Exogenous aralar/slc25a12 can replace citrin/slc25a13 as malate aspartate shuttle component in liver

The deficiency of CITRIN, the liver mitochondrial aspartate–glutamate carrier (AGC), is the cause of four human clinical phenotypes, neonatal intrahepatic cholestasis caused by CITRIN deficiency (NICCD), silent period, failure to thrive and dyslipidemia caused by CITRIN deficiency (FTTDCD), and citrullinemia type II (CTLN2). Clinical symptoms can be traced back to disruption of the malate-aspartate shuttle due to the lack of citrin. A potential therapy for this condition is the expression of aralar, the AGC present in brain, to replace citrin. To explore this possibility we have first verified that the NADH/NAD+ ratio increases in hepatocytes from citrin(−/−) mice, and then found that exogenous aralar expression reversed the increase in NADH/NAD+ observed in these cells. Liver mitochondria from citrin (−/−) mice expressing liver specific transgenic aralar had a small (~ 4–6 nmoles x mg prot−1 x min−1) but consistent increase in malate aspartate shuttle (MAS) activity over that of citrin(−/−) mice. These results support the functional replacement between AGCs in the liver. To explore the significance of AGC replacement in human therapy we studied the relative levels of citrin and aralar in mouse and human liver through absolute quantification proteomics. We report that mouse liver has relatively high aralar levels (citrin/aralar molar ratio of 7.8), whereas human liver is virtually devoid of aralar (CITRIN/ARALAR ratio of 397). This large difference in endogenous aralar levels partly explains the high residual MAS activity in liver of citrin(−/−) mice and why they fail to recapitulate the human disease, but supports the benefit of increasing aralar expression to improve the redox balance capacity of human liver, as an effective therapy for CITRIN deficienc

La enseñanza en el máster de abogacía a través del análisis de casos reales de carácter multidisciplinar. Aprendizaje "a partir del estudio de razonamientos parciales temáticos"

Generar blog para publicaciones de alumnos del Máster Abogacía, con "entradas" dirigidas. Habría análisis desde varias disciplinas añadiéndose estudios con enfoque basado en otras áreas de conocimiento, generando interdisciplinariedad

Çédille, revista de estudios franceses

Presentació

Case report: lupus nephritis with autoantibodies to complement alternative pathway proteins and C3 gene mutation

5 p.-2 fig.[Background] Glomerulonephritis is one of the most severe complications of lupus, a systemic disease with multi-organ involvement, with tissue damage produced mainly by complement activation. As a result of this activation, patients with active lupus present hypocomplementemia during disease flares, but C3 and C4 levels are recovered between episodes.[Case presentation] We present a patient who suffered two lupus nephritis episodes in 5 years, achieving complete remission with treatment after both of them, but with C3 levels persistently below normal range. Genetic study revealed that the patient carried a mutation in heterozygosis in the C3 gene. Serial sera samples were analyzed, and autoantibodies to complement alternative pathway proteins (Factor I, Factor B, C3 and Properdin) were found. Functional assays showed that these autoantibodies cause alternative pathway activation.[Conclusion] This case is the first reported of a heterozygous C3 mutation associated with lupus nephritis and autoantibodies against complement alternative pathway proteins (Factor I, Factor B, C3 and Properdin).These autoantibodies cause activation of this pathway and this fact could explain that the tissue damage is restricted to the kidney.This work was funded by Spanish government, Ministerio de Economía y Competitividad (grant SAF2012-38636), Autonomous region of Madrid (S2010/BMD-2316 to SRdeC y MLT) and Sociedad Española de Nefrología Fundación Senefro to MLT.Peer reviewe

­Toma Salud!

Se trata de ofrecer información sobre prácticas saludables en alimentación, especialmente en el desayuno, y fomentar el desarrollo de hábitos saludables. Se pretende, además, realizar una actividad interdisciplinar que implique al mayor número de profesores y alumnos, incorporar la Educación para la Salud en las áreas curriculares y confeccionar materiales y estrategias de intervención sobre este tema transversal. Las actividades son de formación de profesores, charlas-coloqio de carácter informativo y sesiones de intervención con los alumnos. Se evalúa el grado de implicación de los miembros de la comunidad escolar, la organización de los grupos de trabajo, la calidad y adecuación de los materiales utilizados y la repercusión del proyecto en el alumnado.Madrid (Comunidad Autónoma). Consejería de Sanidad y Servicios SocialesMadridNo disponibleES

Presentation

El pasado mes de abril iniciamos una nueva etapa en Çédille, representada principalmente por su traslado a la plataforma Open Journal System (OJS) de la Universidad de La Laguna, así como por la renovación y reasignación de competencias del Consejo de Redacción. Durante este tiempo, hemos tenido que adaptarnos, experimentar y comprender, pacientemente, el funcionamiento de esta nueva herramienta que es OJS. Ello ha supuesto, en algunos casos, que se hayan producido determinadas dificultades de comunicación con nuestros lectores y evaluadores, o que se hayan ocasionado pequeños retrasos en la gestión de la revista. Como nuestros seguidores saben, muy recientemente hemos sufrido, además, un ataque informático que no solo impidió el acceso a la plataforma durante varios días (justo en el momento final de producción de este número), sino que obligó a trasladar nuestro sitio web a otro servidor y a implementar nuevas medidas de seguridad. Afortunadamente, gracias al buen hacer y profesionalidad de Juan Ascanio Amigó, asesor técnico de OJS para la Universidad de La Laguna, hemos logrado salir airosos de los problemas, complicaciones y secuelas que nos hemos ido encontrando en este tiempo. En este número que ahora ve la luz contamos con treinta y cuatro contri-buciones que superan, en total, las setecientas páginas. Así, Amelia Gamoneda Lanza y Francisco González Fernández se han encargado de coordinar una nueva entrega –la undécima– de la serie «Monografías», donde han reunido una ..

Subcutaneous anti-COVID-19 hyperimmune immunoglobulin for prevention of disease in asymptomatic individuals with SARS-CoV-2 infection: a double-blind, placebo-controlled, randomised clinical trialResearch in context

Summary: Background: Anti-COVID-19 hyperimmune immunoglobulin (hIG) can provide standardized and controlled antibody content. Data from controlled clinical trials using hIG for the prevention or treatment of COVID-19 outpatients have not been reported. We assessed the safety and efficacy of subcutaneous anti-COVID-19 hyperimmune immunoglobulin 20% (C19-IG20%) compared to placebo in preventing development of symptomatic COVID-19 in asymptomatic individuals with SARS-CoV-2 infection. Methods: We did a multicentre, randomized, double-blind, placebo-controlled trial, in asymptomatic unvaccinated adults (≥18 years of age) with confirmed SARS-CoV-2 infection within 5 days between April 28 and December 27, 2021. Participants were randomly assigned (1:1:1) to receive a blinded subcutaneous infusion of 10 mL with 1 g or 2 g of C19-IG20%, or an equivalent volume of saline as placebo. The primary endpoint was the proportion of participants who remained asymptomatic through day 14 after infusion. Secondary endpoints included the proportion of individuals who required oxygen supplementation, any medically attended visit, hospitalisation, or ICU, and viral load reduction and viral clearance in nasopharyngeal swabs. Safety was assessed as the proportion of patients with adverse events. The trial was terminated early due to a lack of potential benefit in the target population in a planned interim analysis conducted in December 2021. ClinicalTrials.gov registry: NCT04847141. Findings: 461 individuals (mean age 39.6 years [SD 12.8]) were randomized and received the intervention within a mean of 3.1 (SD 1.27) days from a positive SARS-CoV-2 test. In the prespecified modified intention-to-treat analysis that included only participants who received a subcutaneous infusion, the primary outcome occurred in 59.9% (91/152) of participants receiving 1 g C19-IG20%, 64.7% (99/153) receiving 2 g, and 63.5% (99/156) receiving placebo (difference in proportions 1 g C19-IG20% vs. placebo, −3.6%; 95% CI -14.6% to 7.3%, p = 0.53; 2 g C19-IG20% vs placebo, 1.1%; −9.6% to 11.9%, p = 0.85). None of the secondary clinical efficacy endpoints or virological endpoints were significantly different between study groups. Adverse event rate was similar between groups, and no severe or life-threatening adverse events related to investigational product infusion were reported. Interpretation: Our findings suggested that administration of subcutaneous human hyperimmune immunoglobulin C19-IG20% to asymptomatic individuals with SARS-CoV-2 infection was safe but did not prevent development of symptomatic COVID-19. Funding: Grifols