muon multiplicities
collected during 21804 hours of operation of the first LVD tower. The measured
depth-angular distribution of muon intensities has been used to obtain the
normalization factor, A, the power index, gamma, of the primary all-nucleon
spectrum and the ratio, R_c, of prompt muon flux to that of pi-mesons - the
main parameters which determine the spectrum of cosmic ray muons at the sea
level. The value of gamma = 2.77 +/- 0.05 (68% C.L.) and R_c < 2.0 x 10^-3 (95%
C.L.) have been obtained. The upper limit to the prompt muon flux favours the
models of charm production based on QGSM and the dual parton model.Comment: 10 pages, 4 figures, RevTex. To appear in Phys. Rev.
Multiplicity Studies and Effective Energy in ALICE at the LHC
In this work we explore the possibility to perform ``effective energy''
studies in very high energy collisions at the CERN Large Hadron Collider (LHC).
In particular, we focus on the possibility to measure in collisions the
average charged multiplicity as a function of the effective energy with the
ALICE experiment, using its capability to measure the energy of the leading
baryons with the Zero Degree Calorimeters. Analyses of this kind have been done
at lower centre--of--mass energies and have shown that, once the appropriate
kinematic variables are chosen, particle production is characterized by
universal properties: no matter the nature of the interacting particles, the
final states have identical features. Assuming that this universality picture
can be extended to {\it ion--ion} collisions, as suggested by recent results
from RHIC experiments, a novel approach based on the scaling hypothesis for
limiting fragmentation has been used to derive the expected charged event
multiplicity in interactions at LHC. This leads to scenarios where the
multiplicity is significantly lower compared to most of the predictions from
the models currently used to describe high energy collisions. A mean
charged multiplicity of about 1000-2000 per rapidity unit (at ) is
expected for the most central collisions at .Comment: 12 pages, 19 figures. In memory of A. Smirnitski
The INFN-grid testbed
The Italian INFN-Grid Project is committed to set-up, run and manage an unprecedented nation-wide Grid infrastructure. The implementation and use of this INFN-Grid Testbed is presented and discussed. Particular care and attention are devoted to those activities, relevant for the management of the Testbed, carried out by the INFN within international Grid Projects
Central Action of Peripherally Applied Botulinum Toxin Type A on Pain and Dural Protein Extravasation in Rat Model of Trigeminal Neuropathy
BACKGROUND:
Infraorbital nerve constriction (IoNC) is an experimental model of trigeminal neuropathy. We investigated if IoNC is accompanied by dural extravasation and if botulinum toxin type A (BoNT/A) can reduce pain and dural extravasation in this model. ----- METHODOLOGY/PRINCIPAL FINDINGS:
Rats which developed mechanical allodynia 14 days after the IoNC were injected with BoNT/A (3.5 U/kg) into vibrissal pad. Allodynia was tested by von Frey filaments and dural extravasation was measured as colorimetric absorbance of Evans blue - plasma protein complexes. Presence of dural extravasation was also examined in orofacial formalin-induced pain. Unilateral IoNC, as well as formalin injection, produced bilateral dural extravasation. Single unilateral BoNT/A injection bilaterally reduced IoNC induced dural extravasation, as well as allodynia (lasting more than 2 weeks). Similarly, BoNT/A reduced formalin-induced pain and dural extravasation. Effects of BoNT/A on pain and dural extravasation in IoNC model were dependent on axonal transport through sensory neurons, as evidenced by colchicine injections (5 mM, 2 µl) into the trigeminal ganglion completely preventing BoNT/A effects. ----- CONCLUSIONS/SIGNIFICANCE:
Two different types of pain, IoNC and formalin, are accompanied by dural extravasation. The lasting effect of a unilateral injection of BoNT/A in experimental animals suggests that BoNT/A might have a long-term beneficial effect in craniofacial pain associated with dural neurogenic inflammation. Bilateral effects of BoNT/A and dependence on retrograde axonal transport suggest a central site of its action
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