Disrupted brain iron homeostasis is a common feature of neurodegenerative disease. To begin to understand how neuronal iron handling might be involved, we focused on dopaminergic neurons and asked how inactivation of transport proteins affected iron homeostasis in vivo in mice. Loss of the cellular iron exporter, ferroportin, had no apparent consequences. However, loss of transferrin receptor 1, involved in iron uptake, caused neuronal iron deficiency, age-progressive degeneration of a subset of dopaminergic neurons, and motor deficits. There was gradual depletion of dopaminergic projections in the striatum followed by death of dopaminergic neurons in the substantia nigra. Damaged mitochondria accumulated, and gene expression signatures indicated attempted axonal regeneration, a metabolic switch to glycolysis, oxidative stress, and the unfolded protein response. We demonstrate that loss of transferrin receptor 1, but not loss of ferroportin, can cause neurodegeneration in a subset of dopaminergic neurons in mice.iron | transferrin receptor | ferroportin | dopaminergic neuron | neurodegeneration
Recurrent implantation failure (RIF) is an uncommon, imprecisely defined clinical disorder characterized by failure to achieve pregnancy after repeated embryo transfers. The diverse etiologies and incomplete understanding of RIF provide significant diagnostic and therapeutic challenges to patients and providers. Careful clinical evaluation prior to assisted reproduction can uncover many treatable causes, including thyroid dysfunction, submucosal myomas, and tobacco use. The more-subtle causes often require a more-targeted assessment. Undetected, small polyps or small areas of intrauterine synechiae are relatively common and easily treated contributors to RIF. Molecular and cellular abnormalities pose a greater therapeutic challenge. Putative causes of RIF, including progesterone resistance, shifted window of receptivity, decreased integrin expression, and immunologic disturbances, should be considered in the evaluation of a patient with otherwise unexplained RIF. It may also be true that a more complex and standardized definition of RIF would be helpful in these cases. In this paper, we review the diagnostic and therapeutic approaches to RIF, with emphasis on disorders of endometrial receptivity.
Problem
Chronic endometritis, inflammation of the uterizzvvne lining caused by common gram‐negative bacterial strains or mycoplasma, has been associated with unexplained implantation failure and infertility. However, limited models of bacteria‐induced implantation loss exist to study the molecular changes that occur in vivo. The goal of this study was to provide a new resource to study the process of bacteria‐induced inflammation and implantation loss utilizing common experimental models: C57Bl/6 mice and primary human endometrial stromal cells.
Method of study
Prior to implantation, mated C57Bl/6 females were administered vehicle (saline) or gram‐negative bacterial lipopolysaccharide (LPS) at a range of concentrations by intraperitoneal injection. Implantation sites were counted, and uteri were harvested to evaluate the molecular changes that accompany LPS‐mediated implantation loss. Primary human endometrial stromal cells were decidualized in vitro in the presence and absence of LPS. Total RNA and conditioned media were harvested to evaluate the expression of known decidualization‐associated genes and various cytokines and chemokines.
Results
Lipopolysaccharide treatment resulted in fewer implantation sites in mice, decreased expression of decidualization‐associated genes, and altered expression and release of cytokines and chemokines. Immunohistological analysis of the uterus from LPS‐exposed mice demonstrated increased apoptosis and decreased proliferation during decidualization.
Conclusion
Lipopolysaccharide exposure disrupted implantation and decidualization in mice and human endometrial stromal cells. This model could be used to study the pathophysiology of implantation failure in patients with chronic endometritis or to test potential therapeutic interventions.
Objective: To evaluate whether superovulation improves fecundity in women undergoing therapeutic donor insemination (TDI). Design: Retrospective cohort study. Setting: University-affiliated fertility clinic. Patient(s): Healthy women aged 23-45 years with no history of or risk factors for infertility who underwent 152 medicated and 104 unmedicated TDI cycles from 2013 to 2018. Intervention: Unmedicated TDI versus use of medication in a TDI cycle (clomiphene citrate or letrozole). Main Outcome Measure(s): Cumulative probability of pregnancy in six TDI cycles. Result(s):In adjusted all-cycle analysis, medicated TDI cycles were less likely to result in pregnancy compared with unmedicated cycles. The incidence of twins was 23% in the medicated group and 0% in the unmedicated group. Medicated cycles were less likely to result in pregnancy in women younger than 40 years or with an antim€ ullerian hormone (AMH) level >1.2. After three cycles not resulting in pregnancy, the only women who conceived were those who crossed over from an unmedicated to a medicated cycle (12% vs. 0%).
Conclusion(s):Patients undergoing unmedicated TDI cycles had higher fecundity and no incidence of twin gestations. Older women, those with low AMH, and those who fail to conceive after three unmedicated cycles may benefit from medication. (Fertil Steril Ò 2020;113:114-20. Ó2019 by American Society for Reproductive Medicine.) El resumen está disponible en Español al final del artículo.
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