A Comparative Study of Age-Related Hearing Loss in Wild Type and Insulin-Like Growth Factor I Deficient Mice

Insulin-like growth factor-I (IGF-I) belongs to the family of insulin-related peptides that fulfils a key role during the late development of the nervous system. Human IGF1 mutations cause profound deafness, poor growth and mental retardation. Accordingly, Igf1−/− null mice are dwarfs that have low survival rates, cochlear alterations and severe sensorineural deafness. Presbycusis (age-related hearing loss) is a common disorder associated with aging that causes social and cognitive problems. Aging is also associated with a decrease in circulating IGF-I levels and this reduction has been related to cognitive and brain alterations, although there is no information as yet regarding the relationship between presbycusis and IGF-I biodisponibility. Here we present a longitudinal study of wild type Igf1+/+ and null Igf1−/− mice from 2 to 12 months of age comparing the temporal progression of several parameters: hearing, brain morphology, cochlear cytoarchitecture, insulin-related factors and IGF gene expression and IGF-I serum levels. Complementary invasive and non-invasive techniques were used, including auditory brainstem-evoked response (ABR) recordings and in vivo MRI brain imaging. Igf1−/− null mice presented profound deafness at all the ages studied, without any obvious worsening of hearing parameters with aging. Igf1+/+ wild type mice suffered significant age-related hearing loss, their auditory thresholds and peak I latencies augmenting as they aged, in parallel with a decrease in the circulating levels of IGF-I. Accordingly, there was an age-related spiral ganglion degeneration in wild type mice that was not evident in the Igf1 null mice. However, the Igf1−/− null mice in turn developed a prematurely aged stria vascularis reminiscent of the diabetic strial phenotype. Our data indicate that IGF-I is required for the correct development and maintenance of hearing, supporting the idea that IGF-I-based therapies could contribute to prevent or ameliorate age-related hearing loss

Desarrollo de vídeos doodle como apoyo a la docencia en anestesiología veterinaria

Depto. de Medicina y Cirugía AnimalFac. de VeterinariaFALSEsubmitte

Updated database and trends of declared low- and no-calorie sweeteners from foods and beverages marketed in spain

Background: The past few years have witnessed an increase in the availability of food products containing one or more low- and no-calorie sweeteners (LNCS) in the Spanish market, mostly due to the new massive reformulation plan. However, these are not included in food composition tables or databases, and, therefore, assessment of their intake among the population is complex. This study aims to update a database including commercialized foods and beverages. Method: A systematic search of ingredients information from the different food and beverage categories was undertaken during 2019 by recording the availability and type of LNCS declared in the information of the product from labels and online shopping platforms of retailers from Spain to update a previous food composition database compiled in 2017. Results: A total of 1,238 products were identified. The major groups were sugar and sweets (24%), non-alcoholic beverages (21%), cereals and grains (19%), and milk and dairy products (14%) accounting for >70% of total products. The mainly declared LNCS were sorbitol (19.5%), sucralose (19.5%), and acesulfame K (19.2%). Conclusion: There is a wide variety of products that include LNCS as a main ingredient with higher availability than when compared with the results of database of 2017, consequently, it might be expected that LNCS are commonly consumed at present in the Spanish diet

Sudden Cardiac Death in Heart Failure: A 20-Year Perspective From a Mediterranean Cohort

Background: The prediction of sudden cardiac death (SCD) in heart failure (HF) remains an unmet need. The aim of our study was to assess the prevalence of SCD over 20 years in outpatients with HF managed in a Mediterranean multidisciplinary HF Clinic, and to compare the proportion of SCD (SCD/all-cause death) to the expected proportional occurrence based on the validated Seattle Proportional Risk Model (SPRM) score. Methods and results: This prospective observational registry study included 2772 outpatients with HF admitted between August 2001 and May 2021. Patients were included when the cause of death was known and SPRM score was available. Over the 20-year study period, 1351 patients (48.7%) died during a median follow-up period of 3.8 years (interquartile range 1.6-7.6). Among these patients, the proportion of SCD out of the total of deaths was 13.6%, whereas the predicted by SPRM was 39.6%. This lower proportion of SCD was observed independently of left ventricular ejection fraction, ischemic etiology, and the presence of an implantable cardiac defibrillator. Conclusions: In a Mediterranean cohort of outpatients with HF, the proportion of SCD was lower than expected based on the SPRM score. Future studies should investigate to what extend epidemiological and guideline-directed medical therapy patterns influence SCD

Folic acid deficiency induces premature hearing loss through mechanisms involving cochlear oxidative stress and impairment of homocysteine metabolism

Nutritional imbalance is emerging as a causative factor of hearing loss (HL). Epidemiological studies have linked HL to elevated plasma homocysteine (pHcy) and folate deficiency, and showed that folate supplementation lowers pHcy levels potentially ameliorating age-related HL. The purpose of this study was to address the potential impact of folate deficiency in HL and to unveil the underlying mechanisms. For this purpose, two-month old C57BL/6J-mice (Animalia Chordata Mus musculus) were randomly divided in two groups (n=65 each) that were fed folate-deficient or standard diets for 8 weeks. HPLC analysis demonstrated 7-fold decline in serum folate and 3-fold increase in pHcy levels. Auditory brainstem recordings showed that only folate-deficient mice exhibited severe HL and cochlear TUNEL+-apoptotic cells. RTqPCR and Western-blotting showed reduced levels of enzymes involved in Hcy production and recycling, together with 30% increased protein homocysteinylation. Redox stress was evidenced by decreased expression of Cat, Gpx4 and Gss genes, increased levels of the proteins MnSOD and the NOX-complex adaptor p22phox, and elevated concentrations of glutathione species. Altogether, our findings show for the first time that the relationship between folate-induced hyperhomocysteinemia and premature HL involves impairment of cochlear Hcy metabolism and associated oxidative stress

Gamificación en Anestesiología Clínica Veterinaria: Ampliación

Desarrollo de un juego de mesa que permitan el aprendizaje de conceptos teóricos relacionados con la anestesia en un entorno de gamificación

Competencias básicas para la aplicación de la medicina regenerativa en la clínica de pequeños animales

Depto. de Medicina y Cirugía AnimalFac. de VeterinariaFALSEsubmitte

RAF Kinase Activity Regulates Neuroepithelial Cell Proliferation and Neuronal Progenitor Cell Differentiation during Early Inner Ear Development

Background: Early inner ear development requires the strict regulation of cell proliferation, survival, migration and differentiation, coordinated by the concerted action of extrinsic and intrinsic factors. Deregulation of these processes is associated with embryonic malformations and deafness. We have shown that insulin-like growth factor I (IGF-I) plays a key role in embryonic and postnatal otic development by triggering the activation of intracellular lipid and protein kinases. RAF kinases are serine/threonine kinases that regulate the highly conserved RAS-RAF-MEK-ERK signaling cascade involved in transducing the signals from extracellular growth factors to the nucleus. However, the regulation of RAF kinase activity by growth factors during development is complex and still not fully understood. Methodology/Principal Findings: By using a combination of qRT-PCR, Western blotting, immunohistochemistry and in situ hybridization, we show that C-RAF and B-RAF are expressed during the early development of the chicken inner ear in specific spatiotemporal patterns. Moreover, later in development B-RAF expression is associated to hair cells in the sensory patches. Experiments in ex vivo cultures of otic vesicle explants demonstrate that the influence of IGF-I on proliferation but not survival depends on RAF kinase activating the MEK-ERK phosphorylation cascade. With the specific RAF inhibitor Sorafenib, we show that blocking RAF activity in organotypic cultures increases apoptosis and diminishes the rate of cell proliferation in the otic epithelia, as well as severely impairing neurogenesis of the acoustic-vestibular ganglion (AVG) and neuron maturation. Conclusions/Significance: We conclude that RAF kinase activity is essential to establish the balance between cell proliferation and death in neuroepithelial otic precursors, and for otic neuron differentiation and axonal growth at the AVG

AKT Signaling Mediates IGF-I Survival Actions on Otic Neural Progenitors

Background: Otic neurons and sensory cells derive from common progenitors whose transition into mature cells requires the coordination of cell survival, proliferation and differentiation programmes. Neurotrophic support and survival of post-mitotic otic neurons have been intensively studied, but the bases underlying the regulation of programmed cell death in immature proliferative otic neuroblasts remains poorly understood. The protein kinase AKT acts as a node, playing a critical role in controlling cell survival and cell cycle progression. AKT is activated by trophic factors, including insulin-like growth factor I (IGF-I), through the generation of the lipidic second messenger phosphatidylinositol 3-phosphate by phosphatidylinositol 3-kinase (PI3K). Here we have investigated the role of IGF-dependent activation of the PI3K-AKT pathway in maintenance of otic neuroblasts. Methodology/Principal Findings: By using a combination of organotypic cultures of chicken (Gallus gallus) otic vesicles and acoustic-vestibular ganglia, Western blotting, immunohistochemistry and in situ hybridization, we show that IGF-I-activation of AKT protects neural progenitors from programmed cell death. IGF-I maintains otic neuroblasts in an undifferentiated and proliferative state, which is characterised by the upregulation of the forkhead box M1 (FoxM1) transcription factor. By contrast, our results indicate that post-mitotic p27Kip-positive neurons become IGF-I independent as they extend their neuronal processes. Neurons gradually reduce their expression of the Igf1r, while they increase that of the neurotrophin receptor, TrkC. Conclusions/Significance: Proliferative otic neuroblasts are dependent on the activation of the PI3K-AKT pathway by IGF-I for survival during the otic neuronal progenitor phase of early inner ear development