Purpose
The formalin-induced rat model of nociception involves moderate continuous pain. Formalin-induced pain results in a typical repetitive flinching behaviour, which displays a biphasic pattern ...characterised by peaks of pain. Here we described the time course of pain response and the analgesic effect of gabapentin using a semi-mechanistic modelling approach.
Methods
Male Sprague-Dawley rats received gabapentin (10–100 mg/kg) or placebo 1 h prior to the formalin injection, as per standard protocol. A reduction in the frequency of the second peak of flinching was used as a behavioural measure of gabapentin-mediated anti-nociception. The flinching response was modelled using a mono-exponential function to characterise the first peak and an indirect response model with a time variant synthesis rate for the second. PKPD modelling was performed using a population approach in NONMEM v.7.1.2.
Results
The time course of the biphasic response was adequately described by the proposed model, which included separate expressions for each phase. Gabapentin was found to reversibly decrease, but not suppress the flinching frequency of the second response peak only. The mean IC
50
estimate was 7,510 ng/ml, with relative standard error (RSE%) of 40%.
Conclusions
A compartmental, semi-mechanistic model provides the basis for further understanding of the formalin-induced flinching response and consequently to better characterisation of the properties of gabapentin, such as the potency in individual animals. Moreover, despite high exposure levels, model predictions show that gabapentin does not completely suppress behavioural response in the formalin-induced pain model.
The CYGNO project aims to study rare events, as low-mass (few GeV) Dark Matter (DM) particle or solar neutrino interactions, exploiting the approach of the optical readout of the scintillation light ...produced in the amplification in a multiple Gas Electron Multiplier (GEM) structure, of the primary ionization originated in large volume Time Projection Chamber (TPCs).
The volume is filled with an He:CF4 gas mixture at atmospheric pressure. The 3D topology, and therefore direction of the recoils, is reconstructed thanks to the combined use of high-granularity, high sensitivity sCMOS cameras, for the precise tracking of the projection of the recoils on the GEM plane, and of fast light sensors in order to obtain the coordinate perpendicular to the camera plane.
To conclude the R&D phase, the 50 L prototype, called Long Imaging ModulE (LIME), was moved underground at the Laboratori Nazionali del Gran Sasso (LNGS) in order to study the performance of the CYGNO experimental approach in a low background environment and to assess the contributions to the background from different sources, also comparing with Monte Carlo simulations.
Stability studies and the effects of environmental condition on the light yield will be discussed, focusing on the effect of humidity on the detector response and stability amount and rate of self-sustaining micro-discharges. This is a crucial step towards the development of a large demonstrator.
•A TPC filled with a gas mixture based on light atoms as target.•The combined usage of PMTs and sCMOS camera enables the 3D tracks reconstruction.•Studies on the effects of environmental condition on the light yield.
The CYGNO project aims at the development of a high precision optical readout gaseous Tima Projection Chamber (TPC) for directional dark matter (DM) searches, to be hosted at Laboratori Nazionali del ...Gran Sasso (LNGS). CYGNO employs a He:CF\(_4\) gas mixture at atmospheric pressure with a Gas Electron Multiplier (GEM) based amplification structure coupled to an optical readout comprised of sCMOS cameras and photomultiplier tubes (PMTs). This experimental setup allows to achieve 3D tracking and background rejection down to O(1) keV energy, to boost sensitivity to low WIMP masses. The characteristics of the optical readout approach in terms of the light yield will be illustrated along with the particle identification properties. The project timeline foresees, in the next 2-3 years, the realisation and installation of a 0.4 m\(^3\) TPC in the underground laboratories at LNGS to act as a demonstrator. Finally, the studies of the expected DM sensitivities of the CYGNO demonstrator will be presented.
The CYGNO experiment aims to build a large ($\mathcal{O}(10)$ m$^3$)
directional detector for rare event searches, such as nuclear recoils (NRs)
induced by dark matter (DM), such as weakly ...interactive massive particles
(WIMPs). The detector concept comprises a time projection chamber (TPC), filled
with a He:CF$_4$ 60/40 scintillating gas mixture at room temperature and
atmospheric pressure, equipped with an amplification stage made of a stack of
three gas electron multipliers (GEMs) which are coupled to an optical readout.
The latter consists in scientific CMOS (sCMOS) cameras and photomultipliers
tubes (PMTs). The maximisation of the light yield of the amplification stage
plays a major role in the determination of the energy threshold of the
experiment. In this paper, we simulate the effect of the addition of a strong
electric field below the last GEM plane on the GEM field structure and we
experimentally test it by means of a 10$\times$10 cm$^2$ readout area
prototype. The experimental measurements analyse stacks of different GEMs and
helium concentrations in the gas mixture combined with this extra electric
field, studying their performances in terms of light yield, energy resolution
and intrinsic diffusion. It is found that the use of this additional electric
field permits large light yield increases without degrading intrinsic
characteristics of the amplification stage with respect to the regular use of
GEMs.
The CYGNO collaboration is developing next generation directional Dark Matter
(DM) detection experiments, using gaseous Time Projection Chambers (TPCs), as a
robust method for identifying Weakly ...Interacting Massive Particles (WIMPs)
below the Neutrino Fog. SF6 is potentially ideal for this since it provides a
high fluorine content, enhancing sensitivity to spin-dependent interactions
and, as a Negative Ion Drift (NID) gas, reduces charge diffusion leading to
improved positional resolution. CF4, although not a NID gas, has also been
identified as a favourable gas target as it provides a scintillation signal
which can be used for a complimentary light/charge readout approach. These
gases can operate at low pressures to elongate Nuclear Recoil (NR) tracks and
facilitate directional measurements. In principle, He could be added to low
pressure SF6/CF4 without significant detriment to the length of 16S, 12C, and
19F recoils. This would improve the target mass, sensitivity to lower WIMP
masses, and offer the possibility of atmospheric operation; potentially
reducing the cost of a containment vessel. In this article, we present gas gain
and energy resolution measurements, taken with a Multi-Mesh Thick Gaseous
Electron Multiplier (MMThGEM), in low pressure SF6 and CF4:SF6 mixtures
following the addition of He. We find that the CF4:SF6:He mixtures tested were
able to produce gas gains on the order of 10^4 up to a total pressure of 100
Torr. These results demonstrate an order of magnitude improvement in charge
amplification in NID gas mixtures with a He component.
The CYGNO experiment aims to build a large (\(\mathcal{O}(10)\) m\(^3\)) directional detector for rare event searches, such as nuclear recoils (NRs) induced by dark matter (DM), such as weakly ...interactive massive particles (WIMPs). The detector concept comprises a time projection chamber (TPC), filled with a He:CF\(_4\) 60/40 scintillating gas mixture at room temperature and atmospheric pressure, equipped with an amplification stage made of a stack of three gas electron multipliers (GEMs) which are coupled to an optical readout. The latter consists in scientific CMOS (sCMOS) cameras and photomultipliers tubes (PMTs). The maximisation of the light yield of the amplification stage plays a major role in the determination of the energy threshold of the experiment. In this paper, we simulate the effect of the addition of a strong electric field below the last GEM plane on the GEM field structure and we experimentally test it by means of a 10\(\times\)10 cm\(^2\) readout area prototype. The experimental measurements analyse stacks of different GEMs and helium concentrations in the gas mixture combined with this extra electric field, studying their performances in terms of light yield, energy resolution and intrinsic diffusion. It is found that the use of this additional electric field permits large light yield increases without degrading intrinsic characteristics of the amplification stage with respect to the regular use of GEMs.
Guidelines tend to consider morphine and morphine-like opioids comparable and interchangeable in the treatment of chronic cancer pain, but individual responses can vary. This study compared the ...analgesic efficacy, changes of therapy and safety profile over time of four strong opioids given for cancer pain.
In this four-arm multicenter, randomized, comparative, of superiority, phase IV trial, oncological patients with moderate to severe pain requiring WHO step III opioids were randomly assigned to receive oral morphine or oxycodone or transdermal fentanyl or buprenorphine for 28 days. At each visit, pain intensity, modifications of therapy and adverse drug reactions (ADRs) were recorded. The primary efficacy end point was the proportion of nonresponders, meaning patients with worse or unchanged average pain intensity (API) between the first and last visit, measured on a 0–10 numerical rating scale. (NCT01809106).
Forty-four centers participated in the trial and recruited 520 patients. Worst pain intensity and API decreased over 4 weeks with no significant differences between drugs. Nonresponders ranged from 11.5% (morphine) to 14.4% (buprenorphine). Appreciable changes were made in the treatment schedules over time. Each group required increases in the daily dose, from 32.7% (morphine) to 121.2% (transdermal fentanyl). Patients requiring adjuvant analgesics ranged from 68.9% (morphine) to 81.6% (oxycodone), switches varied from 22.1% (morphine) to 12% (oxycodone), discontinuation of treatment from 27% ( morphine) to 14.5% (fentanyl). ADRs were similar except for effects on the nervous system, which significantly prevailed with morphine.
The main findings were the similarity in pain control, response rates and main adverse reactions among opioids. Changes in therapy schedules were notable over time. A considerable proportion of patients were nonresponders or poor responders.
NCT01809106 (https://clinicaltrials.gov/ct2/show/NCT01809106?term=cerp&rank=2).
The pathophysiology of fibromyalgia syndrome (FMS) remains elusive, leading to a lack of objective diagnostic criteria and targeted treatment. We globally evaluated immune system changes in FMS by ...conducting multiparametric flow cytometry analyses of peripheral blood mononuclear cells and identified a natural killer (NK) cell decrease in patients with FMS. Circulating NK cells in FMS were exhausted yet activated, evidenced by lower surface expression of CD16, CD96, and CD226 and more CD107a and TIGIT. These NK cells were hyperresponsive, with increased CCL4 production and expression of CD107a when co-cultured with human leukocyte antigen null target cells. Genetic and transcriptomic pathway analyses identified significant enrichment of cell activation pathways in FMS driven by NK cells. Skin biopsies showed increased expression of NK activation ligand, unique long 16-binding protein, on subepidermal nerves of patients FMS and the presence of NK cells near peripheral nerves. Collectively, our results suggest that chronic activation and redistribution of circulating NK cells to the peripheral nerves contribute to the immunopathology associated with FMS.
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