Functional Evaluation of the Visual Pathway in Patients with Multiple Sclerosis Using a Multifunction Stimulator Monitor

Objectives. To assess the capability of the vision monitor unit Monpack One of detecting visual function alterations in patients with multiple sclerosis (MS) and to evaluate the correlation between structural retinal parameters and functional measurements obtained with this device. Methods. Forty-eight patients with MS and 46 healthy controls were included in a cross-sectional study. All participants underwent a complete functional evaluation of the visual pathway, which included low-contrast visual acuity (LCVA), contrast sensitivity vision (CSV), automated perimetry, multifocal visual evoked potentials (mfVEPs), and pattern electroretinogram (ERG). All tests were performed using the vision monitor unit Monpack One (Metrovision, France), a multifunction stimulator device. Retinal structural measurements were obtained in all subjects using Triton swept source optical coherence tomography (Topcon, Japan). Results. Patients with MS presented reduced low-contrast VA (p<0.001) and reduced CSV at medium (p=0.001, p=0.013) and low (p=0.001, p=0.002) spatial frequencies. All visual field parameters were found to be altered in MS patients compared with controls (<= 0.001). Patients with MS presented lower amplitude of the P100 waveform of the mfVEP in areas corresponding to central (p<0.001), inferonasal (p=0.001), and inferotemporal (p=0.003) retina. The pattern ERG did not show significant differences. Significant correlations were observed between structural retinal measurements and functional parameters, especially between the inner macular areas and measurements corresponding to contrast sensitivity and perimetry indexes. Conclusions. Patients with MS present visual dysfunction detectable with the vision monitor unit Monpack One. This device may be a fast and useful tool to provide a full evaluation of axonal damage in patients with multiple sclerosis

Azonia derivatives of the γ-carboline system. A new class of DNA intercalators

1-Methyl-γ-carboline derivatives were transformed into the corresponding N-aminoazinium salts, which were condensed with 1,2-dicarbonyl compounds (Westphal reaction) to afford azonia derivatives with a bridgehead quaternary nitrogen atom. Some of them show DNA intercalating properties.Instituto de Qulmica Computaciona

Pyrrolodiazines. 4. Structure and chemistry of 3,4-dihydropyrrolo[1,2-a]pyrazine

The structure of 3,4-dihydropyrrolo[1,2-a]pyrazine and its N-protonated form is studied by ab initio calculations. Examples of the reactivity of this poorly studied system are presented in which it is shown that the imino moiety does not react with dienes but does undergo inter- and intramolecular 1,3-dipolar cycloadditions by reaction of azomethine ylides of this bicyclic system with suitable dipolarophiles.Ministerio de Educación y CienciaCentro de Computación de Galixia (CESGA

A theory of nonvertical triplet energy transfer in terms of accurate potential energy surfaces: The transfer reaction from π,π∗ triplet donors to 1,3,5,7-cyclooctatetraene

Triplet energy transfer (TET) from aromatic donors to 1,3,5,7-cyclooctatetraene (COT) is an extreme case of “nonvertical” behavior, where the transfer rate for low-energy donors is considerably faster than that predicted for a thermally activated (Arrhenius) process. To explain the anomalous TET of COT and other molecules, a new theoretical model based on transition state theory for nonadiabatic processes is proposed here, which makes use of the adiabatic potential energy surfaces (PES) of reactants and products, as computed from high-level quantum mechanical methods, and a nonadiabatic transfer rate constant. It is shown that the rate of transfer depends on a geometrical distortion parameter γ = (2g2/κ1)1/2 in which g stands for the norm of the energy gradient in the PES of the acceptor triplet state and κ1 is a combination of vibrational force constants of the ground-state acceptor in the gradient direction. The application of the model to existing experimental data for the triplet energy transfer reaction to COT from a series of π,π∗ triplet donors, provides a detailed interpretation of the parameters that determine the transfer rate constant. In addition, the model shows that the observed decrease of the acceptor electronic excitation energy is due to thermal activation of C�C bond stretchings and C–C bond torsions, which collectively change the ground-state COT bent conformation (D2d) toward a planar triplet state (D8h)[email protected]

Ultra low background Micromegas detectors for BabyIAXO solar axion search

The International AXion Observatory (IAXO) is a large scale axion helioscope that will look for axions and axion-like particles produced in the Sun with unprecedented sensitivity. BabyIAXO is an intermediate experimental stage that will be hosted at DESY (Germany) and that will test all IAXO subsystems serving as a prototype for IAXO but at the same time as a fully-fledged helioscope with potential for discovery. One of the crucial components of the project is the ultra-low background X-ray detectors that will image the X-ray photons produced by axion conversion in the experiment. The baseline detection technology for this purpose are Micromegas (Microbulk) detectors. We will show the quest and the strategy to attain the very challenging levels of background targeted for BabyIAXO that need a multi-approach strategy coming from ground measurements, screening campaigns of components of the detector, underground measurements, background models, in-situ background measurements as well as powerful rejection algorithms. First results from the commissioning of the BabyIAXO prototype will be shown.Comment: 4 pages, 2 figures, submitted for the proceedings of the International Conference on Micro Pattern Gaseous Detectors, December 2022, Israe

Search for Dark Matter Axions with CAST-CAPP

The CAST-CAPP axion haloscope, operating at CERN inside the CAST dipole magnet, has searched for axions in the 19.74 $\mu$eV to 22.47 $\mu$eV mass range. The detection concept follows the Sikivie haloscope principle, where Dark Matter axions convert into photons within a resonator immersed in a magnetic field. The CAST-CAPP resonator is an array of four individual rectangular cavities inserted in a strong dipole magnet, phase-matched to maximize the detection sensitivity. Here we report on the data acquired for 4124 h from 2019 to 2021. Each cavity is equipped with a fast frequency tuning mechanism of 10 MHz/min between 4.774 GHz and 5.434 GHz. In the present work, we exclude axion-photon couplings for virialized galactic axions down to $g_{a{\gamma}{\gamma}} = 8 \times {10^{-14}}$ $GeV^{-1}$ at the 90% confidence level. The here implemented phase-matching technique also allows for future large-scale upgrades.Comment: 24 pages, 5 figures, Published version available with Open Access at https://www.nature.com/articles/s41467-022-33913-

Muscle Contraction Regulates BDNF/TrkB Signaling to Modulate Synaptic Function through Presynaptic cPKCα and cPKCβI

The neurotrophin brain-derived neurotrophic factor (BDNF) acts via tropomyosin-related kinase B receptor (TrkB) to regulate synapse maintenance and function in the neuromuscular system. The potentiation of acetylcholine (ACh) release by BDNF requires TrkB phosphorylation and Protein Kinase C (PKC) activation. BDNF is secreted in an activity-dependent manner but it is not known if pre- and/or postsynaptic activities enhance BDNF expression in vivo at the neuromuscular junction (NMJ). Here, we investigated whether nerve and muscle cell activities regulate presynaptic conventional PKC (cPKCα and βI) via BDNF/TrkB signaling to modulate synaptic strength at the NMJ. To differentiate the effects of presynaptic activity from that of muscle contraction, we stimulated the phrenic nerve of rat diaphragms (1 Hz, 30 min) with or without contraction (abolished by μ-conotoxin GIIIB). Then, we performed ELISA, Western blotting, qRT-PCR, immunofluorescence and electrophysiological techniques. We found that nerve-induced muscle contraction: (1) increases the levels of mature BDNF protein without affecting pro-BDNF protein or BDNF mRNA levels; (2) downregulates TrkB.T1 without affecting TrkB.FL or p75 neurotrophin receptor (p75) levels; (3) increases presynaptic cPKCα and cPKCβI protein level through TrkB signaling; and (4) enhances phosphorylation of cPKCα and cPKCβI. Furthermore, we demonstrate that cPKCβI, which is exclusively located in the motor nerve terminals, increases activity-induced acetylcholine release. Together, these results show that nerve-induced muscle contraction is a key regulator of BDNF/TrkB signaling pathway, retrogradely activating presynaptic cPKC isoforms (in particular cPKCβI) to modulate synaptic function. These results indicate that a decrease in neuromuscular activity, as occurs in several neuromuscular disorders, could affect the BDNF/TrkB/PKC pathway that links pre- and postsynaptic activity to maintain neuromuscular function

Patient-reported well-being in value-based care using tildrakizumab in a real-world setting: protocol of a multinational, phase IV, 1-cohort prospective observational study (the POSITIVE study).

INTRODUCTION: Psoriasis is a chronic inflammatory skin disease that negatively impacts the quality of life of patients and their families. However, the most commonly used decision-making tools in psoriasis, Psoriasis Area and Severity Index (PASI), Physician Global Assessment (PGA) and Dermatology Life Quality Index (DLQI), do not fully capture the impact of psoriasis on patients' lives. In contrast, the well-established 5-item WHO Well-being Index (WHO-5) assesses the subjective psychological well-being of patients. Moreover, while drug innovations became available for psoriasis, data on the impact of these therapies on patients' lives and their closest environment (family, physicians) are limited. This study will assess the effect of tildrakizumab, an interleukin-23p19 inhibitor, on the overall well-being of patients with moderate-to-severe psoriasis. Moreover, the long-term benefit of tildrakizumab on physicians' satisfaction and partners' lives of patients with psoriasis will be evaluated. METHODS AND ANALYSIS: This non-interventional, prospective, observational, real-world evidence study will involve multiple sites in Europe and approximately 500 adults with moderate-to-severe psoriasis treated with tildrakizumab. Each patient will be followed for 24 months. The primary endpoint is well-being measured by the WHO-5 questionnaire. Key secondary endpoints include Physician's Satisfaction and partner's quality of life (FamilyPso). Other endpoints will evaluate skin-generic quality of life (DLQI-R), Treatment Satisfaction Questionnaire for Medication (TSQM-9), Treatment-related Patient Benefit Index 'Standard', 10 items (PBI-S-10) and work productivity and activity impairment due to psoriasis (WPAI:PSO). Statistical analyses will be based on observed cases. Multiple imputations will be performed as a sensitivity analysis, and adverse events will be reported. ETHICS AND DISSEMINATION: The study will be conducted according to the protocol, which received ethics committee approval and applicable regulatory requirements of each participating country. The results will be disseminated through scientific publications and congress presentations. TRAIL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT04823247 (Pre-results)