Actitud y habilidades del médico residente de pediatría en la enseñanza de los médicos internos de pregrado, experiencia en hospitales públicos y privados al noroeste de México

No abstract

Background The apolipoprotein E (APOE) ε4 allele confers the strongest risk for late-onset Alzheimer’s disease (AD) besides age itself, but the mechanisms underlying this risk are debated. One hypothesis supported by evidence from multiple labs is that apoE4 binds to the amyloid-β (Aβ) peptide and catalyzes its polymerization into neurotoxic oligomers and fibrils. Inhibiting this early step in the amyloid cascade may thereby reduce or prevent neurodegeneration and AD. Methods Using a design of experiments (DOE) approach, we developed a high-throughput assay to identify inhibitors of apoE4-catalyzed polymerization of Aβ into oligomers and fibrils. We used it to screen the NIH Clinical Collection of small molecule drugs tested previously in human clinical trials. We then evaluated the efficacy and cytotoxicity of the hit compounds in primary neuron models of apoE4-induced Aβ and phosphorylated tau aggregation. Finally, we performed retrospective analyses of the National Alzheimer’s Coordinating Center (NACC) clinical dataset, using Cox regression and Cox proportional hazards models to determine if the use of two FDA-approved hit compounds was associated with better cognitive scores (Mini-Mental State Exam), or improved AD clinical diagnosis, when compared with other medications of the same clinical indication. Results Our high-throughput screen identified eight blood-brain barrier (BBB)-permeable hit compounds that reduced apoE4-catalyzed Aβ oligomer and fibril formation in a dose-dependent manner. Five hit compounds were non-toxic toward cultured neurons and also reduced apoE4-promoted Aβ and tau neuropathology in a dose-dependent manner. Three of the five compounds were determined to be specific inhibitors of apoE4, whereas the other two compounds were Aβ or tau aggregation inhibitors. When prescribed to AD patients for their normal clinical indications, two of the apoE4 inhibitors, imipramine and olanzapine, but not other (non-hit) antipsychotic or antidepressant medications, were associated with improvements in cognition and clinical diagnosis, especially among APOE4 carriers. Conclusions The critical test of any proposed AD mechanism is whether it leads to effective treatments. Our high-throughput screen identified two promising FDA-approved drugs, imipramine and olanzapine, which have no structural, functional, or clinical similarities other than their shared ability to inhibit apoE4-catalyzed Aβ polymerization, thus identifying this mechanism as an essential contribution of apoE4 to AD.

Vocal learning is a complex trait that is expressed differently across different taxa. While many of the best-studied species exhibit close-ended learning, in which vocal signals are learned from adult tutors during juvenile critical learning periods, other species have open-ended learning in which new signals are learned throughout life. Budgerigars (Melopsittacus undulatus) are an extreme example of an open-ended learner, in which both sexes have a repertoire of multiple contact calls types that continually change through adulthood to match the call types of social associates. We discuss the analytical challenges posed by the rapid plasticity of the budgerigar vocal repertoire and compare results from several different approaches to characterizing call variation. We then consider the social implications and benefits of contact call matching in fission–fusion groups. Finally, we examine the mechanisms underlying this plasticity, with a special focus on the role of the gene FoxP2. We find downregulation of FoxP2 mRNA and protein in the primary parrot vocal learning center, MMSt, across a variety of social conditions in which birds also show vocal plasticity. The results support the hypothesis that FoxP2 is a key gene regulating the neural plasticity that underlies the persistent vocal plasticity exhibited by budgerigars.