Use of model systems to understand the etiology of fragile X-associated primary ovarian insufficiency (FXPOI)

Fragile X-associated primary ovarian insufficiency (FXPOI) is among the family of disorders caused by the expansion of a CGG repeat sequence in the 5' untranslated region of the X-linked gene FMR1. About 20% of women who carry the premutation allele (55 to 200 unmethylated CGG repeats) develop hypergonadotropic hypogonadism and cease menstruating before age 40. Some proportion of those who are still cycling show hormonal profiles indicative of ovarian dysfunction. FXPOI leads to subfertility and an increased risk of medical conditions associated with early estrogen deficiency. Little progress has been made in understanding the etiology of this clinically significant disorder. Understanding the molecular mechanisms of FXPOI requires a detailed knowledge of ovarian FMR1 mRNA and FMRP’s function. In humans, non-invasive methods to discriminate the mechanisms of the premutation on ovarian function are not available, thus necessitating the development of model systems. Vertebrate (mouse and rat) and invertebrate (Drosophila melanogaster) animal studies for the FMR1 premutation and ovarian function exist and have been instrumental in advancing our understanding of the disease phenotype. For example, rodent models have shown that FMRP is highly expressed in oocytes where it is important for folliculogenesis. The two premutation mouse models studied to date show evidence of ovarian dysfunction and, together, suggest that the long repeat in the transcript itself may have some pathological effect quite apart from any effect of the toxic protein. Further, ovarian morphology in young animals appears normal and the primordial follicle pool size does not differ from that of wild-type animals. However, there is a progressive premature decline in the levels of most follicle classes. Observations also include granulosa cell abnormalities and altered gene expression patterns. Further comparisons of these models are now needed to gain insight into the etiology of the ovarian dysfunction. Premutation model systems in non-human primates and those based on induced pluripotent stem cells show particular promise and will complement current models. Here, we review the characterization of the current models and describe the development and potential of the new models. Finally, we will discuss some of the molecular mechanisms that might be responsible for FXPOI

Impacto de la hemodiafiltración de alto volumen en sobrevida de pacientes en hemodiálisis de Argentina

Tras una experiencia inicial en el uso de la hemodiafiltración en línea (OL-HDF) que se inició en Argentina en 2006 con máquinas convencionales adaptadas con un módulo ad-hoc, se evolucionó en 2012 al uso de máquinas diseñadas para tal fin, cuya implementación se amplió conforme se fueron adecuando las características de pureza del agua, capacitando a los prestadores, ganando aceptación por los financiadores, y la ampliación de los criterios de inclusión para alcanzar en 2023 un 39% de los pacientes en hemodiálisis. Se logró una elevada tasa de cumplimiento de los objetivos de anemia, depuración de toxinas y volúmenes de sustitución. También se logró demostrar a través metodología estadística (“Propensity score” y técnicas de machine-learning como “DoWhy”) el impacto en la tasa de mortalidad cuando los volúmenes convectivos son superiores a 23 L/sesión, así como la probabilidad de alcanzar otros objetivos (anemia, calcemia, fosfatemia, albúmina, etc)