Reduced bone morphogenetic protein receptor 2 (BMPR2) expression in patients with pulmonary arterial hypertension (PAH) can impair pulmonary arterial EC (PAEC) function. This can adversely affect EC survival and promote SMC proliferation. We hypothesized that interventions to normalize expression of genes that are targets of BMPR2 signaling could restore PAEC function and prevent or reverse PAH. Here we have characterized, in human PAECs, a BMPR2-mediated transcriptional complex between PPARγ and β-catenin and shown that disruption of this complex impaired BMP-mediated PAEC survival. Using whole genome-wide ChIP-Chip promoter analysis and gene expression microarrays, we delineated PPARγ/β-catenin-dependent transcription of target genes including APLN, which encodes apelin. We documented reduced PAEC expression of apelin in PAH patients versus controls. In cell culture experiments, we showed that apelin-deficient PAECs were prone to apoptosis and promoted pulmonary arterial SMC (PASMC) proliferation. Conversely, we established that apelin, like BMPR2 ligands, suppressed proliferation and induced apoptosis of PASMCs. Consistent with these functions, administration of apelin reversed PAH in mice with reduced production of apelin resulting from deletion of PPARγ in ECs. Taken together, our findings suggest that apelin could be effective in treating PAH by rescuing BMPR2 and PAEC dysfunction.

The importance of genetic predisposition, inflammation, and autoimmune mechanisms in the development of pulmonary arterial hypertension (PAH) is becoming increasingly clear. We hypothesized that the analysis of gene expression profiles from peripheral blood mononuclear cells would distinguish patients with PAH from normal volunteers. We also hypothesized that a subset of genes would discriminate between patients with idiopathic PAH and pulmonary hypertension related to secondary causes. Mononuclear cells were isolated from 15 patients diagnosed with PAH and 6 normal control subjects. Microarray expression was performed, and the expression profiles were analyzed for consistent and predictive differences in gene expression. We identified a signature set of 106 genes that discriminated with high certainty (p < or = 0.002) between patients with PAH and normal individuals. The results of the microarray analysis were retrospectively and prospectively confirmed by quantitative polymerase chain reaction for 2 of the 106 genes. Supervised clustering analysis generated a list of differentially expressed genes between patients with idiopathic and secondary causes of pulmonary hypertension. Microarray expression profiling of peripheral blood cells can discriminate between patients with PAH and normal volunteers. These findings may have important implications toward diagnosis, screening, and pathogenesis of this disease.

ESD requires the endoscopist to perform a surgical dissection. Until now, development of these skills required intensive training on porcine models that are not widely available. We were able to create a method using the excised portion from sleeve gastrectomy patients, providing a more accessible and cost-effective model for ESD training and potentially other endoscopic therapeutic modalities.

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Burn injury in children can cause severe and chronic physical and mental sequelae. Opioids are a mainstay in burn pain management but increasing utilization in this country has led to concern for their continued use and potential for dependence. Methadone is a long-acting analgesic that targets the N-methyl-D-aspartate (NMDA) receptor in addition to the mu opioid receptor and has benefit in adult burn patients. However, its use in the pediatric burn population has been less robustly studied. This is a retrospective cohort study at a single Level 1 Burn Center whose primary aim is to compare opioid utilization 36 hours postoperatively between pediatric burn patients who received intraoperative, intravenous methadone and those who did not. Secondary aim was to describe differences in methadone-related complications between the cohorts. There was decreased opioid utilization measured by median morphine equivalents per kilogram (ME/kg) postoperatively in the methadone cohort compared to the control cohort (0.54mg/kg v. 0.77mg/kg, p = 0.18). No adverse events were noted upon chart review. The data suggests methadone use is beneficial in pediatric burn patients, but further prospective studies are warranted on a larger population.

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Introduction Post-operative pain management can be a significant challenge in patients undergoing burn excision. Standard pharmacologic pain management strategies include both opioid and non-opioid medications. Given the national overuse of opioids and the associated negative repercussions, it is prudent that we find ways manage pain with fewer or no opioids. We hypothesize that intraoperative administration of intravenous methadone will reduce the total morphine milligram equivalents (MME) used in the 36 hours following surgery. Methods This is a retrospective single-center cohort study of adult burn patients who underwent a first excision of full thickness burn between January 2019 through January 2021. The exposure group received intraoperative methadone while the control group did not. The primary outcome was total MME utilized in the 36 hours following surgery. Secondary outcomes included average pain score and post-anesthesia care unit (PACU) total MME utilized. Chi squared tests were used for statistical analysis of categorical variables and unpaired t-tests were used for continuous variables. Results The control group contained 35 subjects and the methadone group contained 19 subjects who did not differ in baseline characteristics. The average burned total body surface area (TBSA) was 9% in the control group and 18% in the methadone group (t(53)=-3.9, p &lt; 0.01). Intraoperative narcotic requirements did differ between groups due to intravenous methadone utilization in the intervention group (t(53)=-15, p &lt; 0.01). In the early post-operative period, the methadone group received 155 MME while the control group received 137 MME (t(53)=-0.36, p = 0.72). While in the PACU, patients in the methadone group received 5 MME while the control group received 12 MME (t(53)=1.60, p=0.12). Patient pain scores did not differ significantly between the groups (t(53)=-0.15, p=0.88). Conclusions Intraoperative utilization of methadone for burn surgery did not affect post-operative opioid usage in the first 36 hours or post-operative pain scores in a statistically significant manner. We acknowledge the data set is not large enough to power the study to detect a significant difference; additional data collection is ongoing to include several hundred subjects. Confounding variables such as different multimodal pain regimen techniques, % TBSA, extent of surgical excision, and history of opioid tolerance may exist within this data set. Further analysis is warranted to adequately power this study and account for potential confounding variables. Applicability of Research to Practice Intraoperative use of intravenous methadone may reduce use of opioid medications in the early post-operative period.