ABSTRACT
Over the last 20 years, stem cells of varying origin and their associated secretome have been investigated as a therapeutic option for a myriad of neonatal models of disease, with very promising results. Despite the devastating nature of some of these disorders, translation of the preclinical evidence to the bedside has been slow. In this review, we explore the existing clinical evidence for stem cell therapies in neonates, highlight the barriers faced by researchers and suggest potential solutions to move the field forward.
Subject(s)
Bronchopulmonary Dysplasia , Infant, Newborn, Diseases , Infant, Newborn , Humans , Stem Cell Transplantation/methods , Bronchopulmonary Dysplasia/therapy , Infant, Newborn, Diseases/therapyABSTRACT
OBJECTIVE: The aim of the study is to identify the rates and trends of various procedures performed on newborns. STUDY DESIGN: The Healthcare Cost and Utilization Project (HCUP) database for the years 2002 to 2015 was queried for the number of livebirths, and various procedures using International Classification of Diseases, Ninth Revision (ICD-9) codes. These were adjusted to the rate of livebirths in each particular year. A hypothetical high-volume hospital based on data from the last 5 years was used to estimate the frequency of each procedure. RESULTS: Over the study period, there was a decline in the rates of exchange transfusions and placement of arterial catheters. There was an increase in the rates of thoracentesis, abdominal paracentesis, placement of umbilical venous catheter (UVC) lines, and central lines with ultrasound or fluoroscopic guidance. No change was observed in the rates of unguided central lines, pericardiocentesis, bladder aspiration, intubations, and LP. Intubations were the most performed procedures. Placement of UVC, central venous lines (including PICCs), arterial catheters, and LP were relatively common, whereas others were rare such as pericardiocentesis and paracentesis. CONCLUSION: Some potentially lifesaving procedures are extremely rare or decreasing in incidence. There has also been an increase in utilization of fluoroscopic/ultrasound guidance for the placement of central venous catheters. KEY POINTS: · Advances in neonatal care have impacted the number of procedures performed in the NICU.. · It is unclear whether invasive procedures occur at rates sufficient for adequate training and maintenance of skills.. · Understanding the NICU procedural trends is important in designing simulation and competency-based medical education programs..
ABSTRACT
Mechanical ventilators are safety-critical devices that help patients breathe, commonly found in hospital intensive care units (ICUs)-yet, the high costs and proprietary nature of commercial ventilators inhibit their use as an educational and research platform. We present a fully open ventilator device-The People's Ventilator: PVP1-with complete hardware and software documentation including detailed build instructions and a DIY cost of $1,700 USD. We validate PVP1 against both key performance criteria specified in the U.S. Food and Drug Administration's Emergency Use Authorization for Ventilators, and in a pediatric context against a state-of-the-art commercial ventilator. Notably, PVP1 performs well over a wide range of test conditions and performance stability is demonstrated for a minimum of 75,000 breath cycles over three days with an adult mechanical test lung. As an open project, PVP1 can enable future educational, academic, and clinical developments in the ventilator space.
Subject(s)
Intensive Care Units , Ventilators, Mechanical , Adult , Child , Humans , Respiration, ArtificialABSTRACT
Despite the improving understanding of how lung mechanics and tidal volume requirements evolve during the evolution of bronchopulmonary dysplasia (BPD), clinical management continues to be heterogeneous and inconsistent at many institutions. Recent reports have examined the use of high tidal-volume low respiratory rate strategies in these patients once disease has been well established to help facilitate their eventual extubation and improve their long-term neurodevelopmental outcomes. In this retrospective observational research study, we describe how intentional adjustment of ventilator settings based on patient lung mechanics by an interdisciplinary BPD team improved the care of the at-risk population of infants, reduced the need for tracheostomies, as well as length of stay over a period of over 3 years. The team aimed to establish consistency in the management of these children using a high tidal volume, low-rate approach, and titrating PEEP to address the autoPEEP and bronchomalacia that is frequently observed in this patient population.
ABSTRACT
BACKGROUND AND OBJECTIVES: The use of inhaled nitric oxide (iNO) in +late preterm and term infants with pulmonary hypertension is Food and Drug Administration (FDA) approved and has improved outcomes and survival. iNO use is not FDA approved for preterm infants and previous studies show no mortality benefit. The objectives were 1) to determine the usage of iNO among preterm neonates <35 weeks before and after the 2010 National Institutes of Health consensus statement and 2) to evaluate characteristics and outcomes among preterm neonates who received iNO. METHODS: This is a population-based cross-sectional study. Billing and procedure codes were used to determine iNO usage. Data were queried from the National Inpatient Sample from 2004 to 2016. Neonates were included if gestational age was <35 weeks. The epochs were spilt into 2004-2010 (Epoch 1) and 2011-2016 (Epoch 2). Prevalence of iNO use, mortality, bronchopulmonary dysplasia (BPD), intraventricular hemorrhage, length of stay, mechanical ventilation, and cost of hospitalization. RESULTS: There were 4865 preterm neonates <35 weeks who received iNO. There was a significant increase in iNO use during Epoch 2 (p < 0.001). There was significantly higher use in Epoch 2 among neonates small for gestational age (SGA) 2.3% versus 7.2%, congenital heart disease (CHD) 11.1% versus 18.6%, and BPD 35.2% versus 46.8%. Mortality was significantly lower in Epoch 2 19.8% versus 22.7%. CONCLUSION: Usage of iNO was higher after the release of the consensus statement. The increased use of iNO among preterm neonates may be targeted at specific high-risk populations such as SGA and CHD neonates. There was lower mortality in Epoch 2; however, the cost was doubled.
Subject(s)
Infant, Premature , Nitric Oxide , Administration, Inhalation , Cross-Sectional Studies , Gestational Age , Humans , Infant , Infant, Newborn , Nitric Oxide/therapeutic useABSTRACT
BACKGROUND: The prevalence, morbidity, and mortality associated with Ebstein anomaly (EA) remains poorly characterized in neonates. EA is a rare form of congenital heart disease (CHD) with significant heterogeneity. OBJECTIVE: To determine the recent, 2000-2018, prevalence, mortality, outcomes, and healthcare utilization of infants admitted at ≤28 days of life with EA in comparison to other critical congenital heart defects (CCHD) in the United States using a national data set. METHODS: The National Inpatient Sample (NIS) from the Healthcare Cost and Utilization Project (HCUP) was queried for infants admitted for any reason at ≤28 days of life with a diagnosis of EA between 2000 and 2018 using ICD-9 and 10 codes in the United States. Patient characteristics, morbidity, mortality, and healthcare utilization were evaluated for EA and compared with other CCHD. RESULTS: From 2000 to 2018 a total of 68,312,952 neonatal admissions were identified, of them 4,398 neonates with isolated EA were identified, representing 7 per 100,000 neonatal admissions and 2.2% of CCHD admissions (4,398/197,881). The number of new EA cases ranged from 138 to 375 per year. In-hospital mortality was 12.3% and surgical repair occurred in 4.2% for infants with EA. There were 470 deaths without surgical repair which is 86.6% of the mortality. Arrhythmias were diagnosed in 10.6% and ECMO was used for 2.6% of neonates with EA. CONCLUSION: EA is a rare form of CHD. The prevalence has remained stable over the 19 years whereas other congenital heart defects have had an increase. The mortality in neonates with EA was significantly higher than in pooled CCHD; the burden of mortality occurred in the neonates without surgical intervention.
Subject(s)
Ebstein Anomaly , Heart Defects, Congenital , Ebstein Anomaly/epidemiology , Heart Defects, Congenital/epidemiology , Hospitalization , Humans , Infant , Infant, Newborn , Inpatients , Retrospective Studies , United States/epidemiologyABSTRACT
BACKGROUND: Bronchopulmonary dysplasia (BPD) is a heterogeneous disease that poses a challenge when ventilating premature infants. The purpose of this study was to determine how inspiratory pressure rise time (IRT), different ventilators, and their software updates affect the balance of ventilation among 2 heterogeneous lung units. METHODS: A passive dual-chamber lung model was constructed using the IngMar ASL5000 to approximate moderate BPD. One chamber had a short time constant, and the other had a long time constant. Three ventilators were used to provide pressure control intermittent mandatory ventilation: the Servo-i, an Avea ventilator with the volume guarantee software update, and an Avea ventilator without the volume guarantee software update. Using the same settings for pressure control intermittent mandatory ventilation, the IRT was adjusted between minimum and maximum settings. Data from 100 consecutive breaths/IRT were obtained. Inspiration time to 90% of plateau pressure was used as a surrogate for IRT; this was defined as the time needed to achieve a pressure of 18 cm H2O at the simulated trachea and was measured in 5 random breaths using ImageJ for each ventilator at each IRT. Outcome variables were tidal volume, peak inspiratory flow, mean inspiratory pressure, and volume balance (%) defined as the difference in chamber tidal volumes divided by total tidal volume. Linear regression was used to assess the impact of the IRT and ventilators on the different variables. RESULTS: In this model, increasing IRT decreased peak inspiratory flow, mean inspiratory pressure, chamber-specific tidal volume, and volume balance. Furthermore, different ventilator hardware and software influenced the waveforms in pressure control intermittent mandatory ventilation, which independently affected the measured variables. CONCLUSIONS: In a lung model of BPD with 2 very heterogeneous lung units, prolonging IRT without any volume balancing measures improved volume balance between the chambers at the expense of total tidal volume. Furthermore, the different ventilators acted as independent factors from the measured inspiration time to 90% of plateau pressure.
Subject(s)
Bronchopulmonary Dysplasia , Bronchopulmonary Dysplasia/therapy , Humans , Infant , Infant, Newborn , Lung , Respiration, Artificial , Software , Tidal Volume , Ventilators, MechanicalABSTRACT
BACKGROUND: The rapidly evolving COVID-19 pandemic has led to increased use of critical care resources, particularly mechanical ventilators. Amidst growing concerns that the health care system could face a shortage of ventilators in the future, there is a need for an affordable, simple, easy to use, emergency stockpile ventilator. METHODS: Our team of engineers and clinicians designed and tested an emergency ventilator that uses a single limb portable ventilator circuit. The circuit is controlled by a pneumatic signal with electronic microcontroller input, using air and oxygen sources found in standard patient rooms. Ventilator performance was assessed using an IngMar ASL 5000 breathing simulator, and it was compared with a commercially available mechanical ventilator. RESULTS: The emergency ventilator provides volume control mode, intermittent mandatory ventilation and continuous positive airway pressure. It can generate tidal volumes between 300 and 800 mL with <10% error, with pressure, volume, and waveforms substantially equivalent to existing commercial ventilators. CONCLUSIONS: We describe a cost effective, safe, and easy to use ventilator that can be rapidly manufactured to address ventilator shortages in a pandemic setting. It meets basic clinical needs and can be provided for emergency use in cases requiring mechanical ventilation because of complications due to respiratory failure from infectious diseases.
ABSTRACT
Premature births continue to rise globally with a corresponding increase in various morbidities among this population. Rates of respiratory distress syndrome and the consequent development of Bronchopulmonary Dysplasia (BPD) are highest among the extremely preterm infants. The majority of extremely low birth weight premature neonates need some form of respiratory support during their early days of life. Invasive modes of respiratory assistance have been popular amongst care providers for many years. However, the practice of prolonged invasive mechanical ventilation is associated with an increased likelihood of developing BPD along with other comorbidities. Due to the improved understanding of the pathophysiology of BPD, and technological advances, non-invasive respiratory support is gaining popularity; whether as an initial mode of support, or for post-extubation of extremely preterm infants with respiratory insufficiency. Due to availability of a wide range of modalities, wide variations in practice exist among care providers. This review article aims to address the physical and biological basis for providing non-invasive respiratory support, the current clinical evidence, and the most recent developments in this field of Neonatology.
ABSTRACT
OBJECTIVE: The objective of this study was to use current national data to evaluate the characteristics and survival trends of preterm infants born with CDH from 2004 to 2014. STUDY DESIGN: Data was queried from the National Inpatient Sample (NIS) and KID database from 2004 to 2014. Infants were included if diagnosed with CDH by ICD-9 coding and gestational age <37 weeks. Descriptive statistics, chi-square, and trend analysis were completed. RESULTS: We identified 2356 infants born prematurely with CDH. The overall survival rate was 49%. The survival range is 21.2-62.3% for gestational age <26 weeks to 35-36 weeks, respectively. Total mortality was 1183; of them, 1052 (89%) were not repaired and 363 (30.7%) did not receive mechanical ventilation. Surgical repair occurred in 55.1% of infants. CONCLUSIONS: Preterm infants have lower survival compared with term infants. Survival rates decrease with lower gestational age and have improved over time.
Subject(s)
Hernias, Diaphragmatic, Congenital/mortality , Infant, Premature, Diseases/mortality , Age Factors , Databases, Factual , Extracorporeal Membrane Oxygenation , Female , Gestational Age , Hernias, Diaphragmatic, Congenital/surgery , Hernias, Diaphragmatic, Congenital/therapy , Humans , Infant, Newborn , Infant, Premature , Infant, Premature, Diseases/surgery , Infant, Premature, Diseases/therapy , Length of Stay , Male , Respiration, Artificial , Survival Rate , United States/epidemiologyABSTRACT
OBJECTIVES: Transposition of the great arteries is the most common cyanotic congenital heart defect. Surgical correction usually occurs in the first week of life; presence of restrictive interatrial communication and severe hypoxemia warrants urgent intervention with balloon atrial septostomy and medical stabilization prior to surgery. The main objective of this study is to compare the characteristics, outcomes, and mortality risks in patients with transposition of the great arteries who underwent balloon atrial septostomy during their hospitalization versus transposition of the great arteries patients who have not undergone this procedure. DESIGN: Retrospective analysis of administrative data. SETTING: Data from Kids' Inpatient Database complemented with the National Inpatient Sample dataset for the years 1998-2014, this includes data from participating hospitals in 47 U.S. States and the District of Columbia. PATIENTS: Neonates admitted with transposition of the great arteries. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 17,392 neonates with diagnosis of transposition of the great arteries were captured in the databases we used. Male-to-female ratio was 2:1. The rate of balloon atrial septostomy in patients with transposition of the great arteries was 27.7% without significant change over the years. There was no significant difference in mortality between balloon atrial septostomy and no balloon atrial septostomy (6.3% vs 6.7%; p = 0.29). Neonates with balloon atrial septostomy had a two-fold increase in their length of stay compared with no balloon atrial septostomy (16 d vs 7 d; p < 0.0001). Stroke was present in 1.1% of balloon atrial septostomy group versus 0.6% in those who did not have balloon atrial septostomy (odds ratio, 1.85; 95% CI, 1.29-2.65; p < 0.0001). Extracorporeal membrane oxygenation was used more in balloon atrial septostomy group (5.1% vs 3.1%; p < 0.0001). CONCLUSIONS: There was no difference in mortality rate between balloon atrial septostomy and no balloon atrial septostomy patients. The prevalence of the diagnosis of stroke in this study was higher in patients who underwent balloon atrial septostomy. Furthermore, comparison of in-hospital mortality in balloon atrial septostomy and no balloon atrial septostomy revealed increased mortality risk in no balloon atrial septostomy patients transferred from other institution, no balloon atrial septostomy patients supported with extracorporeal membrane oxygenation, and balloon atrial septostomy patients diagnosed with stroke. Finally, length of stay and charges were higher in balloon atrial septostomy patients.
Subject(s)
Transposition of Great Vessels , Arteries , District of Columbia , Female , Humans , Infant, Newborn , Male , Prevalence , Retrospective Studies , Transposition of Great Vessels/surgeryABSTRACT
BACKGROUND: Bronchopulmonary dysplasia (BPD) is characterized by alveolar simplification and disordered angiogenesis. Stromal derived factor-1 (SDF-1) is a chemokine which modulates cell migration, proliferation, and angiogenesis. Here we tested the hypothesis that intra-tracheal (IT) administration of a naked plasmid DNA expressing SDF-1 would attenuate neonatal hyperoxia-induced lung injury in an experimental model of BPD, by promoting angiogenesis. DESIGN/METHODS: Newborn Sprague-Dawley rat pups (n = 18-20/group) exposed to room air (RA) or hyperoxia (85% O2) from postnatal day (P) 1 to 14 were randomly assigned to receive IT a naked plasmid expressing SDF-1, JVS-100 (Juventas Therapeutics, Cleveland, Ohio) or placebo (PL) on P3. Lung alveolarization, angiogenesis, inflammation, vascular remodeling and pulmonary hypertension (PH) were assessed on P14. PH was determined by measuring right ventricular systolic pressure (RVSP) and the weight ratio of the right to left ventricle + septum (RV/LV + S). Capillary tube formation in SDF-1 treated hyperoxia-exposed human pulmonary microvascular endothelial cells (HPMEC) was determined by matrigel assay. Data is expressed as mean ± SD and analyzed by two-way ANOVA. RESULTS: Exposure of neonatal pups to 14 days of hyperoxia decreased lung SDF-1 gene expression. Moreover, whilst hyperoxia exposure inhibited capillary tube formation in HPMEC, SDF-1 treatment increased tube length and branching in HPMEC. PL-treated hyperoxia-exposed pups had decreased alveolarization and lung vascular density. This was accompanied by an increase in RVSP, RV/LV + S, pulmonary vascular remodeling and inflammation. In contrast, IT JVS-100 improved lung structure, reduced inflammation, PH and vascular remodeling. CONCLUSIONS: Intratracheal administration of a naked plasmid expressing SDF-1 improves alveolar and vascular structure in an experimental model of BPD. These findings suggest that therapies which modulate lung SDF-1 expression may have beneficial effects in preterm infants with BPD.
Subject(s)
Bronchopulmonary Dysplasia/drug therapy , Chemokine CXCL12/administration & dosage , Lung/drug effects , Plasmids/administration & dosage , Trachea/drug effects , Animals , Animals, Newborn , Bronchopulmonary Dysplasia/pathology , Bronchopulmonary Dysplasia/physiopathology , Drug Delivery Systems/methods , Female , Gene Expression , Lung/anatomy & histology , Lung/physiology , Plasmids/biosynthesis , Plasmids/genetics , Pregnancy , Rats , Rats, Sprague-Dawley , Rodentia , Trachea/physiologyABSTRACT
BACKGROUND: Inflammation is a key factor in the pathogenesis of bronchopulmonary dysplasia (BPD). Tumor necrosis factor-stimulated protein 6 (TSG-6) is a glycoprotein that modulates inflammation. Here we tested the hypothesis that intra-tracheal (IT) administration of an adenovirus overexpressing TSG-6 (AdTSG-6) would decrease inflammation and restore lung structure in experimental BPD. METHODS: Newborn Sprague-Dawley rats exposed to normoxia (RA) or hyperoxia (85% O2) from postnatal day (P) 1-P14 were randomly assigned to receive IT AdTSG-6 or placebo (PL) on P3. The effect of IT AdTSG-6 on lung inflammation, alveolarization, angiogenesis, apoptosis, pulmonary vascular remodeling, and pulmonary hypertension were evaluated on P14. Data were analyzed by two-way ANOVA. RESULTS: TSG-6 mRNA was significantly increased in pups who received IT AdTSG-6. Compared to RA, hyperoxia PL-treated pups had increased NF-kß activation and lung inflammation. In contrast, IT AdTSG-6 hyperoxia-treated pups had decreased lung phosphorylated NF-kß expression and markers of inflammation. This was accompanied by an improvement in alveolarization, angiogenesis, pulmonary vascular remodeling, and pulmonary hypertension. CONCLUSIONS: IT AdTSG-6 decreases lung inflammation and improves lung structure in neonatal rats with experimental BPD. These findings suggest that therapies that increase lung TSG-6 expression may have beneficial effects in preterm infants with BPD.
Subject(s)
Bronchopulmonary Dysplasia/therapy , Cell Adhesion Molecules/pharmacology , Hypertension, Pulmonary/therapy , Inflammation/therapy , Lung/pathology , Adenoviridae , Animals , Apoptosis , Bronchopulmonary Dysplasia/metabolism , Cell Proliferation , Female , Hyperoxia , Hypertension, Pulmonary/metabolism , Inflammation/metabolism , Phosphorylation , Pregnancy , Pregnancy, Animal , Random Allocation , Rats , Rats, Sprague-Dawley , Vascular RemodelingABSTRACT
BACKGROUND: Mesenchymal stem cells (MSCs) attenuate lung injury in experimental models of bronchopulmonary dysplasia (BPD). Stromal derived factor-1 (SDF-1), a chemokine secreted by MSCs, modulates angiogenesis and stem cell recruitment. Here we tested the hypothesis that SDF-1 mediates MSC protective effects in experimental BPD by modulating angiogenesis. METHODS: SDF-1 was knocked down in MSCs using lentiviral vectors carrying anti-SDF-1 short hairpin RNA (MSC-SDF KD). Non-silencing short hairpin RNA was used as control (MSC-NS control). Newborn rats exposed to normoxia or hyperoxia (FiO2 = 0.85) for 3 weeks, were randomly assigned to receive a single intra-tracheal injection (IT) of MSC-NS control or MSC-SDF KD (1 × 106 cells/50 µl) or placebo on postnatal day 7. The degree of alveolarization, lung angiogenesis, inflammation, and pulmonary hypertension (PH) were assessed at postnatal day 21. RESULTS: Administration of IT MSC-NS control improved lung alveolarization, angiogenesis and inflammation, and attenuated PH in newborn rats with hyperoxia-induced lung injury (HILI). In contrast, knockdown of SDF-1 in MSCs significantly reduced their beneficial effects on alveolarization, angiogenesis, inflammation and PH. CONCLUSIONS: The therapeutic benefits of MSCs in neonatal HILI are in part mediated by SDF-1, through anti-inflammatory and angiogenesis promoting mechanisms. Therapies directly targeting this chemokine may provide a novel strategy for the treatment of BPD.
Subject(s)
Bronchopulmonary Dysplasia/surgery , Chemokine CXCL12/metabolism , Lung/metabolism , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells/metabolism , Regeneration , Airway Remodeling , Animals , Animals, Newborn , Bronchopulmonary Dysplasia/genetics , Bronchopulmonary Dysplasia/metabolism , Bronchopulmonary Dysplasia/physiopathology , Cell Proliferation , Cells, Cultured , Chemokine CXCL12/genetics , Disease Models, Animal , Hyperoxia/complications , Hypertension, Pulmonary/metabolism , Hypertension, Pulmonary/physiopathology , Hypertension, Pulmonary/prevention & control , Lung/pathology , Lung/physiopathology , Neovascularization, Physiologic , Pneumonia/metabolism , Pneumonia/physiopathology , Pneumonia/prevention & control , RNA Interference , Rats, Sprague-Dawley , Signal Transduction , TransfectionABSTRACT
Soluble endoglin (sENG) is increased in the amniotic fluid of women with preeclampsia and chorioamnionitis. Preterm infants born to women with these disorders have an increased risk of aberrant lung development. Whether this increased risk is secondary to elevated sENG levels is unclear. The objective of this study was to determine whether intrauterine exposure to an adenovirus overexpressing sENG impairs neonatal lung angiogenesis by modulating lung endothelial nitric oxide synthase (eNOS) signaling. Pregnant Sprague-Dawley rats were randomly assigned to receive ultrasound-guided intra-amniotic injections of adenovirus overexpressing sENG (Ad-sENG) or control adenovirus (Ad-control) on embryonic day 17. After this exposure, rat pups were maintained in normoxia and evaluated on postnatal day 14. Intra-amniotic Ad-sENG decreased lung vascular endothelial growth factor receptor 2 and eNOS expression in rat pups. This was accompanied by a marked decrease in lung angiogenesis and alveolarization. Ad-sENG-exposed pups also had an increase in right ventricular systolic pressure, weight ratio of right ventricle to left ventricle plus septum, and pulmonary vascular remodeling. In addition, exposure of human pulmonary artery endothelial cells to recombinant sENG reduced endothelial tube formation and protein levels of eNOS, phosphorylated eNOS, and phosphorylated Smad1/5. Together, our findings demonstrate that intrauterine exposure to an adenovirus overexpressing sENG disrupts lung development by impairing Smad1/5-eNOS signaling. We speculate that sENG-mediated dysregulation of Smad1/5-eNOS signaling contributes to impaired lung development and potentially primes the developing lung for further postnatal insults. Further studies exploring the relationship between amniotic fluid sENG levels and preterm respiratory outcomes will be necessary.
Subject(s)
Amniotic Fluid/metabolism , Endoglin/metabolism , Lung/embryology , Nitric Oxide Synthase Type III/biosynthesis , Pregnancy/metabolism , Signal Transduction/physiology , Animals , Female , Lung/blood supply , Nitric Oxide/metabolism , Phosphorylation/physiology , Rats , Rats, Sprague-Dawley , Receptor, ErbB-2/metabolism , Smad1 Protein/metabolism , Smad5 Protein/metabolismABSTRACT
BACKGROUND: Mesenchymal stem cells (MSC) improve alveolar and vascular structures in experimental models of bronchopulmonary dysplasia (BPD). Female MSC secrete more anti-inflammatory and pro-angiogenic factors as compared to male MSC. Whether the therapeutic efficacy of MSC in attenuating lung injury in an experimental model of BPD is influenced by the sex of the donor MSC or recipient is unknown. Here we tested the hypothesis that female MSC would have greater lung regenerative properties than male MSC in experimental BPD and this benefit would be more evident in males. OBJECTIVE: To determine whether intra-tracheal (IT) administration of female MSC to neonatal rats with experimental BPD has more beneficial reparative effects as compared to IT male MSC. METHODS: Newborn Sprague-Dawley rats exposed to normoxia (RA) or hyperoxia (85% O2) from postnatal day (P) 2- P21 were randomly assigned to receive male or female IT bone marrow (BM)-derived green fluorescent protein (GFP+) MSC (1 x 106 cells/50 µl), or Placebo on P7. Pulmonary hypertension (PH), vascular remodeling, alveolarization, and angiogenesis were assessed at P21. PH was determined by measuring right ventricular systolic pressure (RVSP) and pulmonary vascular remodeling was evaluated by quantifying the percentage of muscularized peripheral pulmonary vessels. Alveolarization was evaluated by measuring mean linear intercept (MLI) and radial alveolar count (RAC). Angiogenesis was determined by measuring vascular density. Data are expressed as mean ± SD, and analyzed by ANOVA. RESULTS: There were no significant differences in the RA groups. Exposure to hyperoxia resulted in a decrease in vascular density and RAC, with a significant increase in MLI, RVSP, and the percentage of partially and fully muscularized pulmonary arterioles. Administration of both male and female MSC significantly improved vascular density, alveolarization, RVSP, percent of muscularized vessels and alveolarization. Interestingly, the improvement in PH and vascular remodeling was more robust in the hyperoxic rodents who received MSC from female donors. In keeping with our hypothesis, male animals receiving female MSC, had a greater improvement in vascular remodeling. This was accompanied by a more significant decrease in lung pro-inflammatory markers and a larger increase in anti-inflammatory and pro-angiogenic markers in male rodents that received female MSC. There were no significant differences in MSC engraftment among groups. CONCLUSIONS: Female BM-derived MSC have greater therapeutic efficacy than male MSC in reducing neonatal hyperoxia-induced lung inflammation and vascular remodeling. Furthermore, the beneficial effects of female MSC were more pronounced in male animals. Together, these findings suggest that female MSC maybe the most potent BM-derived MSC population for lung repair in severe BPD complicated by PH.
Subject(s)
Bronchopulmonary Dysplasia/therapy , Hyperoxia , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells/cytology , Animals , Animals, Newborn , Blood Pressure , Bone Marrow Cells/cytology , Bronchopulmonary Dysplasia/etiology , Cells, Cultured , Disease Models, Animal , Female , Hypertension, Pulmonary/complications , Interleukin-10/metabolism , Lung/pathology , Male , Mesenchymal Stem Cells/metabolism , Neovascularization, Physiologic , Pulmonary Alveoli/physiology , Rats , Rats, Sprague-Dawley , Vascular Endothelial Growth Factor A/metabolism , Vascular RemodelingABSTRACT
INTRODUCTION: The syndrome of isosexual precocious puberty associated with primary malignant hepatic tumors is rare. All previously reported cases in the literature are old and prognosis was grim. CASE PRESENTATION: We present the case of a 15-month-old Asian male baby who presented with precocious puberty associated with hepatoblastoma. Serum concentrations of alpha-fetoprotein and free testosterone were elevated, as was beta human chorionic gonadotropin hormone. He was treated with six courses of chemotherapy and underwent surgery. His surface markers as well as free testosterone level returned to normal during therapy. The child has now been off therapy for 18 months with no evidence of tumor recurrence at follow-up. CONCLUSION: Virilizing hepatoblastoma is rare and reported with poor outcome, but the development of new chemotherapeutic agents and complete surgical resection are promising.