Chorioamnionitis disrupts erythropoietin and melatonin homeostasis through the placental-fetal-brain axis during critical developmental periods.

Introduction: Novel therapeutics are emerging to mitigate damage from perinatal brain injury (PBI). Few newborns with PBI suffer from a singular etiology. Most experience cumulative insults from prenatal inflammation, genetic and epigenetic vulnerability, toxins (opioids, other drug exposures, environmental exposure), hypoxia-ischemia, and postnatal stressors such as sepsis and seizures. Accordingly, tailoring of emerging therapeutic regimens with endogenous repair or neuro-immunomodulatory agents for individuals requires a more precise understanding of ligand, receptor-, and non-receptor-mediated regulation of essential developmental hormones. Given the recent clinical focus on neurorepair for PBI, we hypothesized that there would be injury-induced changes in erythropoietin (EPO), erythropoietin receptor (EPOR), melatonin receptor (MLTR), NAD-dependent deacetylase sirtuin-1 (SIRT1) signaling, and hypoxia inducible factors (HIF1α, HIF2α). Specifically, we predicted that EPO, EPOR, MLTR1, SIRT1, HIF1α and HIF2α alterations after chorioamnionitis (CHORIO) would reflect relative changes observed in human preterm infants. Similarly, we expected unique developmental regulation after injury that would reveal potential clues to mechanisms and timing of inflammatory and oxidative injury after CHORIO that could inform future therapeutic development to treat PBI. Methods: To induce CHORIO, a laparotomy was performed on embryonic day 18 (E18) in rats with transient uterine artery occlusion plus intra-amniotic injection of lipopolysaccharide (LPS). Placentae and fetal brains were collected at 24 h. Brains were also collected on postnatal day 2 (P2), P7, and P21. EPO, EPOR, MLTR1, SIRT1, HIF1α and HIF2α levels were quantified using a clinical electrochemiluminescent biomarker platform, qPCR, and/or RNAscope. MLT levels were quantified with liquid chromatography mass spectrometry. Results: Examination of EPO, EPOR, and MLTR1 at 24 h showed that while placental levels of EPO and MLTR1 mRNA were decreased acutely after CHORIO, cerebral levels of EPO, EPOR and MLTR1 mRNA were increased compared to control. Notably, CHORIO brains at P2 were SIRT1 mRNA deficient with increased HIF1α and HIF2α despite normalized levels of EPO, EPOR and MLTR1, and in the presence of elevated serum EPO levels. Uniquely, brain levels of EPO, EPOR and MLTR1 shifted at P7 and P21, with prominent CHORIO-induced changes in mRNA expression. Reductions at P21 were concomitant with increased serum EPO levels in CHORIO rats compared to controls and variable MLT levels. Discussion: These data reveal that commensurate with robust inflammation through the maternal placental-fetal axis, CHORIO impacts EPO, MLT, SIRT1, and HIF signal transduction defined by dynamic changes in EPO, EPOR, MLTR1, SIRT1, HIF1α and HIF2α mRNA, and EPO protein. Notably, ligand-receptor mismatch, tissue compartment differential regulation, and non-receptor-mediated signaling highlight the importance, complexity and nuance of neural and immune cell development and provide essential clues to mechanisms of injury in PBI. As the placenta, immune cells, and neural cells share many common, developmentally regulated signal transduction pathways, further studies are needed to clarify the perinatal dynamics of EPO and MLT signaling and to capitalize on therapies that target endogenous neurorepair mechanisms.

Corrigendum: Methadone alters the peripheral inflammatory and central immune landscape following prenatal exposure in rats.

[This corrects the article DOI: 10.3389/adar.2022.10792.].

Hyperoxia Improves Repeated-Sprint Ability and the Associated Training Load in Athletes.

This study investigated the impact of hyperoxic gas breathing (HYP) on repeated-sprint ability (RSA) and on the associated training load (TL). Thirteen team- and racquet-sport athletes performed 6-s all-out sprints with 24-s recovery until exhaustion (power decrement ≥ 15% for two consecutive sprints) under normoxic (NOR: FIO2 0.21) and hyperoxic (HYP: FIO2 0.40) conditions in a randomized, single-blind and crossover design. The following variables were recorded throughout the tests: mechanical indices, arterial O2 saturation (SpO2), oxygenation of the vastus lateralis muscle with near-infrared spectroscopy, and electromyographic activity of the vastus lateralis, rectus femoris, and gastrocnemius lateralis muscles. Session TL (work × rate of perceived exertion) and neuromuscular efficiency (work/EMG [Electromyography]) were calculated. Compared with NOR, HYP increased SpO2 (2.7 ± 0.8%, Cohen's effect size ES 0.55), the number of sprints (14.5 ± 8.6%, ES 0.28), the total mechanical work (13.6 ± 6.8%, ES 0.30), and the session TL (19.4 ± 7.0%, ES 0.33). Concomitantly, HYP increased the amplitude of muscle oxygenation changes during sprints (25.2 ± 11.7%, ES 0.36) and recovery periods (26.1 ± 11.4%, ES 0.37), as well as muscle recruitment (9.9 ± 12.1%, ES 0.74), and neuromuscular efficiency (6.9 ± 9.0%, ES 0.24). It was concluded that breathing a hyperoxic mixture enriched to 40% O2 improves the total work performed and the associated training load during an open-loop RSA session in trained athletes. This ergogenic impact may be mediated by metabolic and neuromuscular alterations.

A case report of myocardial infarction with non-obstructive coronary arteries as the initial presentation of eosinophilic granulomatosis with polyangiitis.

BACKGROUND: Eosinophilic granulomatosis with polyangiitis (EGPA) is a multisystem disorder commonly affecting the lung and skin, with cardiovascular involvement found in up to 60% of patients. We present a case of myocardial infarction with non-obstructive coronary arteries (MINOCA) as the initial presentation of EGPA. CASE SUMMARY: A 52-year-old female with past medical history of asthma, recurrent sinusitis, and peripheral neuropathy presented to our hospital with chest pain, rash, acute vision loss, elevated troponin, and peripheral eosinophilia. Electrocardiogram showed no ischaemic changes and coronary angiography displayed normal coronary anatomy. On a subsequent visit, cardiac magnetic resonance (CMR) showed predominant focal anteroseptal and inferoseptal akinesis with focal sub-endocardial delayed enhancement, indicative of a myocardial infarction involving the septal branches of the left anterior descending artery. Due to the focal findings on CMR, peripheral eosinophilia, and rash, the patient was evaluated for EGPA. Rheumatologic workup and skin biopsy were suggestive of small vessel vasculitis. The patient was diagnosed with multi-organ EGPA, involving the coronaries, which was ultimately thought to be the aetiology of her MINOCA. Following steroid and monoclonal antibody therapy, the patient experienced notable improvement in her cardiac function at follow-up appointments. DISCUSSION: This is a unique case MINOCA as the initial presentation of EGPA. Considering the heterogeneous disease presentation of those diagnosed with MINOCA, utilization of CMR is essential to guide diagnosis and management of such patients.

Methadone alters the peripheral inflammatory and central immune landscape following prenatal exposure in rats.

Opioid use during pregnancy continues to rise at alarming rates with a parallel trend in the number of infants and children exposed to opioid medications each year. Prenatal opioid exposure (POE) occurs at a critical timepoint in neurodevelopment disrupting intricate pathways essential for neural-immune maturation with the potential for devastating long-term consequences. Understanding the mechanisms underlying injury associated with POE is essential to address long-term outcomes and identify diagnostic and therapeutic biomarkers in this vulnerable patient population. Using an established preclinical model of POE, we investigated changes in cerebral and peripheral inflammation and peripheral blood mononuclear cell (PBMC) activity. We hypothesized that neuroinflammation, as defined by changes in specific cerebral immune cell populations, would exist in adult rats following POE concomitant with sustained peripheral immune hyperreactivity (SPIHR). Our data demonstrated alterations in cerebral immune cells at postnatal day 60 (P60) typified by increased regulatory T cells (p < 0.01) and neutrophils (p < 0.05) in rats with POE compared to controls. Evaluation of serum revealed increased levels of IL-6 (p < 0.05) and CXCL1 (p < 0.05) at P21 in rats with POE compared to controls with no significant difference in cytokine or chemokine levels between the two groups at P60. Additionally, PBMCs isolated from rats with POE at P21 demonstrated baseline hypersecretion of IL-6 (p < 0.01) and SPIHR with increased levels of TNF-α (p < 0.05) and CXCL1 (p < 0.05) following stimulation with LPS. At P60, however, there was no significant difference found in cytokine or chemokine levels secreted by PBMCs isolated from rats with POE at baseline or with LPS stimulation when compared to controls. Taken together, these data demonstrate cerebral inflammation months after prenatal opioid exposure and long after the resolution of systemic inflammation and SPIHR seen at toddler age equivalent. Chronic alterations in the cerebral immune cell populations secondary to prenatal opioid exposure may underly long-term consequences of developmental brain injury including deficits in cognition and attention. These findings may be invaluable to further investigations of precise biomarkers of injury and targeted therapeutics for this vulnerable population.

A case report of right ventricular outflow tract obstruction caused by B-cell lymphoma: a rare presentation in an adult patient with pulmonary atresia.

BACKGROUND: Right ventricle outflow tract (RVOT) dysfunction is a common long-term complication in adult patients with pulmonary atresia/ventricular septal defect (PA/VSD). Common causes include valve thrombosis, stent fractures, and graft calcification. We present, to the best of our knowledge, the first case of malignant invasion of a Gore-Tex conduit, causing severe right ventricle (RV) failure. CASE SUMMARY: A 30-year-old woman with a history of PA/VSD with major aortopulmonary collateral arteries (MAPCAs) presented with worsening dyspnoea and exercise intolerance. In infancy, she underwent unifocalization of the right- and left-sided AP collaterals utilizing an 18 and 16 mm Gore-Tex graft, respectively. At age 7, she had surgical repair with VSD patch closure and placement of a 20 mm right ventricle-pulmonary artery (RVPA) homograft connected to a 20 mm Gore-Tex graft with linkage to the previously placed right and left unifocalization grafts. A transthoracic echocardiogram revealed a severely dilated RV and a heavily calcified RVOT conduit with severe stenosis. Cardiac computed tomography showed a stenotic RVPA conduit with calcified mural mass. She underwent surgical revision of the RVPA conduit with thromboendarterectomy of bilateral pulmonary arteries. Pathology of the removed conduit revealed fibrin-associated Epstein-Barr virus-positive diffuse large B-cell lymphoma (FA DLBCL). DISCUSSION: One prior case report has demonstrated invasion of DLBCL involving an aortic synthetic tube graft. However, malignant invasion of the RVOT Gore-Tex conduit has yet to be reported. Pathological review can be essential in guiding management. Malignant invasion of Gore-Tex conduits is a rare phenomenon, but one that should be closely monitored following repair of the RVOT.

Sarcoidosis and Systemic Sclerosis: Strange Bedfellows.

Coexistence of systemic sclerosis and sarcoidosis is rare. Both have predominant lung manifestations, each with distinctive features on computed tomography (CT) of the chest. We present herein a 52-year-old male with limited systemic sclerosis manifested primarily by sclerodactyly and subsequently by shortness of breath. A series of CT scans of the chest were reviewed. Initial CT chest one year prior to sclerodactyly onset revealed bilateral hilar and right paratracheal, prevascular, and subcarinal adenopathy. Five-year follow-up demonstrated thin-walled cysts, mediastinal lymphadenopathy, and nonspecific nodules. Due to progression of dyspnea, follow-up CT chest after one year again demonstrated multiple cysts with peripheral nodularity and subpleural nodules, but no longer with hilar or mediastinal adenopathy. Diagnostic open lung biopsy was significant for noncaseating granulomas suggestive of sarcoidosis. This is the first known case of a patient with systemic sclerosis diagnosed with sarcoidosis through lung biopsy without radiographic evidence of hilar or mediastinal lymphadenopathy at the time of biopsy. A review of cases of concomitant sarcoidosis and systemic sclerosis is discussed, including the pathophysiology of each disease with shared pathways leading to the development of both conditions in one patient.

Failure of enema reduction for ileocolic intussusception at a referring hospital does not preclude repeat attempts at a children's hospital.

BACKGROUND: Some children with intussusception undergo attempted enema reduction at a hospital without pediatric radiology expertise and are transferred to a children's hospital (CH) if this is unsuccessful. We sought to determine whether a failed reduction (FR) at a referring hospital predicted failure of repeated attempts by a pediatric radiologist at a CH. METHODS: A retrospective review of all children with ileocolic intussusception admitted to a large CH over 9 years was performed. Differences in outcome between those who initially presented to the CH and those who had a FR elsewhere before transfer (FR --> CH) were assessed. RESULTS: A total of 152 subjects were identified. There was no difference in the frequency of successful enema reduction at the CH for those who initially presented at the CH (60.5%) and those who were transferred after a FR elsewhere (60.7%). The only predictor of successful reduction was anatomy, whereby 64% of intussusceptions proximal to the splenic flexure were reduced, but only 35% of those distal to that point (P < .01). CONCLUSIONS: Children who are transferred to a CH after failed enema reduction elsewhere should undergo a repeat hydrostatic or pneumatic enema reduction in the absence of other contraindications.