Evaluation of the neuroprotective efficacy of the gramine derivative ITH12657 against NMDA-induced excitotoxicity in the rat retina

© 2024. The authors. This document is made available under the CC-BY 4.0 license http://creativecommons.org/licenses/by /4.0/ This document is the published version of a published work that appeared in final form in Frontiers in NeuroanatomyPurpose: The aim of this study was to investigate, the neuroprotective effects of a new Gramine derivative named: ITH12657, in a model of retinal excitotoxicity induced by intravitreal injection of NMDA. Methods: Adult Sprague Dawley rats received an intravitreal injection of 100 mM NMDA in their left eye and were treated daily with subcutaneous injections of ITH12657 or vehicle. The best dose–response, therapeutic window study, and optimal treatment duration of ITH12657 were studied. Based on the best survival of Brn3a + RGCs obtained from the above-mentioned studies, the protective effects of ITH12657 were studied in vivo (retinal thickness and full-field Electroretinography), and ex vivo by quantifying the surviving population of Brn3a + RGCs, αRGCs and their subtypes α-ONsRGCs, α-ONtRGCs, and α-OFFRGCs. Results: Administration of 10 mg/kg ITH12657, starting 12 h before NMDA injection and dispensed for 3 days, resulted in the best significant protection of Brn3a + RGCs against NMDA-induced excitotoxicity. In vivo, ITH12657-treated rats showed significant preservation of retinal thickness and functional protection against NMDA-induced retinal excitotoxicity. Ex vivo results showed that ITH12657 afforded a significant protection against NMDA-induced excitotoxicity for the populations of Brn3a + RGC, αRGC, and αONs-RGC, but not for the population of αOFF-RGC, while the population of α-ONtRGC was fully resistant to NMDA-induced excitotoxicity. Conclusion: Subcutaneous administration of ITH12657 at 10 mg/kg, initiated 12 h before NMDA-induced retinal injury and continued for 3 days, resulted in the best protection of Brn3a + RGCs, αRGC, and αONs-RGC against excitotoxicity-induced RGC death. The population of αOFF-RGCs was extremely sensitive while α-ONtRGCs were fully resistant to NMDA-induced excitotoxicity

Specific targeting of the NRF2/β-TrCP axis promotes beneficial effects in NASH

Non-alcoholic steatohepatitis (NASH) is a common chronic liver disease that compromises liver function, for which there is not a specifically approved medicine. Recent research has identified transcription factor NRF2 as a potential therapeutic target. However, current NRF2 activators, designed to inhibit its repressor KEAP1, exhibit unwanted side effects. Alternatively, we previously introduced PHAR, a protein-protein interaction inhibitor of NRF2/β-TrCP, which induces a mild NRF2 activation and selectively activates NRF2 in the liver, close to normal physiological levels. Herein, we assessed the effect of PHAR in protection against NASH and its progression to fibrosis. We conducted experiments to demonstrate that PHAR effectively activated NRF2 in hepatocytes, Kupffer cells, and stellate cells. Then, we used the STAM mouse model of NASH, based on partial damage of endocrine pancreas and insulin secretion impairment, followed by a high fat diet. Non-invasive analysis using MRI revealed that PHAR protects against liver fat accumulation. Moreover, PHAR attenuated key markers of NASH progression, including liver steatosis, hepatocellular ballooning, inflammation, and fibrosis. Notably, transcriptomic data indicate that PHAR led to upregulation of 3 anti-fibrotic genes (Plg, Serpina1a, and Bmp7) and downregulation of 6 pro-fibrotic (including Acta2 and Col3a1), 11 extracellular matrix remodeling, and 8 inflammatory genes. Overall, our study suggests that the mild activation of NRF2 via the protein-protein interaction inhibitor PHAR holds promise as a strategy for addressing NASH and its progression to liver fibrosisThis research was funded by the Spanish Ministry of Economy and Competitiveness (MINECO) (grants PID2019-110061RB-I00, PID-2021-122766OB-100 and PDC2021-121421-I00, PDC2022-133765-I00, MCIN/AEI/10.13039/501100011033 and “ERDF A way of making Europe” by the European Union.), CIBERdem and CIBERned (ISCIII), and The Autonomous Community of Madrid (grant P2022/BMD-7230). RFG enjoyed a FPI contract of MINECO (FPI-2017). DCS is a holder of a FPI contract of MICINN (Ministry of Science and Innovation, FPI-2020, PRE2020-091886). JJV is holder of a FPU contract of MIU (Ministry of Universities, FPU2020, FPU20/03326

Impact of the “Law on promotion of personal autonomy and care for people dependent” in population with severe mental disorder

Law 39/2006, known as Dependence Law, has generated skepticism since its approval, for being focused on dependancy and barely promoting personal autonomy, treating it as a secondary issue. As it relates to people with severe mental disorder, a major concern to mental health professional organizations and family associations has been the compatibility of the law with the services provided by the National health service and whether the established selection criteria for qualifying for the service fits the needs of this group. This article reflects the work done across several Spanish autonomous regions by different professionals in an attempt to convince the administration to make the necessary adjustment to suit the characteristics of people with serious mental disorders. After discussing its strengths and weaknesses, it outlines three different ways to offset their risks in three different regions, Extremadura, Andalucia and Madrid. Finally it addresses the key aspects of the law which need to be worked on, in order to become a benefit for people with severe mental disorder, and not a barrierLa Ley 39/2006, conocida como Ley de Dependencia, ha generado, desde su aprobación, desconfianza por estar enfocada a la atención a la dependencia, siendo la promoción de la autonomía personal un elemento apenas desarrollado y secundario. En el caso de las personas con trastorno mental grave, lo que mayor preocupación ha causado a las organizaciones de profesionales de la salud mental y a las asociaciones de familiares ha sido la compatibilidad de dicha Ley con las prestaciones del Sistema Nacional de Salud y si el baremo establecido se ajustaba a las necesidades de este colectivo. Este artículo recoge el trabajo realizado desde diferentes comunidades autónomas por diferentes profesionales en un intento de, tras un análisis de la Ley, plantear a la administración responsable de la misma el necesario ajuste para adaptarla a las características de las personas con trastorno mental grave. Se analizan, en primer lugar, sus fortalezas y debilidades. Posteriormente se exponen tres formas diferentes de contrarrestar sus riesgos, en tres comunidades autónomas diferentes, Extremadura, Andalucía y Madrid. Finalmente se dan las claves de los aspectos de la Ley sobre los que hay que seguir trabajando para que sea una oportunidad para las personas con trastorno mental grave, y no una barrer

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Corneal endothelial cell loss after trabeculectomy and phacoemulsification in one or two steps: a prospective study

©. This manuscript version is made available under the CC-BY 4.0 license http://creativecommons.org/licenses/by /4.0/ This document is the Published Manuscript version of a Published Work that appeared in final form in [The Royal college of ophthalmologists]. To access the final edited and published work see[https://doi.org/10.1038/s41433-020-01331-x

Effect of annealing on properties of carbonaceous materials. Part II: porosity and pore geometry

The pore structure of carbonaceous materials was studied using image analysis. The effect of annealing on the porosity and pore geometry of cokes, chars, and pyrolyzed coals (laboratory chars) was examined in the temperature range of 973 K to 1773 K (700 C to 1500 C). The porosity of chars and pyrolyzed coals significantly increased during annealing at temperatures below 1373 K (1100 C) due to volatile matter release. Further increasing of the annealing temperature from 1373 K to 1773 K (1100 C to 1500 C) caused marginal porosity evolution. The porosity of cokes was not affected by annealing at temperatures below 1573 K (1300 C) and slightly increased in the temperature range 1573 to 1773 K (1300 C to 1500 C). The increase in the porosity of chars and pyrolyzed coals during annealing at temperatures 1373 K to 1773 K (1100 C to 1500 C), and cokes at 1573 K to 1773 K (1300 C to 1500 C), was a result of reactions with oxides of their mineral phases. Annealing had a marginal effect on the pore shape (Feret ratio) of carbonaceous materials, but enlarged the pore size of chars and pyrolyzed coals and decreased their pore density