RESUMEN
Autism spectrum disorder (ASD) is a major neurodevelopmental disorder affecting 1 in 36 children in the United States. While neurons have been the focus of understanding ASD, an altered neuro-immune response in the brain may be closely associated with ASD, and a neuro-immune interaction could play a role in the disease progression. As the resident immune cells of the brain, microglia regulate brain development and homeostasis via core functions including phagocytosis of synapses. While ASD has been traditionally considered a polygenic disorder, recent large-scale human genetic studies have identified SCN2A deficiency as a leading monogenic cause of ASD and intellectual disability. We generated a Scn2a-deficient mouse model, which displays major behavioral and neuronal phenotypes. However, the role of microglia in this disease model is unknown. Here, we reported that Scn2a-deficient mice have impaired learning and memory, accompanied by reduced synaptic transmission and lower spine density in neurons of the hippocampus. Microglia in Scn2a-deficient mice are partially activated, exerting excessive phagocytic pruning of post-synapses related to the complement C3 cascades during selective developmental stages. The ablation of microglia using PLX3397 partially restores synaptic transmission and spine density. To extend our findings from rodents to human cells, we established a microglia-incorporated human cerebral organoid model carrying an SCN2A protein-truncating mutation identified in children with ASD. We found that human microglia display increased elimination of post-synapse in cerebral organoids carrying the SCN2A mutation. Our study establishes a key role of microglia in multi-species autism-associated models of SCN2A deficiency from mouse to human cells.
RESUMEN
CONTEXT: One advantage of computed tomographic pulmonary angiograms (CTPA) is that they often show pathology in patients in whom pulmonary embolism (PE) has been excluded. In this investigation, we identified the ancillary findings on CTPAs that were negative for PE to obtain an impression of the type of findings shown. METHODS: This was a retrospective analysis of findings on CTPAs that were negative for PE obtained in nine emergency departments between January 2016 - February 2018. Ancillary findings were assessed by review of the radiographic reports. RESULTS: Ancillary findings were identified in N=338 (40.9%) of 825 patients with CTPAs that were negative for PE. Most ancillary findings, 254 (75.1%) of 338 were pulmonary or pleural abnormalities. Liver, gall bladder, kidney, or pancreatic abnormalities were shown in 26 (7.7%) cases, and abnormalities of the heart or great vessels were shown in 23 (6.8%) of cases. Abnormalities of the esophagus or intestine were shown in 12 (3.6%), abnormalities of the thyroid in 10 (3.0%) and abnormalities of bone or soft tissue lesions were shown in three (0.9%) cases. Inferential statistical procedures demonstrated that the occurrence of ancillary findings in patients with negative CTPAs was proportionately greater in patients who were 50 years and older (p < 0.001), although not between genders (p = 0.145). CONCLUSIONS: Ancillary findings on CTPAs that were negative for PE were frequently reported. Future studies might focus of the extent to which ancillary findings on CTPA assisted physicians in management of the patient.