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Fat embolism syndrome describes a constellation of symptoms that follow an insult and that results in a triad of respiratory distress, neurologic symptoms, and petechia. The antecedent insult usually entails trauma or orthopedic procedure, most frequently involving long bone (especially the femur) and pelvic fractures. The underlying mechanism of injury remains unknown but entails biphasic vascular injury with vascular obstruction from fat emboli followed by an inflammatory response. We present an unusual case of a pediatric patient with acute onset of altered mental status, respiratory distress, hypoxemia, and subsequent retinal vascular occlusions after knee arthroscopy and lysis of adhesions. Diagnostic findings most supportive of the fat embolism syndrome included anemia, thrombocytopenia, pulmonary parenchymal, and cerebral pathologic findings on imaging studies. This case highlights the importance of fat embolism syndrome as a diagnostic consideration after an orthopedic procedure, even absent major trauma or long bone fracture.

This review summarizes our current knowledge on lung vasculogenesis and angiogenesis during normal lung development and the regulation of fetal and postnatal pulmonary vascular tone. In comparison to that of the adult, the pulmonary circulation of the fetus and newborn displays many unique characteristics. Moreover, altered development of pulmonary vasculature plays a more prominent role in compromised pulmonary vasoreactivity than in the adult. Clinically, a better understanding of the developmental changes in pulmonary vasculature and vasomotor tone and the mechanisms that are disrupted in disease states can lead to the development of new therapies for lung diseases characterized by impaired alveolar structure and pulmonary hypertension.

This review summarizes our current knowledge on lung vasculogenesis and angiogenesis during normal lung development and the regulation of fetal and postnatal pulmonary vascular tone. In comparison to that of the adult, the pulmonary circulation of the fetus and newborn displays many unique characteristics. Moreover, altered development of pulmonary vasculature plays a more prominent role in compromised pulmonary vasoreactivity than in the adult. Clinically, a better understanding of the developmental changes in pulmonary vasculature and vasomotor tone and the mechanisms that are disrupted in disease states can lead to the development of new therapies for lung diseases characterized by impaired alveolar structure and pulmonary hypertension.

Medial vascular calcification is a common complication of chronic kidney disease (CKD). Although elevated inorganic phosphate stimulates vascular smooth muscle cell (VSMC) osteogenic transdifferentiation and calcification, the mechanisms involved in their calcification during CKD are not fully defined. Because hypoxic gene activation is linked to CKD and stimulates bone cell osteogenic differentiation, we used in vivoand in vitrorodent models to define the role of hypoxic signaling during elevated inorganic phosphate-induced VSMC calcification. Cell mineralization studies showed that elevated inorganic phosphate rapidly induced VSMC calcification. Hypoxia strongly enhanced elevated inorganic phosphate-induced VSMC calcification and osteogenic transdifferentiation, as seen by osteogenic marker expression. Hypoxia-inducible factor-1 (HIF-1), the key hypoxic transcription factor, was essential for enhanced VSMC calcification. Targeting HIF-1 expression in murine VSMC blocked calcification in hypoxia with elevated inorganic phosphate while HIF-1 activators, including clinically used FG-4592/Roxadustat, recreated a procalcifying environment. Elevated inorganic phosphate rapidly activated HIF-1, even in normal oxygenation; an effect mediated by HIF-1α subunit stabilization. Thus, hypoxia synergizes with elevated inorganic phosphate to enhance VSMC osteogenic transdifferentiation. Our work identifies HIF-1 as an early CKD-related pathological event, prospective marker, and potential target against vascular calcification in CKD-relevant conditions.

Supplemental Digital Content is available in the text.Pulmonary hypertension is associated with diverse cardiac, pulmonary, and systemic diseases in neonates, infants, and older children and contributes to significant morbidity and mortality. However, current approaches to caring for pediatric patients with pulmonary hypertension have been limited by the lack of consensus guidelines from experts in the field. In a joint effort from the American Heart Association and American Thoracic Society, a panel of experienced clinicians and clinician-scientists was assembled to review the current literature and to make recommendations on the diagnosis, evaluation, and treatment of pediatric pulmonary hypertension. This publication presents the results of extensive literature reviews, discussions, and formal scoring of recommendations for the care of children with pulmonary hypertension.

Sleep medicine is an increasingly well subscribed component of pediatric medicine. While knowledge has increased significantly in the past five decades, whether the most widely used tool to assess sleep-disordered breathing possesses demonstrable clinical utility remains unknown. The absence of certainty surrounding the impact of polysomnography (PSG) testing on clinical outcomes, superimposed on the cost and inconvenience of PSG testing, prompts a call to reassess the current normative stance toward PSG testing.

Lung transplantation for infants and children is an accepted but rarely exercised option for the treatment of end-stage lung disease, with outcomes equivalent to those for adults. However, widespread misconceptions regarding pediatric outcomes often confound timely and appropriate referral to specialty centers. We present the updated information for primary pediatricians to utilize when counseling families with children confronted by progressive end-stage pulmonary or cardiovascular disease.

The present review seeks to review the pathophysiologic processes that underlie the development of acute respiratory distress syndrome (ARDS) in children. The review intends to provide the physiologic foundation for the treatment strategies that are associated with the most optimal outcome.

To test the hypothesis that limits on repeating laboratory studies within computerized provider order entry decrease laboratory utilization.

Abstract In utero, pulmonary blood flow is closely circumscribed and oxygenation and ventilation occur via the placental circulation. Within the first few breaths of air-breathing life, the perinatal pulmonary circulation undergoes a dramatic transition as pulmonary blood flow increases 10-fold and the pulmonary arterial blood pressure decreases by 50% within 24 hours of birth. With the loss of the placental circulation, the increase in pulmonary flow enables oxygen to enter the bloodstream. The physiologic mechanisms that account for the remarkable transition of the pulmonary circulation include establishment of an air-liquid interface, rhythmic distention of the lung, an increase in shear stress and elaboration of nitric oxide from the pulmonary endothelium. If the perinatal pulmonary circulation does not dilate, blood is shunted away from the lungs at the level of the patent foramen ovale and the ductus arteriosus leading to the profound and unremitting hypoxemia that characterizes persistent pulmonary hypertension of the newborn (PPHN), a syndrome without either optimally effective preventative or treatment strategies. Despite significant advances in treatment, PPHN remains a major cause of morbidity and mortality in neonatal centers across the globe. While there is information surrounding factors that might increase the risk of PPHN, knowledge remains incomplete. Cesarean section delivery, high maternal body mass index, maternal use of aspirin, nonsteroidal anti-inflammatory agents and maternal diabetes mellitus are among the factors associated with an increased risk for PPHN. Recent data suggest that maternal use of serotonin reuptake inhibitors might represent another important risk factor for PPHN.

In utero, pulmonary blood flow is closely circumscribed and oxygenation and ventilation occur via the placental circulation. Within the first few breaths of air-breathing life, the perinatal pulmonary circulation undergoes a dramatic transition as pulmonary blood flow increases 10-fold and the pulmonary arterial blood pressure decreases by 50% within 24 hours of birth. With the loss of the placental circulation, the increase in pulmonary flow enables oxygen to enter the bloodstream. The physiologic mechanisms that account for the remarkable transition of the pulmonary circulation include establishment of an air-liquid interface, rhythmic distention of the lung, an increase in shear stress and elaboration of nitric oxide from the pulmonary endothelium. If the perinatal pulmonary circulation does not dilate, blood is shunted away from the lungs at the level of the patent foramen ovale and the ductus arteriosus leading to the profound and unremitting hypoxemia that characterizes persistent pulmonary hypertension of the newborn (PPHN), a syndrome without either optimally effective preventative or treatment strategies. Despite significant advances in treatment, PPHN remains a major cause of morbidity and mortality in neonatal centers across the globe. While there is information surrounding factors that might increase the risk of PPHN, knowledge remains incomplete. Cesarean section delivery, high maternal body mass index, maternal use of aspirin, nonsteroidal anti-inflammatory agents and maternal diabetes mellitus are among the factors associated with an increased risk for PPHN. Recent data suggest that maternal use of serotonin reuptake inhibitors might represent another important risk factor for PPHN.

To determine the frequency of positive blood cultures in patients with fevers in the initial 48-hour postoperative period.

Autoimmune pulmonary alveolar proteinosis (APAP) is characterized by autoantibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF) in blood and tissues, resulting in alveolar surfactant protein accumulation. Patients with APAP present with ground-glass opacities (GGOs) and interlobular septal thickening on thin-slice chest CT scans. Aerosolized GM-CSF therapy (aeroGM-SCF) has qualitatively improved the clinical condition of patients with APAP. This report details quantitative chest CT responses to aeroGM-CSF.

Cyclosporin A (CSA) is commonly used to prevent graft-versus-host disease. The influence of CSA on T-cell function has been extensively investigated; however, the effect of CSA on natural killer (NK) cells is less understood. NK cells were cultured with IL-2 and IL-15 with and without CSA for 1 week. Compared with controls, CSA-treated cultures showed fewer CD56+CD16+KIR+ NK cells and a reciprocal increase in CD56+CD16−KIR− cells. These changes were due mainly to a reduced proliferation of the CD56dim NK-cell subpopulation and a relative resistance of CD56bright NK cells to CSA. Following coculture with K562 targets, CSA-exposed NK cells differed from controls and lacked Ca2+ oscillations, nuclear factor of activated T cells (NFAT) dephosphorylation, and NFAT nuclear translocation. NK cells cultured in CSA retained cytotoxicity against K562, Raji, and KIR ligand-expressing lymphoblastoid cells. NK cells cultured in CSA showed increases in NKp30 and reductions in NKp44 and NKG2D. Following IL-12 and IL-18 stimulation, CSA-treated NK cells showed more IFN-γ–producing cells. Using in vitro NK-cell differentiation, progenitor cells gave rise to more CD56+KIR− NK cells in the presence of CSA than controls. Collectively, these studies show that CSA influences NK-cell function and phenotype, which may have important implications for graft-versus-leukemia effects.

Cyclosporin A (CSA) is commonly used to prevent graft-versus-host disease. The influence of CSA on T-cell function has been extensively investigated; however, the effect of CSA on natural killer (NK) cells is less understood. NK cells were cultured with IL-2 and IL-15 with and without CSA for 1 week. Compared with controls, CSA-treated cultures showed fewer CD56+CD16+KIR+NK cells and a reciprocal increase in CD56+CD16−KIR−cells. These changes were due mainly to a reduced proliferation of the CD56dimNK-cell subpopulation and a relative resistance of CD56brightNK cells to CSA. Following coculture with K562 targets, CSA-exposed NK cells differed from controls and lacked Ca2+oscillations, nuclear factor of activated T cells (NFAT) dephosphorylation, and NFAT nuclear translocation. NK cells cultured in CSA retained cytotoxicity against K562, Raji, and KIR ligand-expressing lymphoblastoid cells. NK cells cultured in CSA showed increases in NKp30 and reductions in NKp44 and NKG2D. Following IL-12 and IL-18 stimulation, CSA-treated NK cells showed more IFN-γ–producing cells. Using in vitro NK-cell differentiation, progenitor cells gave rise to more CD56+KIR−NK cells in the presence of CSA than controls. Collectively, these studies show that CSA influences NK-cell function and phenotype, which may have important implications for graft-versus-leukemia effects.

Lack of septation of the cardiac outflow tract (OFT) results in persistent truncus arteriosus (PTA), a form of congenital heart disease. The outflow myocardium expands through addition of cells originating from the pharyngeal mesoderm referred to as secondary/anterior heart field, whereas cardiac neural crest (CNC) cell–derived mesenchyme condenses to form an aortopulmonary septum. We show for the first time that a mutation in Wnt5ain mice leads to PTA. We provide evidence that Wnt5ais expressed in the pharyngeal mesoderm adjacent to CNC cells in both mouse and chicken embryos and in the myocardial cell layer of the conotruncus at the time when CNC cells begin to form the aortopulmonary septum in mice. Although expression domains of secondary heart field markers are not altered in Wnt5amutant embryos, the expression of CNC cell marker PlexinA2is significantly reduced. Stimulation of CNC cells with Wnt5a protein elicits Ca2transients, suggesting that CNC cells are capable of responding to Wnt5a. We propose a novel model in which Wnt5a produced in the OFT by cells originating from the pharyngeal mesoderm signals to adjacent CNC cells during formation of the aortopulmonary septum through a noncanonical pathway vialocalized intracellular increases in Ca2.

Lack of septation of the cardiac outflow tract (OFT) results in persistent truncus arteriosus (PTA), a form of congenital heart disease. The outflow myocardium expands through addition of cells originating from the pharyngeal mesoderm referred to as secondary/anterior heart field, whereas cardiac neural crest (CNC) cell–derived mesenchyme condenses to form an aortopulmonary septum. We show for the first time that a mutation in Wnt5a in mice leads to PTA. We provide evidence that Wnt5a is expressed in the pharyngeal mesoderm adjacent to CNC cells in both mouse and chicken embryos and in the myocardial cell layer of the conotruncus at the time when CNC cells begin to form the aortopulmonary septum in mice. Although expression domains of secondary heart field markers are not altered in Wnt5a mutant embryos, the expression of CNC cell marker PlexinA2 is significantly reduced. Stimulation of CNC cells with Wnt5a protein elicits Ca2+transients, suggesting that CNC cells are capable of responding to Wnt5a. We propose a novel model in which Wnt5a produced in the OFT by cells originating from the pharyngeal mesoderm signals to adjacent CNC cells during formation of the aortopulmonary septum through a noncanonical pathway via localized intracellular increases in Ca2+.

To test the hypothesis that an acute increase in O2tension increases cytosolic calcium (Ca2i) in fetal pulmonary artery endothelial cells (PAECs) viaentry of extracellular calcium and subsequent calcium-induced calcium release (CICR) and nitric oxide release, low-passage PAECs (<10 passages) were isolated from the intralobar pulmonary artery (PA) of fetal sheep and maintained under hypoxic conditions (Po2, 25 Torr). Using the calcium-sensitive dye fura-2, we demonstrated that acute normoxia (Po2120 Torr) increased PAECs Ca2iby increasing the rate of entry of extracellular calcium. In the presence of either ryanodine or 2-aminoethoxy-diphenylborate (2APB), normoxia did not lead to a sustained increase in PAECs Ca2iWhole-cell patch clamp studies demonstrated that acute normoxia causes PAEC membrane depolarization. When loaded with the nitric oxide (NO)–sensitive dye, DAF - FM, acute normoxia increased PAEC fluorescence. In PAECs derived from fetal lambs with pulmonary hypertension, an acute increase in O2tension had no effect on either Ca2ior NO production. Hypoxia increases loading of acetylcholine-sensitive calcium stores, as hypoxia potentiated the response to acetylcholine We conclude that acute normoxia increases Ca2iand NO production in normotensive but not hypertensive fetal PAECs viaextracellular calcium entry and calcium release from calcium-sensitive intracellular stores.

To test the hypothesis that an acute increase in O2tension increases cytosolic calcium ([Ca2+]i) in fetal pulmonary artery endothelial cells (PAECs) via entry of extracellular calcium and subsequent calcium-induced calcium release (CICR) and nitric oxide release, low-passage PAECs (<10 passages) were isolated from the intralobar pulmonary artery (PA) of fetal sheep and maintained under hypoxic conditions (Po2, 25 Torr). Using the calcium-sensitive dye fura-2, we demonstrated that acute normoxia (Po2= 120 Torr) increased PAECs [Ca2+]iby increasing the rate of entry of extracellular calcium. In the presence of either ryanodine or 2-aminoethoxy-diphenylborate (2APB), normoxia did not lead to a sustained increase in PAECs [Ca2+]iWhole-cell patch clamp studies demonstrated that acute normoxia causes PAEC membrane depolarization. When loaded with the nitric oxide (NO)–sensitive dye, DAF - FM, acute normoxia increased PAEC fluorescence. In PAECs derived from fetal lambs with pulmonary hypertension, an acute increase in O2tension had no effect on either [Ca2+]ior NO production. Hypoxia increases loading of acetylcholine-sensitive calcium stores, as hypoxia potentiated the response to acetylcholine We conclude that acute normoxia increases [Ca2+]iand NO production in normotensive but not hypertensive fetal PAECs via extracellular calcium entry and calcium release from calcium-sensitive intracellular stores.

To evaluate the hypotheses that children requiring reintubation are at an increased risk of prolonged hospitalizations, congenital heart disease, and death compared with age- and disease-severity-matched control patients.

TRPV4 channel activity determines myometrial tone and may be a target for treating preterm labor.