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Discrete subaortic stenosis (DSS) is a pediatric condition in which a fibrotic membrane forms within the left ventricular outflow track. The fibrotic membrane is removed surgically; however, there is a high rate of reoccurrence which requires a second surgery. There are currently no tools available to predict the risk of reoccurrence in DSS patients, a limitation addressed by this study. In this study, we analyzed resected fibrotic membranes for DSS patients at the time of first surgery for non-recurrent and recurrent patients, and at the time of second surgery for recurrent patients. RNA-sequencing was conducted to obtain a global screen of changes in RNA expression while mass spectrometry was used to obtain a global screen of changes in protein expression. The results from the RNA-sequencing and mass spectrometry provide valuable insight into genes and the proteins that are differentially regulated in recurrent vs non-recurrent DSS patients.

Traumatic brain injury (TBI) leads to lasting brain dysfunction with chronic neuroinflammation typified by nucleotide-binding domain leucine-rich repeat and pyrin domain-containing receptor 3 (NLRP3) inflammasome activation in microglia. This study probed whether a single intranasal (IN) administration of human mesenchymal stem cell-derived extracellular vesicles (hMSC-EVs) naturally enriched with activated microglia-modulating miRNAs can avert chronic adverse outcomes of TBI. Small RNA sequencing confirmed the enrichment of miRNAs capable of modulating activated microglia in hMSC-EV cargo. IN administration of hMSC-EVs into adult mice ninety minutes after the induction of a unilateral controlled cortical impact injury resulted in their incorporation into neurons and microglia in both injured and contralateral hemispheres. A single higher dose hMSC-EV treatment also inhibited NLRP3 inflammasome activation after TBI, evidenced by reduced NLRP3, apoptosis-associated speck-like protein containing a CARD, activated caspase-1, interleukin-1 beta, and IL-18 levels in the injured brain. Such inhibition in the acute phase of TBI endured in the chronic phase, which could also be gleaned from diminished NLRP3 inflammasome activation in microglia of TBI mice receiving hMSC-EVs. Proteomic analysis and validation revealed that higher dose hMSC-EV treatment thwarted the chronic activation of the p38 mitogen-activated protein kinase (MAPK) signaling pathway by IL-18, which decreased the release of proinflammatory cytokines. Inhibition of the chronic activation of NLRP3-p38/MAPK signaling after TBI also prevented long-term cognitive and mood impairments. Notably, the animals receiving higher doses of hMSC-EVs after TBI displayed better cognitive and mood function in all behavioral tests than animals receiving the vehicle after TBI. A lower dose of hMSC-EV treatment also partially improved cognitive and mood function. Thus, an optimal IN dose of hMSC-EVs naturally enriched with activated microglia-modulating miRNAs can inhibit the chronic activation of NLRP3-p38/MAPK signaling after TBI and prevent lasting brain dysfunction.

This study aimed to determine how the muscle mass of the lower leg affects the preservation of the lower extremities in patients with diabetic foot ulcer. This study analyzed patients with diabetic foot ulcer between January 2014 and June 2018 with a follow-up of at least 2 years. Of these 181 patients whose ulcer is located distal to the metatarsophalangeal joint, which was categorized as grade ≤2 by the Wagner classification were classified into 4 grades: grade 0 (treated without amputation), grade 1 (amputation distal to the metatarsophalangeal joint), grade 2 (Ray, transmetatarsal, Lisfranc, and Chopart amputation), and grade 3 (Syme, below-knee, and above-knee amputation) according to the final amputation degree. The muscles of the lower leg were classified into 4 compartments: anterior, lateral, deep posterior, and superficial posterior. The cross-sectional area and attenuation to estimate the muscle volume and density were measured at the axial image of computed tomography (CT) angiography. No significant differences were observed in the sex ratio and mean age among the grades ( P = .966 and .962). The cross-sectional area of the anterior, lateral, and posterior compartments demonstrated no significant differences, but that of the superficial posterior compartment exhibited significant differences among the grades ( P