Juegos motores Una alternativa para fortalecer los músculos del abdomen

El objetivo del estudio fue comparar la amplitud de la electromiografía (EMG) y el modo en que fueron coactivados los músculos abdominales durante la ejecución del ejercicio de encorvamiento del tronco y dos juegos motores tradicionales: la carretilla y el hula hop. Para ello, se registró la EMG de los músculos rectus, obliquus externus y obliquus internus abdominis durante la ejecución de cada una de las tareas. En el estudio participaron nueve voluntarios sanos sin antecedentes de cirugía abdominal, lesiones raquídeas o síndrome de dolor lumbar. La amplitud de la EMG fue promediada y normalizada respecto a la contracción voluntaria máxima. Se realizó un ANOVA de dos factores (músculo/tarea) y un post hoc Tukey para examinar las diferencias en la actividad eléctrica de cada músculo entre las tareas y en cada tarea entre los músculos. Los juegos analizados produjeron niveles de actividad eléctrica superiores a los generados por el encorvamiento del tronco, por lo que deben ser considerados como un complemento o una alternativa a los ejercicios de fortalecimiento abdominal. La carretilla generó un importante nivel de coactivación abdominal, aunque activó principalmente al obliquus externus abdominis. En el hula hop, las diferencias entre los músculos no fueron estadísticamente significativas

Jocs motors Una alternativa per enfortir els músculs de l’abdomen

L’objectiu de l’estudi va ser comparar l’amplitud de l’electromiografia (EMG) i la forma en què van ser coactivats els músculs abdominals durant l’execució de l’exercici d’encorbament del tronc i dos jocs motors tradicionals: el carretó i l’hula-hop. Per fer-ho, es va enregistrar l’EMG dels músculs recte, oblic extern i oblic intern de l’abdomen, durant l’execució de cada una de les tasques. A l’estudi hi van participar nou voluntaris sans, sense antecedents de cirurgia abdominal, lesions raquídies o síndrome de dolor lumbar. L’amplitud de l’EMG va ser amitjanada i normalitzada respecte a la contracció voluntària màxima. Es va realitzar un ANOVA de dos factors (múscul/tasca) i un post hoc Tukey per examinar les diferències en l’activitat elèctrica de cada múscul entre les tasques i en cada tasca entre els músculs. Els jocs analitzats van produir nivells d’activitat elèctrica superiors als generats per l’encorbament del tronc, i en conseqüència, han de ser considerats com un complement o una alternativa als exercicis d’enfortiment abdominal. El carretó va generar un important nivell de coactivació abdominal, encara que va activar principalment l’oblic extern de l’abdomen. A l’hula-hop, les diferències entre els músculs no van ser estadísticament significatives

Inhibition of soluble epoxide hydrolase modulates inflammation and autophagy in obese adipose tissue and liver. Role for omega-3 epoxides

Soluble epoxide hydrolase (sEH) is an emerging therapeutic target in a number of diseases that have inflammation as a common underlying cause. sEH limits tissue levels of cytochrome P450 (CYP) epoxides derived from omega-6 and omega-3 polyunsaturated fatty acids (PUFA) by converting these antiinflammatory mediators into their less active diols. Here, we explored the metabolic effects of a sEH inhibitor (t-TUCB) in fat-1 mice with transgenic expression of an omega-3 desaturase capable of enriching tissues with endogenous omega-3 PUFA. These mice exhibited increased CYP1A1, CYP2E1, and CYP2U1 expression and abundant levels of the omega-3-derived epoxides 17,18-epoxyeicosatetraenoic acid (17,18-EEQ) and 19,20-epoxydocosapentaenoic (19,20-EDP) in insulin-sensitive tissues, especially liver, as determined by LC-ESI-MS/MS. In obese fat-1 mice, t-TUCB raised hepatic 17,18-EEQ and 19,20-EDP levels and reinforced the omega-3-dependent reduction observed in tissue inflammation and lipid peroxidation. t-TUCB also produced a more intense antisteatotic action in obese fat-1 mice, as revealed by magnetic resonance spectroscopy. Notably, t-TUCB skewed macrophage polarization toward an antiinflammatory M2 phenotype and expanded the interscapular brown adipose tissue volume. Moreover, t-TUCB restored hepatic levels of Atg12-Atg5 and LC3-II conjugates and reduced p62 expression, indicating up-regulation of hepatic autophagy. t-TUCB consistently reduced endoplasmic reticulum stress demonstrated by the attenuation of IRE-1α and eIF2α phosphorylation. These actions were recapitulated in vitro in palmitate-primed hepatocytes and adipocytes incubated with 19,20-EDP or 17,18-EEQ. Relatively similar but less pronounced actions were observed with the omega-6 epoxide, 14,15-EET, and nonoxidized DHA. Together, these findings identify omega-3 epoxides as important regulators of inflammation and autophagy in insulin-sensitive tissues and postulate sEH as a druggable target in metabolic diseases

A new cerkl mouse model generated by CRISPR-Cas9 shows progressive retinal degeneration and altered morphological and electrophysiological phenotype

Purpose: Close to 100 genes cause retinitis pigmentosa, a Mendelian rare disease that affects 1 out of 4000 people worldwide. Mutations in the ceramide kinase-like gene (CERKL) are a prevalent cause of autosomal recessive cause retinitis pigmentosa and cone-rod dystrophy, but the functional role of this gene in the retina has yet to be fully determined. We aimed to generate a mouse model that resembles the phenotypic traits of patients carrying CERKL mutations to undertake functional studies and assay therapeutic approaches. Methods: The Cerkl locus has been deleted (around 97 kb of genomic DNA) by gene editing using the CRISPR-Cas9 D10A nickase. Because the deletion of the Cerkl locus is lethal in mice in homozygosis, a double heterozygote mouse model with less than 10% residual Cerkl expression has been generated. The phenotypic alterations of the retina of this new model have been characterized at the morphological and electrophysiological levels. Results: This CerklKD/KO model shows retinal degeneration, with a decreased number of cones and progressive photoreceptor loss, poorly stacked photoreceptor outer segment membranes, defective retinal pigment epithelium phagocytosis, and altered electrophysiological recordings in aged retinas. Conclusions: To our knowledge, this is the first Cerkl mouse model to mimic many of the phenotypic traits, including the slow but progressive retinal degeneration, shown by human patients carrying CERKL mutations. This useful model will provide unprecedented insights into the retinal molecular pathways altered in these patients and will contribute to the design of effective treatments

Proposed approaches for indicator integration. ECAPRHA Deliverable Wp 4.1

<p>Cross-tabulation of cough and the modified Valsalva maneuver (m-VM) for determining the degree of right-to-left shunt.</p

Mitochondrial dysfunction governs immunometabolism in leukocytes of patients with acute-on-chronic liver failure.

Background & aims: Patients with acute-on-chronic liver failure (ACLF) present a systemic hyperinflammatory response associated with increased circulating levels of small-molecule metabolites. To investigate whether these alterations reflect inadequate cell energy output, we assessed mitochondrial morphology and central metabolic pathways with emphasis on the tricarboxylic acid (TCA) cycle in peripheral leukocytes from patients with acutely decompensated (AD) cirrhosis, with and without ACLF. Methods: The study included samples from patients with AD cirrhosis (108 without and 128 with ACLF) and 41 healthy individuals. Leukocyte mitochondrial ultrastructure was visualized by transmission electron microscopy and cytosolic and mitochondrial metabolic fluxes were determined by assessing NADH/FADH2 production from various substrates. Plasma GDF15 and FGF21 were determined by Luminex and acylcarnitines by LC-MS/MS. Gene expression was analyzed by RNA-sequencing and PCR-based glucose metabolism profiler array. Results: Mitochondrial ultrastructure in patients with advanced cirrhosis was distinguished by cristae rarefication and swelling. The number of mitochondria per leukocyte was higher in patients, accompanied by a reduction in their size. Increased FGF21 and C6:0- and C8:0-carnitine predicted mortality whereas GDF15 strongly correlated with a gene set signature related to leukocyte activation. Metabolic flux analyses revealed increased energy production in mononuclear leukocytes from patients with preferential involvement of extra-mitochondrial pathways, supported by upregulated expression of genes encoding enzymes of the glycolytic and pentose phosphate pathways. In patients with ACLF, mitochondrial function analysis uncovered break-points in the TCA cycle at the isocitrate dehydrogenase and succinate dehydrogenase level, which were bridged by anaplerotic reactions involving glutaminolysis and nucleoside metabolism. Conclusions: Our findings provide evidence at the cellular, organelle and biochemical levels that severe mitochondrial dysfunction governs immunometabolism in leukocytes from patients with AD cirrhosis and ACLF. Lay summary: Patients at advanced stages of liver disease have dismal prognosis due to vital organ failures and the lack of treatment options. In this study, we report that the functioning of mitochondria, which are known as the cell powerhouse, is severely impaired in leukocytes of these patients, probably as a consequence of intense inflammation. Mitochondrial dysfunction is therefore a hallmark of advanced liver disease