Objective: To determine patterns of respiratory medications used in neonatal intensive care unit ... more Objective: To determine patterns of respiratory medications used in neonatal intensive care unit (NICU) graduates. Study design: The Prematurity Respiratory Outcomes Program enrolled 835 babies <29 weeks gestation in the first week. Of 751 survivors, 738 (98%) completed at least 1, and 85% completed
Nuclear Factor I (Nfi) genes encode transcription factors essential for the development of organ ... more Nuclear Factor I (Nfi) genes encode transcription factors essential for the development of organ systems including the lung. Nfib null mice die at birth with immature lungs. Nfib hemizygous mice have reduced lung maturation with decreased survival. We therefore hypothesized that these mice would be more sensitive to lung injury and would have lower survival to hyperoxia. Adult Nfib hemizygous mice and their wild-type (Wt) littermates were exposed to 100% O 2 for 89, 80, 72 and 66 h for survival studies with lung outcome measurements at 66 h. Nfib hemizygous and Wt controls were also studied in RA at 66 h. Cell counts and cytokines were measured in bronchoalveolar lavage (BAL); lung sections examined by histopathology; lung angiogenic and oxidative stress gene expression assessed by real-time PCR. Unexpectedly, Nfib hemizygous mice (0/14-0%) had significantly lower mortality compared to Wt mice (10/22-45%) at 80 h of hyperoxia (P < 0.003). LD 50 was 80 h in the Wt group versus 89 h in the hemizygous group. There were no differences in BAL cell counts between the groups. Among the cytokines studied, MIP-2 was significantly lower in hemizygous mice exposed to hyperoxia. New vessel formation, edema, congestion, and alveolar hemorrhage were noted on histopathology at 72 and 80 h in wild-type mice. Nfib hemizygous lungs had significant downregulation of genes involved in redox signaling and inflammatory pathways. Adult Nfib hemizygous mice are relatively resistant to hyperoxia compared to wild-type littermates. Mechanisms contributing to this resistance are not clear; however, transcription factors such as Nfib may regulate cell survival and play a role in modulating postnatal lung development.
Organized and coordinated lung development follows transcriptional regulation of a complex set of... more Organized and coordinated lung development follows transcriptional regulation of a complex set of cell-cell and cell-matrix interactions resulting in a blood-gas interface ready for physiologic gas exchange at birth. Transcription factors, growth factors, and various other signaling molecules regulate epithelial-mesenchymal interactions by paracrine and autocrine mechanisms. Transcriptional control at the earliest stages of lung development results in cell differentiation and cell commitment in the primitive lung bud, in essence setting up a framework for pattern formation and branching morphogenesis. Branching morphogenesis results in the formation of the conductive airway system, which is critical for alveolization. Lung development is influenced at all stages by spatial and temporal distribution of various signaling molecules and their receptors and also by the positive and negative control of signaling by paracrine, autocrine, and endocrine mechanisms. Lung bud formation, cell differentiation, and its interaction with the splanchnic mesoderm are regulated by HNF-3beta, Shh, Nkx2.1, HNF-3/Forkhead homolog-8 (HFH-8), Gli, and GATA transcription factors. HNF-3beta regulates Nkx2.1, a transcription factor critical to the formation of distal pulmonary structures. Nkx2.1 regulates surfactant protein genes that are important for the development of alveolar stability at birth. Shh, produced by the foregut endoderm, regulates lung morphogenesis signaling through Gli genes expressed in the mesenchyme. FGF10, produced by the mesoderm, regulates branching morphogenesis via its receptors on the lung epithelium. Alveolization and formation of the capillary network are influenced by various factors that include PDGF, vascular endothelial growth factor (VEGF), and retinoic acid. Epithelial-endothelial interactions during lung development are important in establishing a functional blood-gas interface. The effects of various growth factors on lung development have been demonstrated by gain- or loss-of-function studies in null mutant and transgenic mice models. Understanding the role of growth factors and various other signaling molecules and their cellular interactions in lung development will provide us with new insights into the pathogenesis of bronchopulmonary dysplasia and disorders of lung morphogenesis.
We present a full-term male infant who presented with tachypnea and an increased band count on hi... more We present a full-term male infant who presented with tachypnea and an increased band count on his complete blood count (CBC) with an immature to total neutrophil (I:T) ratio of 0.6 raising suspicion of early onset sepsis. A blood culture was drawn and he was started on appropriate antibiotics. The patient's clinical condition rapidly improved; however, the white cell count 'left shift' persisted. When a detailed family history was obtained, it was discovered that the father, paternal uncle and the grandfather had been diagnosed with Pelger-Huet anomaly (PHA). As the urine, blood and CSF cultures were all negative in this now well-appearing infant, the left shift on the CBC was believed to be due to inheritance of the PHA. We present this case to emphasize that even in this age of sophisticated laboratory evaluation, a good clinical history, including family history, and clinical evaluation, are essential for accurate diagnosis.
Beta-adrenergic agents enhance secretion of phosphatidylcholine (PC) by adult and fetal type II c... more Beta-adrenergic agents enhance secretion of phosphatidylcholine (PC) by adult and fetal type II cells. We have previously shown that terbutaline stimulates secretion of PC by fetal type II cells, but the response wanes after 30 minutes. We studied the effects of salmeterol, a highly selective, long-acting beta2-adrenergic agonist that does not cause receptor desensitization, on PC secretion by adult type II alveolar cells in primary culture. Release of lactate-dehydrogenase was &amp;amp;lt; 4% and did not vary with the concentration of salmeterol. Salmeterol stimulated PC secretion in a concentration-dependent manner. The maximum effective-concentration tested was 50 nM and the EC50 was 11.40 +/- 1.14 nM. Propranolol inhibited the effect of salmeterol on release of PC, confirming that the effects of salmeterol are mediated by beta-receptors. OT50, the time for onset of action, was 32.0 +/- 1.6 minutes. RT50, the time to achieve 50% recovery from maximal stimulation was, 393.0 +/- 20.2 minutes. We conclude that salmeterol stimulates PC secretion by type II cells through activation of beta-adrenergic receptors and has a longer duration of action (&amp;amp;gt;6 hours) compared to other beta2-agonists. Salmeterol may be a useful drug with which to study the role of receptor desensitization in the developmental changes in PC secretion.
At birth, the release of surfactant from Alveolar Type II (ATII) cells is stimulated by increased... more At birth, the release of surfactant from Alveolar Type II (ATII) cells is stimulated by increased activity of the beta-adrenergic/adenylyl cyclase/cAMP- signaling cascade. Atrial natriuretic peptide (ANP) stimulates surfactant secretion through Natriuretic peptide receptor A (NPR-A). ANP inhibits adenylyl cyclase activity through its binding to NPR-C. We wished to further understand the role of the NPR-C in perinatal transition. We studied fetal and newborn sheep ATII expression of NPR-C and surfactant secretion in isolated ATIIs by measuring (3)[H] choline release into the media. ANP induced surfactant secretion, and, at higher doses, inhibits the stimulatory effect of the secretagogue terbutaline. ATII NPR-C expression decreased significantly after birth. Premature delivery also markedly decreased ANP and NPR-C in ATIIs. Co-incubation of terbutaline (10(-4)M) with ANP (10(-6)M) significantly decreased (3)[H] choline release from isolated newborn ATII cells when compared to terbuta...
Premature infants with bronchopulmonary dysplasia (BPD), are at risk for frequent respiratory inf... more Premature infants with bronchopulmonary dysplasia (BPD), are at risk for frequent respiratory infections and reduced pulmonary function. We studied whether neonatal hyperoxia disrupts adaptive immune responses in adult mice, contributing to higher respiratory-related morbidities seen in these infants. Newborn mice litters were randomized at 3 days to 85% Oor room air (RA) for 12 days. Whole lung mRNA was isolated in both the groups at 2 weeks and 3 months. Gene expression for T-cell and B-cell adaptive immune response was performed by real-time PCR and qRT-PCR; protein expression (p21, IL4, IL10, IL27, cd4) was performed by enzyme immunoassay along with p21 immunohistochemistry. Hyperoxia increased expression of p21 and decreased expression of 19 genes representing T/B-cell activation by ≥ fourfold; three of them significantly (Rag1, Cd1d1, Cd28) compared to the RA group at 2 weeks. Despite RA recovery, the expression of IFNγ, IL27, and CD40 was significantly reduced at 3 months in ...
The COVID-19 pandemic has affected maternal and infant health globally both directly from infecti... more The COVID-19 pandemic has affected maternal and infant health globally both directly from infection with the SARS-CoV-2 virus and indirectly from changes in health care resulting from social, economic, and health care policies unique to each country. The developing countries have to share the disproportionate burden on maternal and infant health. In this review, we discuss the uncertainties resulting from SARS-CoV-2 infection in pregnancy, vertical transmission of the virus, and its effects on breastfeeding of the newborn. The problems of families and communities caring for mothers with COVID-19 and its impact on breastfeeding in newborns are discussed. The challenges posed by the pandemic have forced us to think and devise innovative solutions, including telemedicine help for antenatal counseling, breastfeeding education, and lactation support. Optimal utilization of resources and technology to find creative solutions at the individual and the community level will help in facilitat...
Coronavirus disease 2019 (COVID-19), a condition associated with SARS-CoV-2, typically results in... more Coronavirus disease 2019 (COVID-19), a condition associated with SARS-CoV-2, typically results in mild infection in infants and children. However, children with risk factors such as chronic lung disease and immunosuppression have higher risk of severe illness from COVID-19. We report a case of a 27-week-gestation extremely premature infant born to a mother with COVID-19 infection. The infant, initially treated for surfactant deficiency, developed worsening hypoxic respiratory failure on the fifth day of life requiring escalating ventilatory support, an elevated level of C-reactive protein, thrombocytopenia, and an elevated level of d-dimer. The infant was positive for SARS-CoV-2 by RT-PCR from Day 1 to Day 42 of his life. The infant responded to a seven-day course of dexamethasone with a gradually decreasing oxygen requirement and could be extubated to non-invasive ventilation by the end of the fifth week after birth. The infant is currently on home oxygen by nasal cannula. Prolonge...
Coronavirus disease 2019 (COVID-19), a condition associated with SARS-CoV-2, typically results in... more Coronavirus disease 2019 (COVID-19), a condition associated with SARS-CoV-2, typically results in mild infection in infants and children. However, children with risk factors such as chronic lung disease and immunosuppression have higher risk of severe illness from COVID-19. We report a case of a 27-week-gestation extremely premature infant born to a mother with COVID-19 infection. The infant, initially treated for surfactant deficiency, developed worsening hypoxic respiratory failure on the fifth day of life requiring escalating ventilatory support, an elevated level of C-reactive protein, thrombocytopenia, and an elevated level of d-dimer. The infant was positive for SARS-CoV-2 by RT-PCR from Day 1 to Day 42 of his life. The infant responded to a seven-day course of dexamethasone with a gradually decreasing oxygen requirement and could be extubated to non-invasive ventilation by the end of the fifth week after birth. The infant is currently on home oxygen by nasal cannula. Prolonge...
Background Hyperoxia at resuscitation increases oxidative stress, and even brief exposure to high... more Background Hyperoxia at resuscitation increases oxidative stress, and even brief exposure to high oxygen concentrations during stabilization may trigger organ injury with adverse long-term outcomes in premature infants. We studied the long-term effects of short-term perinatal oxygen exposure on cell cycle gene expression and lung growth in adult mice. Methods We randomized mice litters at birth to 21, 40, or 100%O2 for 30 min and recovered in room air for 4 or 12 weeks. Cell cycle gene expression, protein analysis, and lung morphometry were assessed at 4 and 12 weeks. Results The principal component analysis demonstrated a high degree of correlation for cell cycle gene expression among the three oxygen groups. Lung elastin was significantly lower in the 100%O2 groups at 4 weeks. On lung morphometry, radial alveolar count, alveolar number, and septal count were similar. However, the mean linear intercept (MLI) and septal length significantly correlated among the oxygen groups. The ML...
This is an open access article under the terms of the Creative Commons Attribution License, which... more This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Design: Prospective cohort study, part of an ongoing “Neurological Outcome of Glucose in Neonatal... more Design: Prospective cohort study, part of an ongoing “Neurological Outcome of Glucose in Neonatal Encephalopathy (NOGIN)” study cohort Exposure: Infants were grouped based on the occurrence of normoglycemia (51–144mg/dl), hypoglycemiadefined as blood or interstitial glucose ≤50mg/dL (2.8mmol/L) and hyperglycemiadefined as glucose >144mg/dL (8.0mmol/L). Blinding: A blinded device, the iPro2 monitor, was used to record interstitial glucose concentrations for 72 h and this data was not made available to the clinical care team. Follow-up period: The study provides data collected in the first 72 h only. Setting: A single referral tertiary care hospital in Toronto, Canada, between August 2014 and March 2017. Patients: Full term infants with neonatal encephalopathy, defined as abnormal consciousness with either neonatal seizures or abnormalities in tone and reflexes. Exclusion criteria: suspected or confirmed congenital malformations, inborn errors of metabolism, congenital infections, gestational age <36 weeks, weight <1500 g, or if it was expected that a continuous glucose monitor (CGM) could not be attached within 6 h of life. Intervention: Continuous glucose monitors were used to record average interstitial glucose concentrations every 5 min. Episodes of interstitial glucose derangements were defined as 2 or more consecutive data points (≥10 min) outside the normal range (51–144 mg/dl). Episodes of glucose derangement were treated as contiguous if they were separated by brief periods of normoglycemia lasting ≤10 min. Clinicians treated newborns for hypoglycemia or hyperglycemia based on the current standard of care using intermittent glucose testing. As per institutional protocol, blood glucose concentrations <49 mg/dL (2.7 mmol/L) were treated with intravenous dextrose, increasing glucose infusion rates or glucagon. Hyperglycemia was treated with insulin infusion as clinically indicated. Outcomes: The primary analyses compared aEEG scores (background, sleep–wake cycling, and seizure scores) during 6-h epochs containing episodes of hypoglycemia or hyperglycemia to normoglycemic epochs. Statistical analysis and sample size: No power or sample size analysis are mentioned. For each subject, mean, minimum, and maximum glucose levels were calculated based on interstitial measurements obtained over a 6-h epoch. The area under the curve was calculated as the area of interstitial glucose concentration over/under the normal glucose range (hours × mg/dL), reflecting the extent and duration of the episode of interstitial glucose derangement. Glucose variability was quantified using the SD, coefficient * Jayasree Nair [email protected]
Background: Caffeine therapy for apnea of prematurity reduces the incidence of bronchopulmonary d... more Background: Caffeine therapy for apnea of prematurity reduces the incidence of bronchopulmonary dysplasia (BPD) in premature neonates. Several mechanisms, including improvement in pulmonary mechanics underly beneficial effects of caffeine in BPD. As vascular development promotes alveologenesis, we hypothesized that caffeine might enhance angiogenesis in the lung, promoting lung growth, thereby attenuating BPD. Methods: C57Bl/6 mice litters were randomized within 12 h of birth to room air (RA) or 95%O 2 to receive caffeine (20 mg/kg/day) or placebo for 4 days and recovered in RA for 12wks. The lung mRNA and protein expression for hypoxia-inducible factors (HIF) and angiogenic genes performed on day 5. Lung morphometry and vascular remodeling assessed on inflation fixed lungs at 12wks. Results: Caffeine and hyperoxia in itself upregulate HIF-2α and vascular endothelial growth factor gene expression. Protein expression of HIF-2α and VEGFR1 were higher in hyperoxia/caffeine and angiopoietin-1 lower in hyperoxia. An increase in radial alveolar count, secondary septal count, and septal length with a decrease in mean linear intercept indicate an amelioration of hyperoxic lung injury by caffeine. An increase in vessel surface area and a significant reduction in smooth muscle thickness of the pulmonary arterioles may suggest a beneficial effect of caffeine on vascular remodeling in hyperoxia, especially in male mice. Conclusions: Postnatal caffeine by modulating angiogenic gene expression early in lung development may restore the pulmonary microvasculature and alveolarization in adult lung.
Caffeine, a stimulant is the most widely used drug in the world in adults with increasing usage i... more Caffeine, a stimulant is the most widely used drug in the world in adults with increasing usage in children. It is commonly used in the treatment of apnea of prematurity in premature infants. Caffeine in a randomized trial has been shown to reduce the incidence of bronchopulmonary dysplasia in infants <1250 grams birth weight when used to treat apnea of prematurity in these infants. In the same cohort of infants, caffeine improved neurodevelopmental outcomes and survival at 18 months of age and was found to be safe without any adverse events up to 11 years of age. Caffeine is an adenosine receptor antagonist and inhibits adenosine receptors at physiologic concentrations with important effects on behavior and cognitive functions. However, higher doses of caffeine may inhibit the enzyme phosphodiesterase and affect vascular smooth muscle function. Anti-oxidant, anti-inflammatory and antiapoptotic properties of caffeine and its ability to scavenge reactive oxygen species may contribute to its lung and neuroprotective effects in premature infants. Animal studies on whether caffeine is protective to the lung are not conclusive at this time. Similarly, caffeine is demonstrated to have adverse effects on brain development in animal studies. Despite the beneficial effects of caffeine in premature infants when administered in the neonatal period, the long-term effects on adult-oriented disease such as cardio-metabolic disease and neurobehavioral states in children and adults needs further study.
Neonatal hypoxic ischemic encephalopathy (HIE) presents a significant clinical burden with its hi... more Neonatal hypoxic ischemic encephalopathy (HIE) presents a significant clinical burden with its high mortality and morbidity rates globally. Therapeutic hypothermia (TH) is now standard of care for infants with moderate to severe HIE, but has not definitively changed outcomes in severe HIE. In this review, we discuss newer promising markers that may help the clinician identify severity of HIE. Therapies that are beneficial and agents that hold promise for neuroprotection are described, both for use either alone or as adjuncts to TH. These include endogenous pathway modifiers such as erythropoietin and analogues, melatonin, and remote ischemic post conditioning. Stem cells have therapeutic potential in this condition, as in many other neonatal conditions. Of the agents listed, only erythropoietin and analogues are currently being evaluated in large randomized controlled trials (RCTs). Exogenous therapies such as argon and xenon, allopurinol, monosialogangliosides, and magnesium sulfat...
Objective: To determine patterns of respiratory medications used in neonatal intensive care unit ... more Objective: To determine patterns of respiratory medications used in neonatal intensive care unit (NICU) graduates. Study design: The Prematurity Respiratory Outcomes Program enrolled 835 babies <29 weeks gestation in the first week. Of 751 survivors, 738 (98%) completed at least 1, and 85% completed
Nuclear Factor I (Nfi) genes encode transcription factors essential for the development of organ ... more Nuclear Factor I (Nfi) genes encode transcription factors essential for the development of organ systems including the lung. Nfib null mice die at birth with immature lungs. Nfib hemizygous mice have reduced lung maturation with decreased survival. We therefore hypothesized that these mice would be more sensitive to lung injury and would have lower survival to hyperoxia. Adult Nfib hemizygous mice and their wild-type (Wt) littermates were exposed to 100% O 2 for 89, 80, 72 and 66 h for survival studies with lung outcome measurements at 66 h. Nfib hemizygous and Wt controls were also studied in RA at 66 h. Cell counts and cytokines were measured in bronchoalveolar lavage (BAL); lung sections examined by histopathology; lung angiogenic and oxidative stress gene expression assessed by real-time PCR. Unexpectedly, Nfib hemizygous mice (0/14-0%) had significantly lower mortality compared to Wt mice (10/22-45%) at 80 h of hyperoxia (P < 0.003). LD 50 was 80 h in the Wt group versus 89 h in the hemizygous group. There were no differences in BAL cell counts between the groups. Among the cytokines studied, MIP-2 was significantly lower in hemizygous mice exposed to hyperoxia. New vessel formation, edema, congestion, and alveolar hemorrhage were noted on histopathology at 72 and 80 h in wild-type mice. Nfib hemizygous lungs had significant downregulation of genes involved in redox signaling and inflammatory pathways. Adult Nfib hemizygous mice are relatively resistant to hyperoxia compared to wild-type littermates. Mechanisms contributing to this resistance are not clear; however, transcription factors such as Nfib may regulate cell survival and play a role in modulating postnatal lung development.
Organized and coordinated lung development follows transcriptional regulation of a complex set of... more Organized and coordinated lung development follows transcriptional regulation of a complex set of cell-cell and cell-matrix interactions resulting in a blood-gas interface ready for physiologic gas exchange at birth. Transcription factors, growth factors, and various other signaling molecules regulate epithelial-mesenchymal interactions by paracrine and autocrine mechanisms. Transcriptional control at the earliest stages of lung development results in cell differentiation and cell commitment in the primitive lung bud, in essence setting up a framework for pattern formation and branching morphogenesis. Branching morphogenesis results in the formation of the conductive airway system, which is critical for alveolization. Lung development is influenced at all stages by spatial and temporal distribution of various signaling molecules and their receptors and also by the positive and negative control of signaling by paracrine, autocrine, and endocrine mechanisms. Lung bud formation, cell differentiation, and its interaction with the splanchnic mesoderm are regulated by HNF-3beta, Shh, Nkx2.1, HNF-3/Forkhead homolog-8 (HFH-8), Gli, and GATA transcription factors. HNF-3beta regulates Nkx2.1, a transcription factor critical to the formation of distal pulmonary structures. Nkx2.1 regulates surfactant protein genes that are important for the development of alveolar stability at birth. Shh, produced by the foregut endoderm, regulates lung morphogenesis signaling through Gli genes expressed in the mesenchyme. FGF10, produced by the mesoderm, regulates branching morphogenesis via its receptors on the lung epithelium. Alveolization and formation of the capillary network are influenced by various factors that include PDGF, vascular endothelial growth factor (VEGF), and retinoic acid. Epithelial-endothelial interactions during lung development are important in establishing a functional blood-gas interface. The effects of various growth factors on lung development have been demonstrated by gain- or loss-of-function studies in null mutant and transgenic mice models. Understanding the role of growth factors and various other signaling molecules and their cellular interactions in lung development will provide us with new insights into the pathogenesis of bronchopulmonary dysplasia and disorders of lung morphogenesis.
We present a full-term male infant who presented with tachypnea and an increased band count on hi... more We present a full-term male infant who presented with tachypnea and an increased band count on his complete blood count (CBC) with an immature to total neutrophil (I:T) ratio of 0.6 raising suspicion of early onset sepsis. A blood culture was drawn and he was started on appropriate antibiotics. The patient's clinical condition rapidly improved; however, the white cell count 'left shift' persisted. When a detailed family history was obtained, it was discovered that the father, paternal uncle and the grandfather had been diagnosed with Pelger-Huet anomaly (PHA). As the urine, blood and CSF cultures were all negative in this now well-appearing infant, the left shift on the CBC was believed to be due to inheritance of the PHA. We present this case to emphasize that even in this age of sophisticated laboratory evaluation, a good clinical history, including family history, and clinical evaluation, are essential for accurate diagnosis.
Beta-adrenergic agents enhance secretion of phosphatidylcholine (PC) by adult and fetal type II c... more Beta-adrenergic agents enhance secretion of phosphatidylcholine (PC) by adult and fetal type II cells. We have previously shown that terbutaline stimulates secretion of PC by fetal type II cells, but the response wanes after 30 minutes. We studied the effects of salmeterol, a highly selective, long-acting beta2-adrenergic agonist that does not cause receptor desensitization, on PC secretion by adult type II alveolar cells in primary culture. Release of lactate-dehydrogenase was &amp;amp;lt; 4% and did not vary with the concentration of salmeterol. Salmeterol stimulated PC secretion in a concentration-dependent manner. The maximum effective-concentration tested was 50 nM and the EC50 was 11.40 +/- 1.14 nM. Propranolol inhibited the effect of salmeterol on release of PC, confirming that the effects of salmeterol are mediated by beta-receptors. OT50, the time for onset of action, was 32.0 +/- 1.6 minutes. RT50, the time to achieve 50% recovery from maximal stimulation was, 393.0 +/- 20.2 minutes. We conclude that salmeterol stimulates PC secretion by type II cells through activation of beta-adrenergic receptors and has a longer duration of action (&amp;amp;gt;6 hours) compared to other beta2-agonists. Salmeterol may be a useful drug with which to study the role of receptor desensitization in the developmental changes in PC secretion.
At birth, the release of surfactant from Alveolar Type II (ATII) cells is stimulated by increased... more At birth, the release of surfactant from Alveolar Type II (ATII) cells is stimulated by increased activity of the beta-adrenergic/adenylyl cyclase/cAMP- signaling cascade. Atrial natriuretic peptide (ANP) stimulates surfactant secretion through Natriuretic peptide receptor A (NPR-A). ANP inhibits adenylyl cyclase activity through its binding to NPR-C. We wished to further understand the role of the NPR-C in perinatal transition. We studied fetal and newborn sheep ATII expression of NPR-C and surfactant secretion in isolated ATIIs by measuring (3)[H] choline release into the media. ANP induced surfactant secretion, and, at higher doses, inhibits the stimulatory effect of the secretagogue terbutaline. ATII NPR-C expression decreased significantly after birth. Premature delivery also markedly decreased ANP and NPR-C in ATIIs. Co-incubation of terbutaline (10(-4)M) with ANP (10(-6)M) significantly decreased (3)[H] choline release from isolated newborn ATII cells when compared to terbuta...
Premature infants with bronchopulmonary dysplasia (BPD), are at risk for frequent respiratory inf... more Premature infants with bronchopulmonary dysplasia (BPD), are at risk for frequent respiratory infections and reduced pulmonary function. We studied whether neonatal hyperoxia disrupts adaptive immune responses in adult mice, contributing to higher respiratory-related morbidities seen in these infants. Newborn mice litters were randomized at 3 days to 85% Oor room air (RA) for 12 days. Whole lung mRNA was isolated in both the groups at 2 weeks and 3 months. Gene expression for T-cell and B-cell adaptive immune response was performed by real-time PCR and qRT-PCR; protein expression (p21, IL4, IL10, IL27, cd4) was performed by enzyme immunoassay along with p21 immunohistochemistry. Hyperoxia increased expression of p21 and decreased expression of 19 genes representing T/B-cell activation by ≥ fourfold; three of them significantly (Rag1, Cd1d1, Cd28) compared to the RA group at 2 weeks. Despite RA recovery, the expression of IFNγ, IL27, and CD40 was significantly reduced at 3 months in ...
The COVID-19 pandemic has affected maternal and infant health globally both directly from infecti... more The COVID-19 pandemic has affected maternal and infant health globally both directly from infection with the SARS-CoV-2 virus and indirectly from changes in health care resulting from social, economic, and health care policies unique to each country. The developing countries have to share the disproportionate burden on maternal and infant health. In this review, we discuss the uncertainties resulting from SARS-CoV-2 infection in pregnancy, vertical transmission of the virus, and its effects on breastfeeding of the newborn. The problems of families and communities caring for mothers with COVID-19 and its impact on breastfeeding in newborns are discussed. The challenges posed by the pandemic have forced us to think and devise innovative solutions, including telemedicine help for antenatal counseling, breastfeeding education, and lactation support. Optimal utilization of resources and technology to find creative solutions at the individual and the community level will help in facilitat...
Coronavirus disease 2019 (COVID-19), a condition associated with SARS-CoV-2, typically results in... more Coronavirus disease 2019 (COVID-19), a condition associated with SARS-CoV-2, typically results in mild infection in infants and children. However, children with risk factors such as chronic lung disease and immunosuppression have higher risk of severe illness from COVID-19. We report a case of a 27-week-gestation extremely premature infant born to a mother with COVID-19 infection. The infant, initially treated for surfactant deficiency, developed worsening hypoxic respiratory failure on the fifth day of life requiring escalating ventilatory support, an elevated level of C-reactive protein, thrombocytopenia, and an elevated level of d-dimer. The infant was positive for SARS-CoV-2 by RT-PCR from Day 1 to Day 42 of his life. The infant responded to a seven-day course of dexamethasone with a gradually decreasing oxygen requirement and could be extubated to non-invasive ventilation by the end of the fifth week after birth. The infant is currently on home oxygen by nasal cannula. Prolonge...
Coronavirus disease 2019 (COVID-19), a condition associated with SARS-CoV-2, typically results in... more Coronavirus disease 2019 (COVID-19), a condition associated with SARS-CoV-2, typically results in mild infection in infants and children. However, children with risk factors such as chronic lung disease and immunosuppression have higher risk of severe illness from COVID-19. We report a case of a 27-week-gestation extremely premature infant born to a mother with COVID-19 infection. The infant, initially treated for surfactant deficiency, developed worsening hypoxic respiratory failure on the fifth day of life requiring escalating ventilatory support, an elevated level of C-reactive protein, thrombocytopenia, and an elevated level of d-dimer. The infant was positive for SARS-CoV-2 by RT-PCR from Day 1 to Day 42 of his life. The infant responded to a seven-day course of dexamethasone with a gradually decreasing oxygen requirement and could be extubated to non-invasive ventilation by the end of the fifth week after birth. The infant is currently on home oxygen by nasal cannula. Prolonge...
Background Hyperoxia at resuscitation increases oxidative stress, and even brief exposure to high... more Background Hyperoxia at resuscitation increases oxidative stress, and even brief exposure to high oxygen concentrations during stabilization may trigger organ injury with adverse long-term outcomes in premature infants. We studied the long-term effects of short-term perinatal oxygen exposure on cell cycle gene expression and lung growth in adult mice. Methods We randomized mice litters at birth to 21, 40, or 100%O2 for 30 min and recovered in room air for 4 or 12 weeks. Cell cycle gene expression, protein analysis, and lung morphometry were assessed at 4 and 12 weeks. Results The principal component analysis demonstrated a high degree of correlation for cell cycle gene expression among the three oxygen groups. Lung elastin was significantly lower in the 100%O2 groups at 4 weeks. On lung morphometry, radial alveolar count, alveolar number, and septal count were similar. However, the mean linear intercept (MLI) and septal length significantly correlated among the oxygen groups. The ML...
This is an open access article under the terms of the Creative Commons Attribution License, which... more This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Design: Prospective cohort study, part of an ongoing “Neurological Outcome of Glucose in Neonatal... more Design: Prospective cohort study, part of an ongoing “Neurological Outcome of Glucose in Neonatal Encephalopathy (NOGIN)” study cohort Exposure: Infants were grouped based on the occurrence of normoglycemia (51–144mg/dl), hypoglycemiadefined as blood or interstitial glucose ≤50mg/dL (2.8mmol/L) and hyperglycemiadefined as glucose >144mg/dL (8.0mmol/L). Blinding: A blinded device, the iPro2 monitor, was used to record interstitial glucose concentrations for 72 h and this data was not made available to the clinical care team. Follow-up period: The study provides data collected in the first 72 h only. Setting: A single referral tertiary care hospital in Toronto, Canada, between August 2014 and March 2017. Patients: Full term infants with neonatal encephalopathy, defined as abnormal consciousness with either neonatal seizures or abnormalities in tone and reflexes. Exclusion criteria: suspected or confirmed congenital malformations, inborn errors of metabolism, congenital infections, gestational age <36 weeks, weight <1500 g, or if it was expected that a continuous glucose monitor (CGM) could not be attached within 6 h of life. Intervention: Continuous glucose monitors were used to record average interstitial glucose concentrations every 5 min. Episodes of interstitial glucose derangements were defined as 2 or more consecutive data points (≥10 min) outside the normal range (51–144 mg/dl). Episodes of glucose derangement were treated as contiguous if they were separated by brief periods of normoglycemia lasting ≤10 min. Clinicians treated newborns for hypoglycemia or hyperglycemia based on the current standard of care using intermittent glucose testing. As per institutional protocol, blood glucose concentrations <49 mg/dL (2.7 mmol/L) were treated with intravenous dextrose, increasing glucose infusion rates or glucagon. Hyperglycemia was treated with insulin infusion as clinically indicated. Outcomes: The primary analyses compared aEEG scores (background, sleep–wake cycling, and seizure scores) during 6-h epochs containing episodes of hypoglycemia or hyperglycemia to normoglycemic epochs. Statistical analysis and sample size: No power or sample size analysis are mentioned. For each subject, mean, minimum, and maximum glucose levels were calculated based on interstitial measurements obtained over a 6-h epoch. The area under the curve was calculated as the area of interstitial glucose concentration over/under the normal glucose range (hours × mg/dL), reflecting the extent and duration of the episode of interstitial glucose derangement. Glucose variability was quantified using the SD, coefficient * Jayasree Nair [email protected]
Background: Caffeine therapy for apnea of prematurity reduces the incidence of bronchopulmonary d... more Background: Caffeine therapy for apnea of prematurity reduces the incidence of bronchopulmonary dysplasia (BPD) in premature neonates. Several mechanisms, including improvement in pulmonary mechanics underly beneficial effects of caffeine in BPD. As vascular development promotes alveologenesis, we hypothesized that caffeine might enhance angiogenesis in the lung, promoting lung growth, thereby attenuating BPD. Methods: C57Bl/6 mice litters were randomized within 12 h of birth to room air (RA) or 95%O 2 to receive caffeine (20 mg/kg/day) or placebo for 4 days and recovered in RA for 12wks. The lung mRNA and protein expression for hypoxia-inducible factors (HIF) and angiogenic genes performed on day 5. Lung morphometry and vascular remodeling assessed on inflation fixed lungs at 12wks. Results: Caffeine and hyperoxia in itself upregulate HIF-2α and vascular endothelial growth factor gene expression. Protein expression of HIF-2α and VEGFR1 were higher in hyperoxia/caffeine and angiopoietin-1 lower in hyperoxia. An increase in radial alveolar count, secondary septal count, and septal length with a decrease in mean linear intercept indicate an amelioration of hyperoxic lung injury by caffeine. An increase in vessel surface area and a significant reduction in smooth muscle thickness of the pulmonary arterioles may suggest a beneficial effect of caffeine on vascular remodeling in hyperoxia, especially in male mice. Conclusions: Postnatal caffeine by modulating angiogenic gene expression early in lung development may restore the pulmonary microvasculature and alveolarization in adult lung.
Caffeine, a stimulant is the most widely used drug in the world in adults with increasing usage i... more Caffeine, a stimulant is the most widely used drug in the world in adults with increasing usage in children. It is commonly used in the treatment of apnea of prematurity in premature infants. Caffeine in a randomized trial has been shown to reduce the incidence of bronchopulmonary dysplasia in infants <1250 grams birth weight when used to treat apnea of prematurity in these infants. In the same cohort of infants, caffeine improved neurodevelopmental outcomes and survival at 18 months of age and was found to be safe without any adverse events up to 11 years of age. Caffeine is an adenosine receptor antagonist and inhibits adenosine receptors at physiologic concentrations with important effects on behavior and cognitive functions. However, higher doses of caffeine may inhibit the enzyme phosphodiesterase and affect vascular smooth muscle function. Anti-oxidant, anti-inflammatory and antiapoptotic properties of caffeine and its ability to scavenge reactive oxygen species may contribute to its lung and neuroprotective effects in premature infants. Animal studies on whether caffeine is protective to the lung are not conclusive at this time. Similarly, caffeine is demonstrated to have adverse effects on brain development in animal studies. Despite the beneficial effects of caffeine in premature infants when administered in the neonatal period, the long-term effects on adult-oriented disease such as cardio-metabolic disease and neurobehavioral states in children and adults needs further study.
Neonatal hypoxic ischemic encephalopathy (HIE) presents a significant clinical burden with its hi... more Neonatal hypoxic ischemic encephalopathy (HIE) presents a significant clinical burden with its high mortality and morbidity rates globally. Therapeutic hypothermia (TH) is now standard of care for infants with moderate to severe HIE, but has not definitively changed outcomes in severe HIE. In this review, we discuss newer promising markers that may help the clinician identify severity of HIE. Therapies that are beneficial and agents that hold promise for neuroprotection are described, both for use either alone or as adjuncts to TH. These include endogenous pathway modifiers such as erythropoietin and analogues, melatonin, and remote ischemic post conditioning. Stem cells have therapeutic potential in this condition, as in many other neonatal conditions. Of the agents listed, only erythropoietin and analogues are currently being evaluated in large randomized controlled trials (RCTs). Exogenous therapies such as argon and xenon, allopurinol, monosialogangliosides, and magnesium sulfat...
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