Effect of mofezolac-galactose distance in conjugates targeting cyclooxygenase (COX)-1 and CNS GLUT-1 carrier

Neuroinflammation is the earliest stage of several neurological and neurodegenerative diseases. In the case of neurodegenerative disorders, it takes place about 15â 20 years before the appearance of specific neurodegenerative clinical symptoms. Constitutive microglial COX-1 is one of the pro-inflammatory players of the neuroinflammation. Novel compounds 3, 14 and 15 (Galmof0, Galmof5and Galmof11, respectively) were projected, and their synthetic methodologies developed, by linking by an ester bond, directly or through a C5 or C11 unit linker the highly selective COX-1 inhibitor mofezolac (COXs selectivity index > 6000) to galactose in order to obtain substances capable to cross blood-brain barrier (BBB) and control the CNS inflammatory response. 3, 14 and 15 (Galmofs) were prepared in good to fair yields. Galmof0(3) was found to be a selective COX-1 inhibitor (COX-1 IC50= 0.27 μM and COX-2 IC50= 3.1 μM, selectivity index = 11.5), chemically and metabolically stable, and capable to cross Caco-2 cell monolayer, resembling BBB, probing that its transport is GLUT-1-mediated. Furthermore, Galmof0(3) powerfully inhibits PGE2release higher than mofezolac (1) in LPS-stimulated mouse BV2 microglial cell line, a worldwide recognized neuroinflammation model. In addition, Fingerprints for Ligands and Proteins (FLAP) was used to explain the different binding interactions of Galmofs with the COX-1 active site

Congestion and systemic inflammation in acute heart failure: correlations and prognostic role

BackgroundThe reciprocal correlation between systemic inflammation and heart failure (HF) is a hotline research topic although the exact role in risk stratification and prognosis within the acute setting is a matter of debate. This study aimed to evaluate the correlation among two inflammatory biomarkers—namely, high-sensitivity C-reactive protein (hs-CRP) and neutrophil–lymphocyte ratio (NLR), congestion status, and prognosis in patients with acute HF (AHF).MethodsWe consecutively enrolled 314 AHF patients. Congestion biomarkers [brain natriuretic peptide, estimated plasma volume status (ePVS), hydration index (HI), blood urea nitrogen to creatinine ratio (BUN/Cr)] were evaluated to assess hemodynamic intravascular, peripheral, and venous congestion. We also measured hs-CRP and NLR as markers of inflammation. The endpoint was all-cause mortality at 90 days.Resultshs-CRP concentrations at admission [12.1 mg/L, 95% confidence interval (CI) 10–15] were associated with NLR values (4.8, 95% CI: 4.3–5.3) (R2 = 0.11; p < 0.0001). They both positively correlated with congestion indexes (log hs-CRP, ePVS r = 0.2, HI r = 0.24, p < 0.0001 for both; log NLR, ePVS r = 0.20, HI r = 0.29, BUN/Cr 0.14, log brain natriuretic peptide (BNP) r = 0.16, p < 0.01 for all). After 90 days, the cumulative mortality rate was 26%. Inflammatory biomarkers (hs-CRP and NLR cutoffs were >60 pg/mL and >7.5, respectively) were predictors of death. By using all these parameters, we performed an index of inflammation (from 0 to 2) for each patient. Congestion and inflammation indexes were independent predictors of mortality (hazard ratios 1.4 and 2.3, respectively; C-index 0.72).ConclusionSystemic inflammation seemed directly associated with congestion burden in patients with AHF. Both of them have different impacts on the prediction of adverse outcomes in these patients. Further studies are needed to address unmet needs

Phosphosilicate Multimode Optical Fiber for Sensing and Diagnostics at Inertial Confinement Fusion Facilities

We characterized the radiation response in the visible domain of a new multimode graded-index (GI) phosphosilicate optical fiber (GIMMF), exposed to the harsh environment (pulses of 14-MeV neutrons, X-rays, and γ -rays) associated with laser experiments at the OMEGA facility. The growth of permanent radiation-induced attenuation (RIA) was measured in situ after a series of laser shots involving a large production of 14-MeV neutrons (yields > 10^14 n per shot). RIA linearly increases with accumulated neutron fluence without recovery between shots. The obtained results allow a precise evaluation of this GIMMF vulnerability when implemented as part of laser or plasma diagnostics. Our work also reveals the potential of this class of optical fiber to serve as a radiation monitor in the radiation-rich mixed environments of megajoule class laser facilities and to provide a very fast and online estimation of the accumulated deposited dose at various locations of their experimental halls. In our experimental test configuration at OMEGA, 14-MeV neutrons are estimated to contribute to about 55% of the total deposited dose on the fibers, and the other optical losses are related to X-ray and γ -ray contributions. Those measurements could be, for example, benchmarked to the radiation maps obtained by Monte Carlo simulation tools, potentially facilitating the evaluation of the aging of diagnostics, components, and systems as well as their maintenance operations

Infected pancreatic necrosis: outcomes and clinical predictors of mortality. A post hoc analysis of the MANCTRA-1 international study

: The identification of high-risk patients in the early stages of infected pancreatic necrosis (IPN) is critical, because it could help the clinicians to adopt more effective management strategies. We conducted a post hoc analysis of the MANCTRA-1 international study to assess the association between clinical risk factors and mortality among adult patients with IPN. Univariable and multivariable logistic regression models were used to identify prognostic factors of mortality. We identified 247 consecutive patients with IPN hospitalised between January 2019 and December 2020. History of uncontrolled arterial hypertension (p = 0.032; 95% CI 1.135-15.882; aOR 4.245), qSOFA (p = 0.005; 95% CI 1.359-5.879; aOR 2.828), renal failure (p = 0.022; 95% CI 1.138-5.442; aOR 2.489), and haemodynamic failure (p = 0.018; 95% CI 1.184-5.978; aOR 2.661), were identified as independent predictors of mortality in IPN patients. Cholangitis (p = 0.003; 95% CI 1.598-9.930; aOR 3.983), abdominal compartment syndrome (p = 0.032; 95% CI 1.090-6.967; aOR 2.735), and gastrointestinal/intra-abdominal bleeding (p = 0.009; 95% CI 1.286-5.712; aOR 2.710) were independently associated with the risk of mortality. Upfront open surgical necrosectomy was strongly associated with the risk of mortality (p < 0.001; 95% CI 1.912-7.442; aOR 3.772), whereas endoscopic drainage of pancreatic necrosis (p = 0.018; 95% CI 0.138-0.834; aOR 0.339) and enteral nutrition (p = 0.003; 95% CI 0.143-0.716; aOR 0.320) were found as protective factors. Organ failure, acute cholangitis, and upfront open surgical necrosectomy were the most significant predictors of mortality. Our study confirmed that, even in a subgroup of particularly ill patients such as those with IPN, upfront open surgery should be avoided as much as possible. Study protocol registered in ClinicalTrials.Gov (I.D. Number NCT04747990)

Effets combinés des radiations et de la température sur les fibres optiques à base de silice

When optical fibers are exposed to radiation, their signal transmission properties are degraded due to the generation of radiation-induced point defects in the optical fiber silica-based matrix. this phenomenon, named radiation-induced attenuation (ria), is the most studied among the radiation-involving processes as is the one with the major impact on the systems performances. Ria levels and kinetics can be affected by many parameters as the irradiation conditions, fiber composition, probing light power and pre-treatments. the knowledge of the ria dependence on these factors is of fundamental importance for applications such as in-situ diagnostics in nuclear industry or for the monitoring of environmental parameters in nuclear waste dismantling sites or nuclear waste repositories. These applications are associated with severe mixed environments characterized by the presence of ionizing radiations, temperature variations and presence of various gases. a typical example is encountered by andra in the framework of the cigeo project, which led to the conception of the certyf consortium, a fundamental research project aiming to improve the current knowledge on the basic mechanisms responsible for the fiber degradation in the simultaneous presence of radiation, hydrogen and temperature constraints. The acquired knowledge may contribute to improve the design of radiation-resistant optical fibers in order to develop radiation-tolerant systems or sensors able to operate in radioactive waste storage facilities or, conversely, to the enhance the radiation sensitivity in order to improve the performances of dosimetry systems.Lorsque les fibres optiques sont exposées à des radiations, leurs propriétés de transmission de signaux se dégradent en raison de la génération de défauts induits par les rayonnements. Ce phénomène, nommé atténuation induite par irradiation (ria), est le plus étudié parmi les processus impliquant des rayonnements car c'est celui qui a le plus d'impact sur les performances des systèmes. Les niveaux et la cinétique de la ria peuvent être affectés par de nombreux paramètres tels que les conditions d'irradiation, la composition de la fibre, la puissance de la lumière injectée et les prétraitements. La connaissance de la dépendance de la ria à ces facteurs est d'une importance fondamentale pour des applications telles que le diagnostic in situ dans l'industrie nucléaire ou la surveillance des paramètres environnementaux dans les sites de démantèlement et de stockage des déchets radioactifs. Ces applications sont associées à des environnements mixtes sévères caractérisés par la présence de rayonnements ionisants, des variations de température et la présence de divers gaz. un exemple est le cas du projet cigeo, mené par l'andra, qui a conduit à la conception du consortium certyf, un projet de recherche fondamentale visant à améliorer les connaissances actuelles sur les mécanismes de base responsables de la dégradation des fibres en présence simultanée de radiations, d'hydrogène et de contraintes thermiques. Les connaissances acquises peuvent contribuer à améliorer la conception de fibres optiques en fonction des objectifs souhaités que ce soit le durcissement des fibres ou, au contraire, augmenter leurs sensibilités aux radiations

Effets combinés des radiations et de la température sur les fibres optiques à base de silice

Lorsque les fibres optiques sont exposées à des radiations, leurs propriétés de transmission de signaux se dégradent en raison de la génération de défauts induits par les rayonnements. Ce phénomène, nommé atténuation induite par irradiation (ria), est le plus étudié parmi les processus impliquant des rayonnements car c'est celui qui a le plus d'impact sur les performances des systèmes. Les niveaux et la cinétique de la ria peuvent être affectés par de nombreux paramètres tels que les conditions d'irradiation, la composition de la fibre, la puissance de la lumière injectée et les prétraitements. La connaissance de la dépendance de la ria à ces facteurs est d'une importance fondamentale pour des applications telles que le diagnostic in situ dans l'industrie nucléaire ou la surveillance des paramètres environnementaux dans les sites de démantèlement et de stockage des déchets radioactifs. Ces applications sont associées à des environnements mixtes sévères caractérisés par la présence de rayonnements ionisants, des variations de température et la présence de divers gaz. un exemple est le cas du projet cigeo, mené par l'andra, qui a conduit à la conception du consortium certyf, un projet de recherche fondamentale visant à améliorer les connaissances actuelles sur les mécanismes de base responsables de la dégradation des fibres en présence simultanée de radiations, d'hydrogène et de contraintes thermiques. Les connaissances acquises peuvent contribuer à améliorer la conception de fibres optiques en fonction des objectifs souhaités que ce soit le durcissement des fibres ou, au contraire, augmenter leurs sensibilités aux radiations.When optical fibers are exposed to radiation, their signal transmission properties are degraded due to the generation of radiation-induced point defects in the optical fiber silica-based matrix. this phenomenon, named radiation-induced attenuation (ria), is the most studied among the radiation-involving processes as is the one with the major impact on the systems performances. Ria levels and kinetics can be affected by many parameters as the irradiation conditions, fiber composition, probing light power and pre-treatments. the knowledge of the ria dependence on these factors is of fundamental importance for applications such as in-situ diagnostics in nuclear industry or for the monitoring of environmental parameters in nuclear waste dismantling sites or nuclear waste repositories. These applications are associated with severe mixed environments characterized by the presence of ionizing radiations, temperature variations and presence of various gases. a typical example is encountered by andra in the framework of the cigeo project, which led to the conception of the certyf consortium, a fundamental research project aiming to improve the current knowledge on the basic mechanisms responsible for the fiber degradation in the simultaneous presence of radiation, hydrogen and temperature constraints. The acquired knowledge may contribute to improve the design of radiation-resistant optical fibers in order to develop radiation-tolerant systems or sensors able to operate in radioactive waste storage facilities or, conversely, to the enhance the radiation sensitivity in order to improve the performances of dosimetry systems

Effets combinés des radiations et de la température sur les fibres optiques à base de silice

When optical fibers are exposed to radiation, their signal transmission properties are degraded due to the generation of radiation-induced point defects in the optical fiber silica-based matrix. this phenomenon, named radiation-induced attenuation (ria), is the most studied among the radiation-involving processes as is the one with the major impact on the systems performances. Ria levels and kinetics can be affected by many parameters as the irradiation conditions, fiber composition, probing light power and pre-treatments. the knowledge of the ria dependence on these factors is of fundamental importance for applications such as in-situ diagnostics in nuclear industry or for the monitoring of environmental parameters in nuclear waste dismantling sites or nuclear waste repositories. These applications are associated with severe mixed environments characterized by the presence of ionizing radiations, temperature variations and presence of various gases. a typical example is encountered by andra in the framework of the cigeo project, which led to the conception of the certyf consortium, a fundamental research project aiming to improve the current knowledge on the basic mechanisms responsible for the fiber degradation in the simultaneous presence of radiation, hydrogen and temperature constraints. The acquired knowledge may contribute to improve the design of radiation-resistant optical fibers in order to develop radiation-tolerant systems or sensors able to operate in radioactive waste storage facilities or, conversely, to the enhance the radiation sensitivity in order to improve the performances of dosimetry systems.Lorsque les fibres optiques sont exposées à des radiations, leurs propriétés de transmission de signaux se dégradent en raison de la génération de défauts induits par les rayonnements. Ce phénomène, nommé atténuation induite par irradiation (ria), est le plus étudié parmi les processus impliquant des rayonnements car c'est celui qui a le plus d'impact sur les performances des systèmes. Les niveaux et la cinétique de la ria peuvent être affectés par de nombreux paramètres tels que les conditions d'irradiation, la composition de la fibre, la puissance de la lumière injectée et les prétraitements. La connaissance de la dépendance de la ria à ces facteurs est d'une importance fondamentale pour des applications telles que le diagnostic in situ dans l'industrie nucléaire ou la surveillance des paramètres environnementaux dans les sites de démantèlement et de stockage des déchets radioactifs. Ces applications sont associées à des environnements mixtes sévères caractérisés par la présence de rayonnements ionisants, des variations de température et la présence de divers gaz. un exemple est le cas du projet cigeo, mené par l'andra, qui a conduit à la conception du consortium certyf, un projet de recherche fondamentale visant à améliorer les connaissances actuelles sur les mécanismes de base responsables de la dégradation des fibres en présence simultanée de radiations, d'hydrogène et de contraintes thermiques. Les connaissances acquises peuvent contribuer à améliorer la conception de fibres optiques en fonction des objectifs souhaités que ce soit le durcissement des fibres ou, au contraire, augmenter leurs sensibilités aux radiations

Cognitive and anatomical underpinnings of the conceptual knowledge for common objects and familiar people: a repetitive transcranial magnetic stimulation study.

Several studies have addressed the issue of how knowledge of common objects is organized in the brain, whereas the cognitive and anatomical underpinnings of familiar people knowledge have been less explored. Here we applied repetitive transcranial magnetic stimulation (rTMS) over the left and right temporal poles before asking healthy individuals to perform a speeded word-to-picture matching task using familiar people and common objects as stimuli. We manipulated two widely used semantic variables, namely the semantic distance and the familiarity of stimuli, to assess whether the semantic organization of familiar people knowledge is similar to that of common objects. For both objects and faces we reliably found semantic distance and familiarity effects, with less accurate and slower responses for stimulus pairs that were more closely related and less familiar. However, the effects of semantic variables differed across categories, with semantic distance effects larger for objects and familiarity effects larger for faces, suggesting that objects and faces might share a partially comparable organization of their semantic representations. The application of rTMS to the left temporal pole modulated, for both categories, semantic distance, but not familiarity effects, revealing that accessing object and face concepts might rely on overlapping processes within left anterior temporal regions. Crucially, rTMS of the left temporal pole affected only the recognition of pairs of stimuli that could be discriminated at specific levels of categorization (e.g., two kitchen tools or two famous persons), with no effect for discriminations at either superordinate or individual levels. Conversely, rTMS of the right temporal pole induced an overall slowing of reaction times that positively correlated with the visual similarity of the stimuli, suggesting a more perceptual rather than semantic role of the right anterior temporal regions. Results are discussed in the light of current models of face and object semantic representations in the brain

Mindfulness-oriented meditation improves self-related character scales in healthy individuals

Previous studies have shown that mindfulness meditation may improve well-being in healthy individuals and be effective in the treatment of mental and neurological disorders. Here, we investigated the effects of an 8-week mindfulness-mediation program on the personality profiles of three groups of healthy individuals with no previous experience with meditation as compared to a control group not enrolled in any training. Personality profiles were obtained through the Temperament and Character Inventory (Cloninger et al., 1993). In the experimental groups, significant increments after the training were obtained in all the three character scales describing the levels of self maturity at the intrapersonal (Self-Directedness), interpersonal (Cooperativeness), and transpersonal (Self-Transcendence) levels. No changes were found in the control group. Strikingly, these effects were significant only in those groups who were engaged in consistent daily meditation practice but not in the group who attended the meditation training but were less consistent in home practice. Since higher scores in the character scales are associated to a lower risk of personality disorder, we propose that the increase of self maturity after the training may be an important mechanism for the effectiveness of mindfulness-oriented meditation in psychotherapeutic contexts

Mean accuracy and reaction times (+/− standard error) for each condition of semantic distance, frequency/familiarity and rTMS stimulation.

<p>Mean accuracy and reaction times (+/− standard error) for each condition of semantic distance, frequency/familiarity and rTMS stimulation.</p