273 results on '"David K. Stevenson"'
Search Results
2. The Impact of Hypoxia in Early Pregnancy on Placental Cells
- Author
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Hui Zhao, Ronald J. Wong, and David K. Stevenson
- Subjects
angiogenesis ,decidual macrophages ,dysregulation ,hofbauer cells ,heme oxygenase-1 ,implantation ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Oxygen levels in the placental microenvironment throughout gestation are not constant, with severe hypoxic conditions present during the first trimester. This hypoxic phase overlaps with the most critical stages of placental development, i.e., blastocyst implantation, cytotrophoblast invasion, and spiral artery remodeling initiation. Dysregulation of any of these steps in early gestation can result in pregnancy loss and/or adverse pregnancy outcomes. Hypoxia has been shown to regulate not only the self-renewal, proliferation, and differentiation of trophoblast stem cells and progenitor cells, but also the recruitment, phenotype, and function of maternal immune cells. In this review, we will summarize how oxygen levels in early placental development determine the survival, fate, and function of several important cell types, e.g., trophoblast stem cells, extravillous trophoblasts, syncytiotrophoblasts, uterine natural killer cells, Hofbauer cells, and decidual macrophages. We will also discuss the cellular mechanisms used to cope with low oxygen tensions, such as the induction of hypoxia-inducible factor (HIF) or mammalian target of rapamycin (mTOR) signals, regulation of the metabolic pathway, and adaptation to autophagy. Understanding the beneficial roles of hypoxia in early placental development will provide insights into the root cause(s) of some pregnancy disorders, such as spontaneous abortion, preeclampsia, and intrauterine growth restriction.
- Published
- 2021
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3. Low‐dose lipopolysaccharide exposure can increase in vivo bilirubin production rates in newborn mice
- Author
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Danielle R. Jacobsen, Ronald J. Wong, Sota Iwatani, and David K. Stevenson
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Lipopolysaccharides ,medicine.medical_specialty ,Bilirubin ,Sepsis ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,In vivo ,030225 pediatrics ,Internal medicine ,medicine ,Animals ,030212 general & internal medicine ,Hyperbilirubinemia ,Neonatal sepsis ,business.industry ,Neurotoxicity ,General Medicine ,Jaundice ,medicine.disease ,Haemolysis ,Endocrinology ,Animals, Newborn ,chemistry ,Heme Oxygenase (Decyclizing) ,Pediatrics, Perinatology and Child Health ,Kernicterus ,medicine.symptom ,business - Abstract
AIM Neonatal haemolysis increases bilirubin production rates, which can then lead to severe hyperbilirubinaemia and bilirubin neurotoxicity. During haemolysis, haem is degraded by haem oxygenase (HO), which can be induced under stress conditions. It is known that neonatal sepsis is a risk factor for haemolysis and severe hyperbilirubinaemia. Here, we evaluated whether an exposure to lipopolysaccharide (LPS) to induce sepsis can upregulate HO-1, further increasing in vivo bilirubin production rates in mouse pups under haem loads. METHODS Three-day-old pups were given LPS (1250 μg/kg) or saline (controls). Liver HO enzyme activity, HO-1 mRNA and HO-1 protein were measured post-LPS exposure. We then assessed the effects of LPS treatment on in vivo bilirubin production rates after haem loading. RESULTS Liver HO activity significantly increased (142%) over controls 24 hours after treatment with LPS (1250 μg/kg) without mortality. Liver HO-1 mRNA was significantly upregulated 2.47-fold at 24 hours post-LPS administration, while liver HO-1 protein increased 1.29-fold 24 hours post-LPS treatment. After haem loading, pups exposed to LPS had significantly higher bilirubin production rates (1.30-fold) compared with age-matched, saline-treated controls. CONCLUSION Low-dose LPS treatment can upregulate liver HO-1 expression and may underlie the severe hyperbilirubinaemia seen in septic infants, particularly when undergoing haemolysis.
- Published
- 2020
4. Increased Carbon Monoxide Washout Rates in Newborn Infants
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Ronald S. Cohen, Hendrik J. Vreman, David K. Stevenson, Ronald J. Wong, Clint R. Ostrander, and Ivana Maric
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Carbon Monoxide ,Term Birth ,Bilirubin ,Infant, Newborn ,Washout ,Hemolysis ,Healthy Volunteers ,Excretion ,chemistry.chemical_compound ,Animal science ,Carboxyhemoglobin ,chemistry ,Pediatrics, Perinatology and Child Health ,Least squares curve fitting ,Humans ,Washout rate ,Steady state (chemistry) ,Hyperbilirubinemia, Neonatal ,Developmental Biology ,Carbon monoxide - Abstract
Background: Endogenous carbon monoxide (CO) production is primarily due to heme degradation, which also results in the equimolar production of bilirubin. Thus, estimates of total body CO production can serve as indices of total body bilirubin formation. The elimination rate of CO from a person’s body (CO washout rate) after exposure to an elevated ambient CO concentration is determined by a variety of factors, and is very different between babies and adults. Objective: We determined CO washout rates for babies using a simplified technique to measure total body CO excretion rates (VeCO). Methods: Using a simplified technique, we measured the times to reach an approximate steady state after a change in ambient CO concentration (decay time constant) and CO washout rates in normal newborn infants using non-linear least squares curve fitting. Results: We found a mean CO washout time of 18.7 ± 4.2 min and a CO equilibration (decay time) constant of 0.12 ± 0.04/min (0.08–0.21) for newborn infants. Conclusions: We confirm that CO washout rates for babies are much faster than those for adults. Therefore, measurements of carboxyhemoglobin (COHb) or end-tidal CO (ETCO), corrected for ambient CO, (COHbc and ETCOc, respectively) can be used as surrogates for VeCO and can provide accurate estimates of endogenous CO (VCO) and bilirubin production rates under normal environmental conditions. Such measurements can be used to identify infants with severe hyperbilirubinemia due to hemolysis and thus at high risk for bilirubin neurotoxicity.
- Published
- 2019
5. The Impact of Hypoxia in Early Pregnancy on Placental Cells
- Author
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Ronald J. Wong, David K. Stevenson, and Hui Zhao
- Subjects
Syncytiotrophoblasts ,Review ,decidual macrophages ,angiogenesis ,Pregnancy ,implantation ,Biology (General) ,Hypoxia ,Spectroscopy ,reproductive and urinary physiology ,natural killer cells ,heme oxygenase-1 ,Cell Differentiation ,General Medicine ,Computer Science Applications ,Cell biology ,Trophoblasts ,Chemistry ,medicine.anatomical_structure ,embryonic structures ,Female ,Stem cell ,dysregulation ,Spiral artery ,placenta ,QH301-705.5 ,Biology ,Catalysis ,Inorganic Chemistry ,preeclampsia ,Placenta ,medicine ,Animals ,Humans ,Physical and Theoretical Chemistry ,Progenitor cell ,hofbauer cells ,QD1-999 ,Molecular Biology ,PI3K/AKT/mTOR pathway ,Cytotrophoblast ,Macrophages ,Organic Chemistry ,Trophoblast ,preterm birth ,Placentation ,Pregnancy Trimester, First ,Gene Expression Regulation ,Energy Metabolism ,Biomarkers - Abstract
Oxygen levels in the placental microenvironment throughout gestation are not constant, with severe hypoxic conditions present during the first trimester. This hypoxic phase overlaps with the most critical stages of placental development, i.e., blastocyst implantation, cytotrophoblast invasion, and spiral artery remodeling initiation. Dysregulation of any of these steps in early gestation can result in pregnancy loss and/or adverse pregnancy outcomes. Hypoxia has been shown to regulate not only the self-renewal, proliferation, and differentiation of trophoblast stem cells and progenitor cells, but also the recruitment, phenotype, and function of maternal immune cells. In this review, we will summarize how oxygen levels in early placental development determine the survival, fate, and function of several important cell types, e.g., trophoblast stem cells, extravillous trophoblasts, syncytiotrophoblasts, uterine natural killer cells, Hofbauer cells, and decidual macrophages. We will also discuss the cellular mechanisms used to cope with low oxygen tensions, such as the induction of hypoxia-inducible factor (HIF) or mammalian target of rapamycin (mTOR) signals, regulation of the metabolic pathway, and adaptation to autophagy. Understanding the beneficial roles of hypoxia in early placental development will provide insights into the root cause(s) of some pregnancy disorders, such as spontaneous abortion, preeclampsia, and intrauterine growth restriction.
- Published
- 2021
6. A Novel Point-Of-Care Device for Measuring Glucose-6-Phosphate Dehydrogenase Enzyme Deficiency
- Author
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Vinod K. Bhutani, Cynthia Montiel, David K. Stevenson, Ronald J. Wong, and Megana Kunda
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medicine.medical_specialty ,Enzyme deficiency ,Bilirubin ,Point-of-Care Systems ,Dehydrogenase ,Glucosephosphate Dehydrogenase ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,030225 pediatrics ,Internal medicine ,parasitic diseases ,medicine ,Glucose-6-phosphate dehydrogenase ,Humans ,Reproducibility ,030219 obstetrics & reproductive medicine ,business.industry ,Neurotoxicity ,Infant, Newborn ,Obstetrics and Gynecology ,Infant ,Reproducibility of Results ,medicine.disease ,Point of care device ,Hemolysis ,Endocrinology ,Glucosephosphate Dehydrogenase Deficiency ,chemistry ,Pediatrics, Perinatology and Child Health ,business - Abstract
Extreme hyperbilirubinemia can cause bilirubin neurotoxicity. Infants with glucose-6-phosphate dehydrogenase (G6PD) deficiency can develop hemolysis and thus are at high risk. We evaluated a device that quantitatively measures G6PD activity kinetically using digital microfluidics (DMF). Intra- and inter-instrument and -day imprecision (CVs) were first assessed. G6PD activity in 86 samples was then measured and compared between DMF and 2 reference methods. Overall DMF reproducibility was 3.8% over 5 days by 2 operators on 2 instruments. Mean intra- and inter-instrument variabilities were 3.6% and 3.9%, respectively (n = 28), with a user variability of 4.3%. Mean G6PD activity was 6.40±4.62 and 6.37±4.62 U/g hemoglobin for DMF and Reference Methods 1 (n = 46) and 12.15±3.86 and 11.48±1.55 for DMF and 2 (n = 40), respectively, and strongly correlated (r = 0.95 and 0.95) with mean biases of +0.04±2.90 and +0.67±1.55 for methods 1 and 2, respectively. The novel device could be used for early newborn G6PD screening.
- Published
- 2020
7. Quantitative LCMS for ceramides/dihydroceramides: pregnancy baseline biomarkers and potential metabolic messengers
- Author
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Xiaoming Yao, Donghai Lai, Kuo-Yuan Hwa, John C. Whitin, Doff B. McElhinney, Henry Chubb, Xuefeng B. Ling, Harvey J. Cohen, Gary M. Shaw, Xiao Li, Karl G. Sylvester, James Schilling, Scott R. Ceresnak, David K. Stevenson, Shiying Hao, Qianyang Huang, Sheeno Thyparambil, Jin You, and Chunle Han
- Subjects
Ceramide ,chemistry.chemical_compound ,Pregnancy ,Chromatographic separation ,Chromatography ,Chemistry ,Coefficient of variation ,Selected reaction monitoring ,medicine ,Enhanced sensitivity ,Sample preparation ,medicine.disease ,Sphingolipid - Abstract
Ceramides and dihydroceramides are sphingolipids that present in abundance at the cellular membrane of eukaryotes. Although their metabolic dysregulation has been implicated in many diseases, our knowledge about circulating ceramide changes during the pregnancy remains limited. In this study, we present the development and validation of a high-throughput liquid chromatography-tandem mass spectrometric (LC/MS/MS) method for simultaneous quantification of 16 ceramides and 10 dihydroceramides in human serum within 5 mins by using stable isotope-labeled ceramides as internal standards (ISs). This method employs a protein precipitation method for high throughput sample preparation, reverse phase isocratic elusion for chromatographic separation, and Multiple Reaction Monitoring (MRM) for mass spectrometric detection. To qualify for clinical applications, our assay was validated against the FDA guidelines: the Lower Limit of Quantitation (LLOQ as low as 1 nM), linearity (R2>0.99), precision (Coefficient of Variation90%), stability (>85%), and carryover (
- Published
- 2020
8. Molecular physiology and pathophysiology of bilirubin handling by the blood, liver, intestine, and brain in the newborn
- Author
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Thor Willy Ruud Hansen, David K. Stevenson, and Ronald J. Wong
- Subjects
Physiology ,Bilirubin ,Excretion ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,030225 pediatrics ,Physiology (medical) ,medicine ,Humans ,Intestinal Mucosa ,Molecular Biology ,Unconjugated hyperbilirubinemia ,Mechanism (biology) ,Infant, Newborn ,Neurotoxicity ,Brain ,General Medicine ,Metabolism ,medicine.disease ,Pathophysiology ,Liver ,chemistry ,Molecular physiology ,030217 neurology & neurosurgery - Abstract
Bilirubin is the end product of heme catabolism formed during a process that involves oxidation-reduction reactions and conserves iron body stores. Unconjugated hyperbilirubinemia is common in newborn infants, but rare later in life. The basic physiology of bilirubin metabolism, such as production, transport, and excretion, has been well described. However, in the neonate, numerous variables related to nutrition, ethnicity, and genetic variants at several metabolic steps may be superimposed on the normal physiological hyperbilirubinemia that occurs in the first week of life and results in bilirubin levels that may be toxic to the brain. Bilirubin exists in several isomeric forms that differ in their polarities and is considered a physiologically important antioxidant. Here we review the chemistry of the bilirubin molecule and its metabolism in the body with a particular focus on the processes that impact the newborn infant, and how differences relative to older children and adults contribute to the risk of developing both acute and long-term neurological sequelae in the newborn infant. The final section deals with the interplay between the brain and bilirubin and its entry, clearance, and accumulation. We conclude with a discussion of the current state of knowledge regarding the mechanism(s) of bilirubin neurotoxicity.
- Published
- 2020
9. The biology of bilirubin production: overview of detection and inhibition
- Author
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David K. Stevenson and Ronald J. Wong
- Subjects
chemistry.chemical_compound ,chemistry ,Biochemistry ,Bilirubin ,Pediatrics, Perinatology and Child Health ,Biology - Published
- 2021
10. The effect of light wavelength on in vitro bilirubin photodegradation and photoisomer production
- Author
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Benjamin K. Cline, Lucie Ludvíková, Lucie Muchová, Petr Klán, Hendrik J. Vreman, Libor Vítek, David K. Stevenson, Stephanie Kourula, Ronald J. Wong, and Jana Jašprová
- Subjects
Light ,Bilirubin ,Serum albumin ,Quantum yield ,Serum Albumin, Human ,In Vitro Techniques ,Photochemistry ,chemistry.chemical_compound ,Isomerism ,Spectrophotometry ,medicine ,Humans ,Photodegradation ,Action spectrum ,Photolysis ,medicine.diagnostic_test ,biology ,Lumirubin ,Infant, Newborn ,Phototherapy ,Human serum albumin ,chemistry ,Pediatrics, Perinatology and Child Health ,biology.protein ,Hyperbilirubinemia, Neonatal ,medicine.drug - Abstract
The action spectrum for bilirubin photodegradation has been intensively studied. However, questions still remain regarding which light wavelength most efficiently photodegrades bilirubin. In this study, we determined the in vitro effects of different irradiation wavelength ranges on bilirubin photodegradation. In our in vitro method, normalized absolute irradiance levels of 4.2 × 1015 photons/cm2/s from light-emitting diodes (ranging from 390–530 nm) and 10-nm band-pass filters were used to irradiate bilirubin solutions (25 mg/dL in 4% human serum albumin). Bilirubin and its major photoisomer concentrations were determined; the half-life time of bilirubin (t1/2) was calculated for each wavelength range, and the spectral characteristics for bilirubin photodegradation products were obtained for key wavelengths. The in vitro photodegradation of bilirubin at 37 °C decreased linearly as the wavelength was increased from 390 to 500 nm with t1/2 decreasing from 63 to 17 min, respectively. At 460 ± 10 nm, a significantly lower rate of photodegradation and thus higher t1/2 (31 min) than that at 500 nm (17 min) was demonstrated. In our system, the optimum bilirubin photodegradation and lumirubin production rates occurred between 490 and 500 nm. Spectra shapes were remarkably similar, suggesting that lumirubin production was the major process of bilirubin photodegradation.
- Published
- 2018
11. Impact of post-collection freezing delay on the reliability of serum metabolomics in samples reflecting the California mid-term pregnancy biobank
- Author
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Chen Ma, Macy Hardley, Suzan L. Carmichael, John W. Newman, Tong Shen, Lorenzo Rosales, Michael R. La Frano, Theresa L. Pedersen, David K. Stevenson, Gary M. Shaw, Oliver Fiehn, Ronald J. Wong, and Kamil Borkowski
- Subjects
Adult ,0301 basic medicine ,Endocrinology, Diabetes and Metabolism ,Metabolite ,Clinical Biochemistry ,Population ,Lysophospholipids ,Biochemistry ,California ,03 medical and health sciences ,chemistry.chemical_compound ,Metabolomics ,Pregnancy ,Humans ,Food science ,education ,Cryopreservation ,chemistry.chemical_classification ,education.field_of_study ,Term pregnancy ,Fatty acid ,Biobank ,030104 developmental biology ,chemistry ,Blood Preservation ,Blood Banks ,Female ,Polyunsaturated fatty acid - Abstract
Population-based biorepositories are important resources, but sample handling can affect data quality. Identify metabolites of value for clinical investigations despite extended postcollection freezing delays, using protocols representing a California mid-term pregnancy biobank. Blood collected from non-pregnant healthy female volunteers (n = 20) underwent three handling protocols after 30 min clotting at room temperature: (1) ideal—samples frozen (− 80 °C) within 2 h of collection; (2) delayed freezing—samples held at room temperature for 3 days, then 4 °C for 9 days, the median times for biobank samples, and then frozen; (3) delayed freezing with freeze–thaw—the delayed freezing protocol with a freeze–thaw cycle simulating retrieved sample sub-aliquoting. Mass spectrometry-based untargeted metabolomic analyses of primary metabolism and complex lipids and targeted profiling of oxylipins, endocannabinoids, ceramides/sphingoid-bases, and bile acids were performed. Metabolite concentrations and intraclass correlation coefficients (ICC) were compared, with the ideal protocol as the reference. Sixty-two percent of 428 identified compounds had good to excellent ICCs, a metric of concordance between measurements of samples handled with the different protocols. Sphingomyelins, phosphatidylcholines, cholesteryl esters, triacylglycerols, bile acids and fatty acid diols were the least affected by non-ideal handling, while sugars, organic acids, amino acids, monoacylglycerols, lysophospholipids, N-acylethanolamides, polyunsaturated fatty acids, and numerous oxylipins were altered by delayed freezing. Freeze–thaw effects were assay-specific with lipids being most stable. Despite extended post-collection freezing delays characteristic of some biobanks of opportunistically collected clinical samples, numerous metabolomic compounds had both stable levels and good concordance.
- Published
- 2018
12. High-throughput quantitation of serological ceramides/dihydroceramides by LC/MS/MS: Pregnancy baseline biomarkers and potential metabolic messengers
- Author
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David K. Stevenson, Karl G. Sylvester, Xiaoming Yao, Doff B. McElhinney, Gary M. Shaw, Shiying Hao, Xiao Li, Sheeno Thyparambil, John C. Whitin, James Schilling, Henry Chubb, Xuefeng B. Ling, Donghai Lai, Scott R. Ceresnak, Harvey J. Cohen, Kuo-Yuan Hwa, Jin You, Chunle Han, Qianyang Huang, and Ronald J. Wong
- Subjects
Ceramide ,Clinical Biochemistry ,Pharmaceutical Science ,Ceramides ,01 natural sciences ,Analytical Chemistry ,Serology ,chemistry.chemical_compound ,Pregnancy ,Tandem Mass Spectrometry ,Drug Discovery ,Lc ms ms ,medicine ,Humans ,Enhanced sensitivity ,Sample preparation ,Spectroscopy ,Chromatography ,010405 organic chemistry ,010401 analytical chemistry ,Selected reaction monitoring ,Reproducibility of Results ,medicine.disease ,Sphingolipid ,0104 chemical sciences ,chemistry ,Female ,Biomarkers ,Chromatography, Liquid - Abstract
Ceramides and dihydroceramides are sphingolipids that present in abundance at the cellular membrane of eukaryotes. Although their metabolic dysregulation has been implicated in many diseases, our knowledge about circulating ceramide changes during the pregnancy remains limited. In this study, we present the development and validation of a high-throughput liquid chromatography-tandem mass spectrometric method for simultaneous quantification of 16 ceramides and 10 dihydroceramides in human serum within 5 min. by using stable isotope-labeled ceramides as internal standards. This method employs a protein precipitation method for high throughput sample preparation, reverse phase isocratic elusion for chromatographic separation, and Multiple Reaction Monitoring for mass spectrometric detection. To qualify for clinical applications, our assay has been validated against the FDA guidelines for Lower Limit of Quantitation (1 nM), linearity (R2>0.99), precision (imprecision 90 %), stability (>85 %), and carryover (
- Published
- 2021
13. Phototherapy and the Risk of Photo-Oxidative Injury in Extremely Low Birth Weight Infants
- Author
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Ronald J. Wong, Jon E. Tyson, Cody Arnold, Claudia Pedroza, and David K. Stevenson
- Subjects
Pediatrics ,medicine.medical_specialty ,Bilirubin ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,030225 pediatrics ,Humans ,Medicine ,Oxidative injury ,030212 general & internal medicine ,business.industry ,Presumption ,Infant, Newborn ,Obstetrics and Gynecology ,Phototherapy ,Jaundice ,Jaundice, Neonatal ,Oxidative Stress ,Low birth weight ,Hematocrit ,chemistry ,Infant, Extremely Low Birth Weight ,Pediatrics, Perinatology and Child Health ,Hyperbilirubinemia, Neonatal ,medicine.symptom ,business ,Infant, Premature - Abstract
Phototherapy has been used to treat newborns with jaundice for more than 50 years with the presumption that it is safe and effective for all infants. In fact, this presumption may not be true for all infants, especially the smallest and most immature. The safety and efficacy of phototherapy have never really been questioned or adequately tested in the latter, yet clinical applications of phototherapy have been further refined as its mechanisms of action have been better understood and alternative light sources have become available. This article addresses what is known about the possible risks of photo-oxidative injury in extremely low birth weight infants.
- Published
- 2016
14. Identification of neonatal haemolysis: an approach to predischarge management of neonatal hyperbilirubinemia
- Author
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Ronald J. Wong, Vinod K. Bhutani, Martin E. Castillo Cuadrado, Janelle L. Aby, Shanmukha Srinivas, and David K. Stevenson
- Subjects
Male ,Pediatrics ,medicine.medical_specialty ,Percentile ,Bilirubin ,Clinical Decision-Making ,Hemolysis ,Decision Support Techniques ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Reference Values ,Interquartile range ,030225 pediatrics ,Humans ,Medicine ,030212 general & internal medicine ,Carbon Monoxide ,Newborn jaundice ,business.industry ,Infant, Newborn ,General Medicine ,Haemolysis ,Patient Discharge ,Postnatal age ,chemistry ,Point-of-Care Testing ,Pediatrics, Perinatology and Child Health ,Female ,Hyperbilirubinemia, Neonatal ,business ,Algorithms ,Biomarkers - Abstract
Aim Relative contributions of increased production [by end-tidal carbon monoxide concentrations (ETCOc)] and decreased elimination of bilirubin to predischarge hour-specific total bilirubin (TB) levels were assessed in healthy late-preterm and term newborns. Secondly, we report predischarge ETCOc ranges to guide clinical management of hyperbilirubinemia. Methods TB and ETCOc (≤3 timepoints) determinations of newborns aged between six hours and 1.5 (p < 0.00003). Conclusion Near-simultaneous ETCOc and TB measurements in infants with TB >75th percentile accurately identify haemolytic hyperbilirubinemia.
- Published
- 2016
15. Bilirubin Production Is Increased in Newborn Mice Exposed to Isoflurane
- Author
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Flora Kalish, Jordan Burgess, David K. Stevenson, Ronald J. Wong, and Sota Iwatani
- Subjects
Male ,medicine.medical_specialty ,Bilirubin ,Hemolysis ,Excretion ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,030225 pediatrics ,Internal medicine ,medicine ,Animals ,030212 general & internal medicine ,Heme ,Carbon Monoxide ,Isoflurane ,business.industry ,Neurotoxicity ,Membrane Proteins ,Jaundice ,medicine.disease ,Heme oxygenase ,Endocrinology ,chemistry ,Animals, Newborn ,Liver ,Pediatrics, Perinatology and Child Health ,Anesthetics, Inhalation ,Female ,medicine.symptom ,Hyperbilirubinemia, Neonatal ,business ,Heme Oxygenase-1 ,Developmental Biology ,medicine.drug - Abstract
Background: Increased bilirubin production due to hemolysis can lead to severe neonatal hyperbilirubinemia and, if left untreated, to bilirubin neurotoxicity. Post-cardiac surgery newborns have been shown to be at an increased risk for developing hyperbilirubinemia and also hemolysis. Isoflurane (ISO), a volatile anesthetic agent routinely used in newborn surgery, has been reported to upregulate heme oxygenase 1 (HO-1) expression. HO is the rate-limiting enzyme in the bilirubin production pathway. Objective: Here, we evaluated whether ISO exposure induces HO-1 and further increases bilirubin production in a hemolytic newborn mouse model. Methods: Three-day-old newborn mice were exposed to 2% ISO for 18 min or air. Liver HO activity and HO-1 protein were measured after exposure to ISO. Next, we evaluated the effect of ISO exposure on bilirubin production as indexed by the total body excretion rate of carbon monoxide following heme loading. Results: ISO significantly increased liver HO activity 120% and 116% at 24 and 48 h, respectively, after exposure. HO-1 protein levels also similarly increased after ISO exposure, but the increases were not statistically significant compared with controls. After heme loading, ISO-exposed pups had significantly higher bilirubin production rates (1.24-fold), and also peaked earlier, than age-matched nonexposed pups. Conclusions: ISO exposure can induce HO-1 expression in the liver and may explain the development of severe hyperbilirubinemia in postsurgical infants, especially in those undergoing hemolysis.
- Published
- 2018
16. Prethreshold retinopathy of prematurity: VEGF inhibition without VEGF inhibitors
- Author
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David K. Stevenson, Michael W. Gaynon, Philip Sunshine, and Ronald J. Wong
- Subjects
Vascular Endothelial Growth Factor A ,medicine.medical_specialty ,Time Factors ,genetic structures ,Supplemental oxygen ,VEGF receptors ,Nutritional Status ,Blindness ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Oxygen Consumption ,030225 pediatrics ,Ophthalmology ,Medicine ,Humans ,Retinopathy of Prematurity ,biology ,business.industry ,Adaptation, Ocular ,Infant, Newborn ,Oxygen Inhalation Therapy ,Obstetrics and Gynecology ,Infant ,Retinopathy of prematurity ,Retinal ,Anemia ,Hypoxia (medical) ,medicine.disease ,eye diseases ,Vascular endothelial growth factor ,Plus disease ,Oxygen ,Rod Photoreceptors ,chemistry ,Pediatrics, Perinatology and Child Health ,030221 ophthalmology & optometry ,biology.protein ,sense organs ,medicine.symptom ,business - Abstract
The risk of developing treatment-warranted Type 1 retinopathy of prematurity (ROP) might be reduced in preterm infants by modifying certain systemic factors. There are steps that can be taken both early and late in the course of retinal vascular maturation that may potentially reduce an infant's risk of developing Type 1 ROP. In prethreshold stage 2-3 ROP without plus disease, a combination of supplemental oxygen, correction of severe anemia, and light adaptation to reduce rod photoreceptor oxygen consumption helped us to reduce ROP severity, and encouraged a return to a more physiologic retinal vascular maturation pattern. Thus, it may be possible to reduce the risk of developing Type 1 ROP by making adjustments in certain systemic parameters aimed at reducing retinal hypoxia, thereby gently lowering pathologically elevated levels of vascular endothelial growth factor (VEGF) within the eye.
- Published
- 2018
17. Neuro-inflammatory effects of photodegradative products of bilirubin
- Author
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Jana Jašprová, Claudio Tiribelli, D. Hurný, M. Dal Ben, David K. Stevenson, Jan Kotek, K. Žížalová, Ronald J. Wong, Sungwoo Hwang, Silvia Gazzin, Libor Vítek, Jašprová, J., Dal Ben, M, Hurný, D., Hwang, S., Žížalová, K., Kotek, J., Wong, R. J., Stevenson, D. K., Gazzin, S., Tiribelli, C., and Vítek, L.
- Subjects
Bilirubin ,Cell Survival ,Science ,Neuroimmunology ,Pharmacology ,Hippocampus ,Article ,neuroinflammation ,Cell Line ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,030225 pediatrics ,Neuroblastoma ,medicine ,Animals ,Humans ,Viability assay ,Rats, Wistar ,Neuroinflammation ,photoisomers ,organotypic ,Inflammation ,Multidisciplinary ,Photolysis ,business.industry ,Tumor Necrosis Factor-alpha ,Lumirubin ,photoisomer ,Infant, Newborn ,Jaundice ,Phototherapy ,medicine.disease ,Jaundice, Neonatal ,Rats ,neurotoxicity syndrome ,chemistry ,Medicine ,neurotoxicity syndromes ,medicine.symptom ,bilirubin ,business ,030217 neurology & neurosurgery ,Ex vivo - Abstract
Phototherapy was introduced in the early 1950’s, and is the primary treatment of severe neonatal jaundice or Crigler-Najjar syndrome. Nevertheless, the potential biological effects of the products generated from the photodegradation of bilirubin during phototherapy remain unknown. This is very relevant in light of recent clinical observations demonstrating that the use of aggressive phototherapy can increase morbidity or even mortality, in extremely low birthweight (ELBW) infants. The aim of our study was to investigate the effects of bilirubin, lumirubin (LR, its major photo-oxidative product), and BOX A and B (its monopyrrolic oxidative products) on the central nervous system (CNS) using in vitro and ex vivo experimental models. The effects of bilirubin photoproducts on cell viability and expression of selected genes were tested in human fibroblasts, three human CNS cell lines (neuroblastoma SH-SY5Y, microglial HMC3, and glioblastoma U-87 cell lines), and organotypic rat hippocampal slices. Neither bilirubin nor its photo-oxidative products affected cell viability in any of our models. In contrast, LR in biologically-relevant concentrations (25 μM) significantly increased gene expression of several pro-inflammatory genes as well as production of TNF-α in organotypic rat hippocampal slices. These findings might underlie the adverse outcomes observed in ELBW infants undergoing aggressive phototherapy.
- Published
- 2018
18. Hemolysis and Glucose-6-Phosphate Dehydrogenase Deficiency-Related Neonatal Hyperbilirubinemia
- Author
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Ronald J. Wong, Michael Kaplan, and David K. Stevenson
- Subjects
0301 basic medicine ,congenital, hereditary, and neonatal diseases and abnormalities ,Enzyme deficiency ,Erythrocytes ,Bilirubin ,Physiology ,Hemolysis ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,hemic and lymphatic diseases ,030225 pediatrics ,parasitic diseases ,medicine ,Humans ,Heme catabolism ,business.industry ,Neurotoxicity ,Infant, Newborn ,nutritional and metabolic diseases ,Favism ,Jaundice ,medicine.disease ,Pathophysiology ,030104 developmental biology ,Glucosephosphate Dehydrogenase Deficiency ,chemistry ,Pediatrics, Perinatology and Child Health ,medicine.symptom ,Hyperbilirubinemia, Neonatal ,business ,Developmental Biology ,Glucose-6-phosphate dehydrogenase deficiency - Abstract
Background: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common enzyme deficiency affecting more than 300 million individuals worldwide. Extreme neonatal hyperbilirubinemia, with its severe sequelae of bilirubin neurotoxicity and the potential of death, is the most devastating manifestation of G6PD deficiency. In a recent review of Favism, Luzzatto and Arese state that the pathophysiology of jaundice in G6PD-deficient neonates is different from that of favism, as there is little evidence of hemolysis in these infants. Objectives: To explore the role of hemolysis in neonatal hyperbilirubinemia associated with G6PD deficiency. Methods: Previously published works including studies of endogenous production of carbon monoxide (CO), an index of heme catabolism, in hyperbilirubinemic G6PD-deficient neonates were reviewed to determine the role of hemolysis in this condition. Results: Three studies demonstrated that endogenous CO production is elevated in G6PD-deficient neonates with extreme hyperbilirubinemia. Conclusions: Hemolysis is an important pathogenetic factor in G6PD deficiency-associated neonatal hyperbilirubinemia.
- Published
- 2018
19. In Vitro Study on the Effect of Maraviroc or Dolutegravir on Bilirubin to Albumin Binding
- Author
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Mark Mirochnick, Cynthia N Schreiner, David K. Stevenson, Ronald J. Wong, Charles E. Ahlfors, and Diana F Clarke
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Microbiology (medical) ,Bilirubin ,Pyridones ,Plasma protein binding ,Pharmacology ,030226 pharmacology & pharmacy ,Piperazines ,Maraviroc ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,In vivo ,HIV Fusion Inhibitors ,030225 pediatrics ,Oxazines ,Medicine ,HIV Integrase Inhibitors ,Serum Albumin ,business.industry ,Albumin ,Sulfisoxazole ,In vitro ,Infectious Diseases ,chemistry ,Pediatrics, Perinatology and Child Health ,Dolutegravir ,business ,Heterocyclic Compounds, 3-Ring ,Protein Binding - Abstract
We performed an in vitro evaluation of the effect of maraviroc or dolutegravir on bilirubin to albumin binding. At typical treatment and low albumin concentrations, maraviroc had no impact, while dolutegravir affected bilirubin to albumin binding to an equivalent extent as sulfisoxazole. However in vivo, neither is likely to significantly impact bilirubin to albumin binding because of their low concentrations relative to albumin.
- Published
- 2018
20. Hypoxia regulates placental angiogenesis via alternatively activated macrophages
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Flora Kalish, Ronald J. Wong, David K. Stevenson, and Hui Zhao
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0301 basic medicine ,GPX1 ,medicine.medical_specialty ,GPX3 ,Angiogenesis ,Placenta ,Immunology ,SOD2 ,Neovascularization, Physiologic ,Mice, Inbred Strains ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Th2 Cells ,Pregnancy ,Internal medicine ,medicine ,Immunology and Allergy ,Animals ,Hypoxia ,Cells, Cultured ,Progesterone ,chemistry.chemical_classification ,030219 obstetrics & reproductive medicine ,Neovascularization, Pathologic ,Glutathione peroxidase ,Macrophages ,Obstetrics and Gynecology ,Membrane Proteins ,Cell Differentiation ,Estrogens ,Hypoxia (medical) ,Macrophage Activation ,Vascular endothelial growth factor A ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,Reproductive Medicine ,chemistry ,Cellular Microenvironment ,Cytokines ,Matrix Metalloproteinase 2 ,Female ,medicine.symptom - Abstract
Problem Uterine and placental macrophages play critical roles in maintaining a normal pregnancy. The majority of these macrophages are believed to be alternatively activated macrophages (M2). Method of study Mouse bone marrow cells were differentiated into macrophages and polarized to M2 in vitro by treatment with IL-4 [M2a] or IL-10 [M2c] and M1 with LPS/IFN-γ as controls. Macrophage subtypes were confirmed by surface markers and characterized by gene expression profiles. Results Compared to M1, M2 showed strong pro-angiogenic activity by expressing higher mRNA for angiogenic-associated factors (Cxcl12, Vegfa, PlGF, Mmp2). M2c produced the highest levels of PlGF, Mmp2, and Cxcr4. To mimic the normal placental microenvironment, M2 were exposed to hypoxia and sex hormones (progesterone, estrogen). In both M2c and M2a, severe hypoxic (1%-3% O2 ) exposure significantly suppressed PlGF, Cxcl12, and Mmp2 mRNA, but not Vegfa, compared to normoxia (21% O2 ) or physiological hypoxia (5% O2 ). mRNA expression returned to normal when hypoxic cells were returned to normoxia. Hypoxia (1%) reduced antioxidant levels in M2 and re-exposure to normoxia significantly increased superoxide dismutase (Sod1, Sod2) and heme oxygenase-1 (HO-1) levels in M2a, and only glutathione peroxidase (Gpx1, Gpx3, Gpx4) in M2c. However, progesterone and estrogen treatment had minimal effects on angiogenic factor expression in M2. Conclusion M2, particularly M2c, displayed strong pro-angiogenic potential, which decreased under severe hypoxia such as in early pregnancy. Thus, conditions that alter the placental oxygen microenvironment or macrophage response in early pregnancy might cause aberrant angiogenesis and vascular remodeling, and lead to abnormal placental vascular development.
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- 2018
21. Heme oxygenase-1 deficiency promotes severity of sepsis in a non-surgical preterm mouse model
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Hui Zhao, Ronald J. Wong, Flora Kalish, Kazumichi Fujioka, and David K. Stevenson
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Anemia, Hemolytic ,Anemia ,Anti-Inflammatory Agents ,Spleen ,Heme ,Bacterial counts ,Sepsis ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,030225 pediatrics ,Internal medicine ,medicine ,Animals ,Humans ,Cecum ,Crosses, Genetic ,Growth Disorders ,Mice, Knockout ,business.industry ,Membrane Proteins ,medicine.disease ,Iron Metabolism Disorders ,Peripheral ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,chemistry ,Animals, Newborn ,Heme Oxygenase 1 Deficiency ,Pediatrics, Perinatology and Child Health ,Female ,business ,Heme Oxygenase-1 ,Infant, Premature - Abstract
Sepsis in preterm infants is associated with systemic inflammatory responses. The stress-response protein heme oxygenase-1 (HO-1) has protective anti-inflammatory properties. Recently, we reported a protective role of HO-1 using our non-surgical cecal slurry (CS) model in wild-type (WT) mouse pups. Here, we extend these findings to investigate the association of HO-1 deficiency with sepsis severity. Adapting the Wynn model, we induced sepsis in 4-day-old HO-1-deficient (HO-1+/−, Het) pups to determine if HO-1 deficiency affected survival rates at the LD40 (2.0 mg/g) of WT pups. To see if HO-1 induction affected sepsis severity, we gave 30-μmol heme/kg subcutaneously to 3-day-old mice 24 h prior to sepsis induction. Post-sepsis induction, Het pups had a mortality of 85.0% (n = 20) and increased expression of the pro-inflammatory gene in the livers and affected hematologic profiles. Heme treatment 24 h prior to sepsis induction significantly increased liver HO activity, reduced mortality to 24.5% (n = 17), attenuated inflammatory responses, reduced spleen bacterial counts, and significantly increased peripheral neutrophils. A partial deficiency in HO-1 increased the progression and mortality in sepsis. Furthermore, induction of HO-1 significantly reduced the mortality even in Het pups. Thus, we conclude that HO-1 plays an important role in the protection against preterm sepsis.
- Published
- 2018
22. Identification of risk for neonatal haemolysis
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Janelle L. Aby, Debra L. Bogen, M. Jeffrey Maisels, David K. Stevenson, Robert D. Christensen, Ronald J. Wong, Jon F. Watchko, Vinod K. Bhutani, Martin E. Castillo Cuadrado, and David L. Schutzman
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Male ,medicine.medical_specialty ,Percentile ,Bilirubin ,Combined use ,Gestational Age ,Gastroenterology ,Hemolysis ,Risk Assessment ,Cohort Studies ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Neonatal Screening ,Predictive Value of Tests ,030225 pediatrics ,Internal medicine ,medicine ,Tidal Volume ,Humans ,030212 general & internal medicine ,Prospective Studies ,Analysis of Variance ,Carbon Monoxide ,Transcutaneous bilirubin ,Newborn jaundice ,business.industry ,Infant, Newborn ,General Medicine ,Phototherapy ,Haemolysis ,Treatment Outcome ,chemistry ,Pediatrics, Perinatology and Child Health ,Female ,Hyperbilirubinemia, Neonatal ,Breath carbon monoxide ,business ,Nurseries, Infant ,Rate of rise - Abstract
AIM To identify neonates at risk of haemolytic hyperbilirubinaemia through near-concurrent measurements of total serum/plasma bilirubin (TB) or transcutaneous bilirubin (TcB) and end-tidal breath carbon monoxide (CO), corrected for ambient CO (ETCOc), an index of bilirubin production and haemolysis. METHODS Paired TB/TcB (mg/dL) and ETCOc (ppm) measurements were obtained in newborns (n = 283) at 20 to
- Published
- 2017
23. Bilirubin binding in jaundiced newborns: from bench to bedside?
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David K. Stevenson, Ronald J. Wong, Charles E. Ahlfors, and Vinod K. Bhutani
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medicine.medical_specialty ,Bilirubin ,medicine.medical_treatment ,Population ,Exchange transfusion ,Gastroenterology ,Risk Assessment ,Infant, Newborn, Diseases ,Bilirubin binding ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Neonatal Screening ,030225 pediatrics ,Internal medicine ,Albumins ,Medicine ,Humans ,Mass Screening ,In patient ,Fluorometry ,education ,education.field_of_study ,Binding Sites ,business.industry ,Infant, Newborn ,Jaundice ,Models, Theoretical ,Phototherapy ,Bench to bedside ,Jaundice, Neonatal ,Kinetics ,Increased risk ,chemistry ,Pediatrics, Perinatology and Child Health ,medicine.symptom ,business ,030217 neurology & neurosurgery ,Protein Binding - Abstract
Background: Bilirubin-induced neurologic dysfunction (BIND) is a spectrum of preventable neurological sequelae in jaundiced newborns. Current total plasma bilirubin (BT) concentration thresholds for phototherapy and/or exchange transfusion poorly predict BIND. Methods: The unbound (free) bilirubin (Bf) measured at these BT thresholds provides additional information about the risk for BIND. Bf can be readily adapted to clinical use by determining Bf population parameters at current BT thresholds. These parameters can be established using a plasma bilirubin binding panel (BBP) consisting of BT, Bf, and two empiric constants, the maximum BT (BTmax) and the corresponding equilibrium association bilirubin constant (K). Results: BTmax and K provide the variables needed to accurately estimate Bf at BT
- Published
- 2017
24. Association ofHMOX1gene promoter polymorphisms with hyperbilirubinemia in the early neonatal period
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Tomoyuki Yokota, Kazumoto Iijima, Hajime Nakamura, Ichiro Morioka, Mariko Taniguchi-Ikeda, Yoshinori Katayama, Hui Zhao, Ronald J. Wong, and David K. Stevenson
- Subjects
education.field_of_study ,HMOX1 ,Bilirubin ,Population ,Promoter ,Biology ,Molecular biology ,Genotype frequency ,Heme oxygenase ,chemistry.chemical_compound ,chemistry ,Pediatrics, Perinatology and Child Health ,Gene expression ,Allele ,education - Abstract
Background Heme oxygenase (HO) is the rate-limiting enzyme in the heme degradation pathway that produces bilirubin. The promoter region of human heme oxygenase-1 (HMOX1) contains a polymorphic (GT)n repeat that can regulate gene expression. Here, we investigated the association of (GT)n repeat length in the HMOX1 promoter region with neonatal hyperbilirubinemia in a population of Japanese term neonates. Methods Using polymerase chain reaction and fragment analysis, we determined the number of (GT)n repeats in 149 Japanese neonates. To omit the effects of the G71R mutation in uridine diphosphoglucuronosyltransferase on hyperbilirubinemia, we excluded 41 neonates with the G71R mutation. As a result, 25 neonates with hyperbilirubinemia and 83 non-hyperbilirubinemic controls were included in this prospective case–control study. Allele and genotype frequencies of (GT)n repeats in the HMOX1 gene were compared between hyperbilirubinemic and non-hyperbilirubinemic control neonates. Results The prevalence of short alleles (
- Published
- 2015
25. Neonatal bilirubin binding capacity discerns risk of neurological dysfunction
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Lizhong Du, Lihua Chen, Ronald J. Wong, Zheng Shen, Vinod K. Bhutani, David K. Stevenson, Angelo A. Lamola, and Martin E. Castillo Cuadrado
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medicine.medical_specialty ,Bilirubin ,medicine.medical_treatment ,Exchange transfusion ,Gestational Age ,Logistic regression ,Risk Assessment ,Gastroenterology ,chemistry.chemical_compound ,Internal medicine ,medicine ,Humans ,Fluorometry ,Prospective Studies ,Prospective cohort study ,Whole blood ,Analysis of Variance ,business.industry ,Infant, Newborn ,Albumin ,Gestational age ,Logistic Models ,chemistry ,Pediatrics, Perinatology and Child Health ,Neurotoxicity Syndromes ,Analysis of variance ,business ,Infant, Premature ,Protein Binding - Abstract
Bilirubin binding capacity (BBC) defines the dynamic relationship between an infant’s level of unbound or “free” bilirubin and his/her ability to “tolerate” increasing bilirubin loads. BBC is not synonymous with albumin (Alb) levels because Alb binding of bilirubin is confounded by a variety of molecular, biologic, and metabolic factors. We utilized a novel modification of a previously developed hematofluorometric method to directly assay BBC in whole blood from preterm and term neonates and then combined these data with an archived database. Total bilirubin (TB) was also measured, and multiple regression modeling was used to determine whether BBC in combination with TB measurements can assess an infant’s risk for developing bilirubin-induced neurotoxicity. TB and BBC levels ranged from 0.7–22.8 to 6.3–47.5 mg/dl, respectively. Gestational age (GA) correlated with BBC (r = 0.54; P < 0.0002) with a slope of 0.93 mg/dl/wk by logistic regression. Our calculations demonstrate that recently recommended GA-modulated TB thresholds for phototherapy and exchange transfusion correspond to 45 and 67% saturation of our observed regression line, respectively. We speculate that the spread of BBC levels around the regression line (±5.8 mg/dl) suggests that individualized BBC assays would provide a robust approach to gauge risk of bilirubin neurotoxicity compared with TB and GA.
- Published
- 2014
26. Direct Antiglobulin Titer Strength and Hyperbilirubinemia
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Ronald J. Wong, Michael Kaplan, David K. Stevenson, Hendrik J. Vreman, and Cathy Hammerman
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Male ,medicine.medical_specialty ,Bilirubin ,Gastroenterology ,Agglutination technique ,Cohort Studies ,chemistry.chemical_compound ,Internal medicine ,mental disorders ,parasitic diseases ,medicine ,Humans ,Hyperbilirubinemia ,business.industry ,Infant, Newborn ,food and beverages ,Increased hemolysis ,medicine.disease ,Confidence interval ,Total hemoglobin ,Hemolysis ,Surgery ,Coombs Test ,Titer ,nervous system ,chemistry ,Pediatrics, Perinatology and Child Health ,Carboxyhemoglobin ,Blood Group Antigens ,Female ,business - Abstract
BACKGROUND AND OBJECTIVES: We recently demonstrated that direct antiglobulin titer (DAT) positive, blood group A or B newborns born to group O mothers had a high incidence of hyperbilirubinemia, attributable to increased hemolysis. We reanalyzed our data asking whether increasing DAT strength plays a modulating role in the pathophysiology of the hemolysis and hyperbilirubinemia. METHODS: Data from previously published DAT-positive, ABO-heterospecific neonates were analyzed for hyperbilirubinemia and hemolysis according to strength of DAT. DAT was measured by using a gel agglutination technique and reported as values ranging from DAT ± to DAT ++++. Hemolysis was evaluated by blood carboxyhemoglobin corrected for inspired, ambient CO (COHbc), and expressed as percent total hemoglobin (tHb). Hyperbilirubinemia was defined as any plasma total bilirubin value >95th percentile on the hour-specific nomogram. RESULTS: Hyperbilirubinemia was more prevalent in those with DAT ++ readings (16 of 20, 80%) than those both DAT ± (37 of 87 [42.5%], relative risk: 1.88, 95% confidence interval: 1.35–2.61) and DAT + (32 of 56 [57.1%], relative risk: 1.40, 95% confidence interval: 1.02–1.92). COHbc values were higher for those with DAT ++ (1.45 ± 0.49% tHb [mean ± SD]) than those DAT ± (1.20 ± 0.37% tHb, P = .01) or DAT + (1.22 ± 0.37% tHb, P = .02). CONCLUSIONS: DAT ++ readings were associated with a higher incidence of hyperbilirubinemia and higher COHbc values than DAT ± or DAT + counterparts. Increasing DAT strength may be a modulator of hemolysis and hyperbilirubinemia in ABO-heterospecific neonates. DAT strength, and not merely DAT presence or absence, should be taken into consideration in the management of ABO-heterospecific newborns.
- Published
- 2014
27. The Importance of Hemolysis and Its Clinical Detection in Neonates with Hyperbilirubinemia
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Ronald J. Wong, David K. Stevenson, and Vinod K. Bhutani
- Subjects
Pediatrics ,medicine.medical_specialty ,Bilirubin ,02 engineering and technology ,Disease ,Hemolysis ,Bilirubin binding ,Genetic profile ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,030225 pediatrics ,medicine ,Humans ,Hyperbilirubinemia ,business.industry ,Infant, Newborn ,Increased bilirubin ,Jaundice ,021001 nanoscience & nanotechnology ,medicine.disease ,Increased risk ,chemistry ,Pediatrics, Perinatology and Child Health ,medicine.symptom ,0210 nano-technology ,business - Abstract
Hyperbilirubinemia is a benign transitional phenomenon that occurs in 60% to 80% of all term infants. The degree of hyperbilirubinemia and hence risk for developing bilirubin-induced neurologic dysfunction or BIND is dependent upon two major processes: (i) bilirubin production and its elimination.The aim of this review is to address the importance of hemolysis and its clinical detection in neonates with hyperbilirubinemia.In newborns, an increased bilirubin production rate due to hemolysis is often the primary cause of hyperbilirubinemia during the first week of life. If undiagnosed or untreated, it may lead to an increased risk for BIND. Therefore, the ability to identify infants with hemolytic disease is important in assessing those at risk for developing BIND. In addition, an infant's genetic profile and bilirubin binding status can also affect their overall capacity to cope with the resultant tissue bilirubin load and affect risk and guide appropriate management strategies.Therefore, the determination of a newborn's bilirubin production rate is critical to the assessment of a newborn's risk for developing unpredictable extreme hyperbilirubinemia and preventing BIND.
- Published
- 2017
28. Heme Oxygenase Activity and Heme Binding in a Neonatal Mouse Model
- Author
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David K. Stevenson, Stephanie Kourula, Joyce Ang, Flora Kalish, Peter Vandenabeele, Hui Zhao, Karl G. Sylvester, and Ronald J. Wong
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Heterozygote ,Erythrocytes ,Time Factors ,Heme binding ,Cell Survival ,Heme ,Hemolysis ,Lipid peroxidation ,Erythroblastosis, Fetal ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Hemopexin ,Internal medicine ,medicine ,Animals ,Genetic Predisposition to Disease ,Aspartate Aminotransferases ,Promoter Regions, Genetic ,Mice, Knockout ,biology ,Membrane Proteins ,Alanine Transaminase ,Methemalbumin ,Heme oxygenase ,Disease Models, Animal ,Oxidative Stress ,030104 developmental biology ,Endocrinology ,Phenotype ,chemistry ,Alanine transaminase ,Animals, Newborn ,Liver ,Pediatrics, Perinatology and Child Health ,Toxicity ,biology.protein ,NIH 3T3 Cells ,Lipid Peroxidation ,030217 neurology & neurosurgery ,Heme Oxygenase-1 ,Developmental Biology ,Protein Binding - Abstract
Background: Severe hemolytic disease of the newborn leads to the release of pro-oxidative free heme (FH). Heme oxygenase (HO) is primarily responsible for detoxifying FH. Objective: To investigate the protective effects of HO in a model of heme overload. Methods: For in vitro studies, NIH3T3 HO-1-luc cells were incubated with 10, 30, or 60 µM FH or methemalbumin (MHA). HO-1 promoter activity was assessed 3, 6, and 24 h after treatment. Cell survival was indexed by viability assays. For in vivo studies, 1- and 5-week-old wild-type (Wt) or HO-1-heterozygous (Het, HO-1+/-) mice were given 60 µmol FH or MHA/kg intraperitoneally. After 24 h, plasma aspartate aminotransferease (AST)/alanine transaminase (ALT) and hemopexin, liver HO activity, and lipid peroxidation (LP) were determined. Results: In HO-1-luc cells, HO-1 promoter activity peaked 6 h after incubation with 30 µM FH (1.6-fold) or 60 µM MHA (2.1-fold) over baseline. Twenty-four hours after exposure to 60 µM FH, a decrease in viability of 80% was found, compared with no decrease after exposure to 60 µM MHA. In 1-week-old Wt and HO-1 Het pups given 60 µmol FH/kg, HO activity significantly increased 3.5- and 3.1-fold, respectively. No changes in LP or AST/ALT levels were observed. In adult Wt and HO-1 Het mice, HO activity increased (3.0- and 2.6-fold, respectively). LP and AST levels significantly increased 28.4- and 2.7-fold, respectively, in adult HO-1 Het mice. Hemopexin levels at baseline were higher in adults compared with newborns for both Wt and Het mice. In addition, FH induced hemopexin levels in both adults and newborns, but to a lesser degree in newborns. Conclusions: FH is highly toxic in vitro, but its toxicity is abolished when bound to albumin. Newborns appear to be protected from the pro-oxidative effects of FH, which may be mediated by heme binding and a higher absolute HO activity at baseline and after FH-mediated induction.
- Published
- 2017
29. Humans are colonized by many uncharacterized and highly divergent microbes
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David K. Stevenson, Norma F. Neff, Lance Martin, Mark Kowarsky, Wenying Pan, Yair J. Blumenfeld, Nathan D. Wolfe, Joan Camunas-Soler, Gary M. Shaw, Michael Kertesz, Stephen R. Quake, Sandhya Kharbanda, Ronald J. Wong, Iwijn De Vlaminck, Jennifer Okamoto, Lcw Koh, and Yasser Y. El-Sayed
- Subjects
Genetics ,Contig ,biology ,Shotgun sequencing ,Microbial diversity ,Human microbiome ,Tree of life ,biology.organism_classification ,law.invention ,chemistry.chemical_compound ,chemistry ,law ,Evolutionary biology ,Bacteria ,Polymerase chain reaction ,DNA - Abstract
Blood circulates throughout the entire body and contains molecules drawn from virtually every tissue, including the microbes and viruses which colonize the body. Through massive shotgun sequencing of circulating cell-free DNA from the blood, we identified hundreds of new bacteria and viruses which represent previously unidentified members of the human microbiome. Analysing cumulative sequence data from 1,351 blood samples collected from 188 patients enabled us to assemble 7,190 contiguous regions (contigs) larger than 1 kbp, of which 3,761 are novel with little or no sequence homology in any existing databases. The vast majority of these novel contigs possess coding sequences, and we have validated their existence both by finding their presence in independent experiments and by performing direct PCR amplification. When their nearest neighbors are located in the tree of life, many of the organisms represent entirely novel taxa, showing that microbial diversity within the human body is substantially broader than previously appreciated.
- Published
- 2017
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30. Heme Oxygenase-1 Promoter Polymorphisms and Neonatal Jaundice
- Author
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Michael Kaplan, Ronald J. Wong, Hendrik J. Vreman, Paul Renbaum, David K. Stevenson, and Cathy Hammerman
- Subjects
Bilirubin ,Promoter ,Biology ,Molecular biology ,Heme oxygenase ,chemistry.chemical_compound ,chemistry ,Pediatrics, Perinatology and Child Health ,Genotype ,Carboxyhemoglobin ,Gene expression ,Heme ,Gene ,Developmental Biology - Abstract
Background: Heme oxygenase (HO) is the initial, rate-limiting enzyme in the conversion of heme to bilirubin. Dinucleotide (GT)n repeat length in the promoter region of the encoding gene modulates transcription: shorter alleles, in contrast with longer allele counterparts, are associated with greater gene expression and should result in increased heme catabolism. Objective: We compared the rates of heme catabolism and plasma total bilirubin (TB) between HO-1 promoter genotypes of varying (GT)n repeat lengths in glucose-6-phosphate dehydrogenase (G6PD)-normal and -deficient neonates. Methods:HO-1 promoter length was determined from genomic DNA from previous studies by size discrimination of fluorescently-labeled PCR products with capillary electrophoresis. Sizing was confirmed by sequencing homozygote samples. Alleles were categorized as: short (≤24 GT repeats), medium (25-33 GT repeats), and long (≥34 GT repeats). Previously determined values for blood carboxyhemoglobin, corrected for inspired carbon monoxide (COHbc), and TB were used to determine the rate of heme catabolism and 3rd day TB values for each HO-1 promoter length genotype, respectively. G6PD Mediterranean was determined by PCR analysis. Results: Neither COHbc nor TB values were significantly different between various HO-1 promoter genotypes for either G6PD-normal or -deficient neonates. Conclusions: In the steady state, HO-1 promoter genotypes, based on the length of (GT)n repeats, do not modulate heme catabolism or 3rd day TB values in either G6PD-normal or -deficient neonates.
- Published
- 2014
31. Heme oxygenase-1 promoter polymorphisms: do they modulate neonatal hyperbilirubinemia?
- Author
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Michael Kaplan, Ronald J. Wong, and David K. Stevenson
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Bilirubin ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,030225 pediatrics ,Internal medicine ,medicine ,Humans ,Heme ,chemistry.chemical_classification ,Biliverdin ,Polymorphism, Genetic ,business.industry ,Obstetrics and Gynecology ,Promoter ,Metabolism ,Pathophysiology ,Heme oxygenase ,030104 developmental biology ,Endocrinology ,Enzyme ,chemistry ,Pediatrics, Perinatology and Child Health ,Hyperbilirubinemia, Neonatal ,business ,Heme Oxygenase-1 - Abstract
The role of genetic factors in the modulation of serum bilirubin levels and the pathophysiology of neonatal hyperbilirubinemia is being increasingly recognized. Heme oxygenase-1 (HO-1) is the rate-limiting enzyme by which heme is catabolized to biliverdin and thence to bilirubin, with the simultaneous release of equimolar quantities of ferrous iron (Fe3+) and carbon monoxide. Polymorphisms of the HO-1 gene promoter may modulate transcriptional activity, thereby augmenting or attenuating HO-1 expression with resultant modulation of the production of bilirubin. Few studies have related these polymorphisms to neonatal bilirubin metabolism and have reported conflicting results. In this clinical review, we surveyed the role of HO-1 gene promoter polymorphisms in the control of bilirubin production and further considered their role, if any, in the pathophysiology of neonatal hyperbilirubinemia.
- Published
- 2016
32. Heme oxygenase-1 deficiency promotes the development of necrotizing enterocolitis-like intestinal injury in a newborn mouse model
- Author
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Hui Zhao, Stephanie Schulz, Ronald J. Wong, Hendrik J. Vreman, Kyu Yun Jang, Karen M. Chisholm, Flora Kalish, Karl G. Sylvester, and David K. Stevenson
- Subjects
Genotype ,Transcription, Genetic ,Physiology ,Interleukin-1beta ,Apoptosis ,Ileum ,Heme ,Biology ,Enteral administration ,Inflammation/Immunity/Mediators ,Jejunum ,Mice ,chemistry.chemical_compound ,Injury Severity Score ,Intestinal mucosa ,Enterocolitis, Necrotizing ,Physiology (medical) ,medicine ,Animals ,Intestinal Mucosa ,Hypoxia ,Mice, Knockout ,Mucous Membrane ,Hepatology ,Gastroenterology ,Membrane Proteins ,Mucous membrane ,medicine.disease ,Collagen Type XVIII ,Disease Models, Animal ,P-Selectin ,medicine.anatomical_structure ,Animals, Newborn ,chemistry ,Necrotizing enterocolitis ,Immunology ,Matrix Metalloproteinase 2 ,Heme Oxygenase-1 - Abstract
Necrotizing enterocolitis (NEC) is typified by mucosal destruction, which subsequently can lead to intestinal necrosis. Prematurity, enteral feeding, and bacterial colonization are the main risk factors and, combined with other stressors, can cause increased intestinal permeability, injury, and an exaggerated inflammatory response. Heme oxygenase-1 (HO-1) mediates intestinal protection due to anti-inflammatory, antioxidative, and antiapoptotic effects of its products carbon monoxide, biliverdin, and bilirubin. This study investigates a possible role of HO-1 in the pathogenesis of NEC using a newborn mouse model. We induced NEC-like intestinal injury in 7-day-old HO-1 heterozygous (HO-1 Het, Hmox1+/-) and wild-type (Wt, Hmox1+/+) mice by gavage feeding and hypoxic exposures. Control (Con) pups of both genotypes were dam-fed. Intestines of HO-1 Het Con pups appeared predisposed to injury, with higher histological damage scores, more TUNEL-positive cells, and a significant reduction in muscularis externa thickness compared with Wt Con pups. The increase in HO activity after HO-1 induction by the substrate heme or by hypoxic stress was significantly impaired in HO-1 Het pups. After induction of intestinal injury, HO-1 Het pups displayed significantly higher NEC incidence (78 vs. 43%), mortality (83 vs. 54%), and median scores (2.5 vs. 1.5) than Wt NEC pups. PCR array analyses revealed increased expressions of IL-1β, P-selectin, matrix metallopeptidase 2, collagen type XVIII-α1, serpine 1, and others in NEC-induced HO-1 Het ileal and jejunal tissues. We conclude that a partial HO-1 deficiency promotes experimental NEC-like intestinal injury, possibly mediated by exaggerated inflammation and disruption in tissue repair.
- Published
- 2013
33. Hyperbilirubinemia in Preterm Neonates
- Author
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Vinod K. Bhutani, Ronald J. Wong, and David K. Stevenson
- Subjects
medicine.medical_specialty ,Pediatrics ,Time Factors ,Adverse outcomes ,Bilirubin ,medicine.medical_treatment ,Exchange transfusion ,Gestational Age ,Risk Assessment ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Effective interventions ,030225 pediatrics ,medicine ,Humans ,030212 general & internal medicine ,Intensive care medicine ,Kernicterus ,business.industry ,Neurotoxicity ,Infant, Newborn ,Obstetrics and Gynecology ,Expert consensus ,Increased bilirubin ,Phototherapy ,medicine.disease ,chemistry ,Pediatrics, Perinatology and Child Health ,Hyperbilirubinemia, Neonatal ,business ,Infant, Premature - Abstract
Preterm neonates with increased bilirubin production loads are more likely to sustain adverse outcomes due to either neurotoxicity or overtreatment with phototherapy and/or exchange transfusion. Clinicians should rely on expert consensus opinions to guide timely and effective interventions until there is better evidence to refine bilirubin-induced neurologic dysfunction or benefits of bilirubin. In this article, we review the evolving evidence for bilirubin-induced brain injury in preterm infants and highlight the clinical approaches that minimize the risk of bilirubin neurotoxicity.
- Published
- 2016
34. Heme Oxygenase-1 Expression Affects Murine Abdominal Aortic Aneurysm Progression
- Author
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Alicia C. Deng, Ronald J. Wong, Hui Zhao, Joshua M. Spin, Mark Hsu, Yosuke Kayama, Matthew B. Wallenstein, Flora Kalish, Takeshi Morisawa, Ronald L. Dalman, David K. Stevenson, Junya Azuma, Philip S. Tsao, Lars Maegdefessel, and Bader, Michael
- Subjects
0301 basic medicine ,Male ,Physiology ,Swine ,lcsh:Medicine ,Gene Expression ,030204 cardiovascular system & hematology ,Reductase ,Cardiovascular ,Biochemistry ,Vascular Medicine ,chemistry.chemical_compound ,White Blood Cells ,Mice ,0302 clinical medicine ,Animal Cells ,Genes, Reporter ,Immune Physiology ,Gene expression ,Medicine and Health Sciences ,2.1 Biological and endogenous factors ,Aetiology ,Post-Translational Modification ,lcsh:Science ,Promoter Regions, Genetic ,Heme ,Pancreatic elastase ,Aorta ,Mice, Knockout ,Innate Immune System ,Multidisciplinary ,Drugs ,Animal Models ,Lipids ,Aortic Aneurysm ,cardiovascular system ,Disease Progression ,Cytokines ,Cellular Types ,Anatomy ,Inflammation Mediators ,Aneurysms ,Research Article ,Statin ,medicine.drug_class ,General Science & Technology ,Knockout ,Immune Cells ,Inflammatory Diseases ,Immunology ,Mouse Models ,Biology ,Research and Analysis Methods ,Promoter Regions ,03 medical and health sciences ,Enzyme activator ,Rare Diseases ,Model Organisms ,Downregulation and upregulation ,Genetic ,medicine ,Genetics ,Animals ,Abdominal ,Vascular Diseases ,Reporter ,Pharmacology ,Blood Cells ,Animal ,Macrophages ,lcsh:R ,Body Weight ,Statins ,Biology and Life Sciences ,Proteins ,Cell Biology ,Molecular Development ,Heme oxygenase ,Enzyme Activation ,Disease Models, Animal ,030104 developmental biology ,Orphan Drug ,chemistry ,Genes ,Immune System ,Disease Models ,Cancer research ,Cardiovascular Anatomy ,Blood Vessels ,lcsh:Q ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,Heme Oxygenase-1 ,Developmental Biology ,Aortic Aneurysm, Abdominal - Abstract
Heme oxygenase-1 (HO-1), the rate-limiting enzyme in heme degradation, is a cytoprotective enzyme upregulated in the vasculature by increased flow and inflammatory stimuli. Human genetic data suggest that a diminished HO-1 expression may predispose one to abdominal aortic aneurysm (AAA) development. In addition, heme is known to strongly induce HO-1 expression. Utilizing the porcine pancreatic elastase (PPE) model of AAA induction in HO-1 heterozygous (HO-1+/-, HO-1 Het) mice, we found that a deficiency in HO-1 leads to augmented AAA development. Peritoneal macrophages from HO-1+/- mice showed increased gene expression of pro-inflammatory cytokines, including MCP-1, TNF-alpha, IL-1-beta, and IL-6, but decreased expression of anti-inflammatory cytokines IL-10 and TGF-beta. Furthermore, treatment with heme returned AAA progression in HO-1 Het mice to a wild-type profile. Using a second murine AAA model (Ang II-ApoE-/-), we showed that low doses of the HMG-CoA reductase inhibitor rosuvastatin can induce HO-1 expression in aortic tissue and suppress AAA progression in the absence of lipid lowering. Our results support those studies that suggest that pleiotropic statin effects might be beneficial in AAA, possibly through the upregulation of HO-1. Specific targeted therapies designed to induce HO-1 could become an adjunctive therapeutic strategy for the prevention of AAA disease.
- Published
- 2016
35. End-Tidal Breath Carbon Monoxide Measurements: Current Directions
- Author
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David K. Stevenson, Ronald S. Cohen, and Ronald J. Wong
- Subjects
Heme catabolism ,medicine.medical_specialty ,Bilirubin ,business.industry ,Jaundice ,Carboxyhemoglobin Measurement ,End tidal ,chemistry.chemical_compound ,chemistry ,Biochemistry ,Lung disease ,Internal medicine ,Pediatrics, Perinatology and Child Health ,medicine ,Cardiology ,medicine.symptom ,Breath carbon monoxide ,business ,Carbon monoxide - Abstract
Because heme catabolism leads to the formation of equimolar amounts of carbon monoxide (CO) and bilirubin, a variety of techniques have been developed to correlate CO production rates as indices of bilirubin production. The use of end-tidal breath CO measurements for estimating rates of bilirubin production in infants has been well documented and validated in a number of clinical studies for its use and predictive value in identifying infants who are high producers of bilirubin and hence at risk for developing pathologic neonatal hyperbilirubinemia. Recently, end-tidal breath CO has been suggested as a marker for chronic lung disease and developmental problems. Trace gas analysis remains an area for interesting investigation in the future.
- Published
- 2012
36. Effect of light exposure on metalloporphyrin-treated newborn mice
- Author
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David K. Stevenson, Hendrik J. Vreman, Ronald J. Wong, Kyu Yun Jang, Stephanie Schulz, Hui Zhao, and Flora Kalish
- Subjects
medicine.medical_specialty ,Antioxidant ,Light ,Bilirubin ,medicine.medical_treatment ,Lethal Dose 50 ,Mice ,chemistry.chemical_compound ,Weight loss ,Internal medicine ,medicine ,Animals ,Adverse effect ,chemistry.chemical_classification ,Photosensitizing Agents ,Dose-Response Relationship, Drug ,Chemistry ,Lethal dose ,Survival Analysis ,Heme oxygenase ,Enzyme ,Endocrinology ,Animals, Newborn ,Mesoporphyrins ,Heme Oxygenase (Decyclizing) ,Pediatrics, Perinatology and Child Health ,Hyperbilirubinemia, Neonatal ,medicine.symptom ,Phototoxicity ,Deuteroporphyrins - Abstract
Neonatal hyperbilirubinemia arises from increased bilirubin production and decreased bilirubin elimination. Although phototherapy safely and effectively reduces bilirubin levels, recent evidence shows that it has adverse effects. Therefore, alternative treatments are warranted. Metalloporphyrins, competitive inhibitors of heme oxygenase (HO), the rate-limiting enzyme in bilirubin production, effectively reduce bilirubin formation; however, many are photoreactive. Here, we investigated possible photosensitizing effects of chromium mesoporphyrin (CrMP) and zinc deuteroporphyrin bis-glycol (ZnBG). Administration of CrMP or ZnBG to 3-d-old mouse pups (3.75–30.0 µmol/kg intraperitoneally) and exposure to cool white (F20T12CW) and blue (TL20W/52) fluorescent lights (+L) for 3 h, resulted in a dose-dependent mortality (50% lethal dose (LD50) = 21.5 and 19.5 µmol/kg, respectively). In contrast to ZnBG, there was no significant difference in survival between the CrMP+L and CrMP groups. Following 30 µmol/kg ZnBG+L, we found significant weight loss, decreased liver antioxidant capacities, and increased aspartate aminotransaminase levels. At 6-d post-light exposure, ZnBG+L-treated pups showed gross and histologic skin changes at doses >7.5 µmol/kg. No lethality was observed following treatment with 30 µmol ZnBG/kg plus exposure to blue light-emitting diodes. Phototoxicity of ZnBG was dependent on light source, emission spectrum, and irradiance. Low doses of ZnBG (
- Published
- 2012
37. Heme Oxygenase Biology: Part 2: Neonatal Disorders
- Author
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Hui Zhao, David K. Stevenson, Stephanie Schulz, and Ronald J. Wong
- Subjects
chemistry.chemical_classification ,Reactive oxygen species ,business.industry ,Neurotoxicity ,Inflammation ,Pharmacology ,medicine.disease ,Heme oxygenase ,Downregulation and upregulation ,chemistry ,Pediatrics, Perinatology and Child Health ,Immunology ,Medicine ,Kernicterus ,medicine.symptom ,business ,Barrier function ,Neonatal Disorder - Abstract
A number of neonatal disorders have etiologies originating from acute inflammation and the destructive action of reactive oxygen species. As previously described in Part 1, heme oxygenase (HO) and its byproducts provide a newborn with antioxidative, antiapoptotic, anti-inflammatory, and cytoprotective defenses during the perinatal period. A finely balanced expression of the inducible HO-1 isoform is critically important for normal development of a number of organs. For example, increases in bilirubin levels observed in newborn infants provide significant antioxidant protection at birth and during the first few weeks after birth. However, if not tightly controlled, harmful levels may be reached and cause irreversible bilirubin-induced neurotoxicity (kernicterus). In addition, HO-1 and the constitutive HO-2 isoform are important in pulmonary vascular development during the perinatal period. In the developing brain, the upregulation of HO-1 expression may be adaptive and beneficial or a part of a pathological inflammatory process. Furthermore, there is strong evidence that HO and its byproduct, carbon monoxide (CO), play a significant role in maintaining intestinal barrier function and regulating inflammatory and apoptotic pathways. Therefore, disruption of this balanced HO-1 expression may lead to a number of neonatal disorders.
- Published
- 2012
38. Inflammatory Biomarkers and Spontaneous Preterm Birth Among Obese Women
- Author
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Suzan L. Carmichael, Wei Yang, Gary M. Shaw, Matthew B. Wallenstein, Kelli K. Ryckman, Laura L. Jelliffe-Pawlowski, and David K. Stevenson
- Subjects
Adult ,medicine.medical_specialty ,Adolescent ,Population ,Article ,chemistry.chemical_compound ,Young Adult ,Pregnancy ,Medicine ,Humans ,Obesity ,education ,Inflammation ,education.field_of_study ,business.industry ,Obstetrics ,Obstetrics and Gynecology ,Odds ratio ,medicine.disease ,Confidence interval ,Vascular endothelial growth factor ,chemistry ,Case-Control Studies ,Pregnancy Trimester, Second ,Pediatrics, Perinatology and Child Health ,Immunology ,Cohort ,Term Birth ,Gestation ,Premature Birth ,Female ,business ,Biomarkers - Abstract
To identify associations between second-trimester serum inflammatory biomarkers and preterm birth among obese women.In this nested case-control study, we compared 65 serum inflammatory biomarkers in obese women whose pregnancies resulted in early spontaneous preterm birth (32 weeks gestation, n = 34) to obese women whose pregnancies resulted in term birth (n = 34). These women were selected from a larger population-based California cohort. Random forest and classification and regression tree techniques were employed to identify biomarkers of importance, and adjusted odds ratios (aORs) and 95% confidence intervals (CI) were estimated using logistic regression.Random forest and classification and regression tree techniques found that soluble vascular endothelial growth factor receptor-3 (sVEGFR3), soluble interleukin-2 receptor alpha-chain (sIL-2RA) and soluble tumor necrosis factor receptor-1 (sTNFR1) were related to preterm birth. Using multivariable logistic regression to compare preterm cases and term controls, decreased serum levels of sVEGFR3 and increased serum levels of sIL-2RA and sTNFR1 were associated with increased risk of preterm birth among obese women, aOR = 3.2 (95% CI: 1.0-9.9), aOR = 2.8 (95% CI: 0.9-9.0), and aOR = 4.1 (95% CI: 1.2-14.1), respectively.In this pilot study, we identified three serum biomarkers indicative of inflammation to be associated with spontaneous preterm birth among obese women: sVEGFR3, sIL-2RA and sTNFR1.
- Published
- 2015
39. Effects of Zinc Deuteroporphyrin Bis Glycol on Newborn Mice After Heme Loading
- Author
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Ronald J. Wong, Claire M Campbell, Hendrik J. Vreman, Flora Kalish, Cynthia X. He, Hui Zhao, David K. Stevenson, and Stephanie Schulz
- Subjects
Chromatography, Gas ,Bilirubin ,Blotting, Western ,Spleen ,Pharmacology ,Real-Time Polymerase Chain Reaction ,Article ,Mice ,chemistry.chemical_compound ,In vivo ,Gene expression ,medicine ,Animals ,Heme ,chemistry.chemical_classification ,Carbon Monoxide ,Dose-Response Relationship, Drug ,In vitro ,Heme oxygenase ,medicine.anatomical_structure ,Enzyme ,Animals, Newborn ,Gene Expression Regulation ,Liver ,chemistry ,Biochemistry ,Heme Oxygenase (Decyclizing) ,Pediatrics, Perinatology and Child Health ,Hyperbilirubinemia, Neonatal ,Deuteroporphyrins - Abstract
Infants with hemolytic diseases frequently develop hyperbilirubinemia and are treated with phototherapy, which only eliminates bilirubin after its production. A better strategy might be to directly inhibit heme oxygenase (HO), the rate-limiting enzyme in bilirubin production. Metalloporphyrins (Mps) are heme analogs that competitively inhibit HO activity in vitro and in vivo and suppress plasma bilirubin levels in vivo. A promising Mp, zinc deuteroporphyrin bis glycol (ZnBG), is orally absorbed and effectively inhibits HO activity at relatively low doses. We determined the I(50) (the dose needed to inhibit HO activity by 50%) of orally administered ZnBG in vivo and then evaluated ZnBG's effects on in vivo bilirubin production, HO activity, HO protein levels, and HO-1 gene expression in newborn mice after heme loading, a model analogous to a hemolytic infant. The I(50) of ZnBG was found to be 4.0 μmol/kg body weight (BW). At a dose of 15 μmol/kg BW, ZnBG reduced in vivo bilirubin production, inhibited heme-induced liver HO activity and spleen HO activity to and below baseline, respectively, transiently induced liver and spleen HO-1 gene transcription, and induced liver and spleen HO-1 protein levels. We conclude that ZnBG may be an attractive compound for treating severe neonatal hyperbilirubinemia caused by hemolytic disease.
- Published
- 2011
40. In vitro inhibition of heme oxygenase isoenzymes by metalloporphyrins
- Author
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H J Vreman, Ronald J. Wong, N. W. Pierce, Stephanie Schulz, Flora Kalish, and David K. Stevenson
- Subjects
Male ,Metalloporphyrins ,Bilirubin ,In Vitro Techniques ,Isozyme ,Mice ,chemistry.chemical_compound ,Animals ,Medicine ,Rats, Wistar ,Heme ,chemistry.chemical_classification ,Dose-Response Relationship, Drug ,business.industry ,Brain ,Obstetrics and Gynecology ,Jaundice ,In vitro ,Rats ,Heme oxygenase ,Enzyme ,chemistry ,Biochemistry ,Heme Oxygenase (Decyclizing) ,Pediatrics, Perinatology and Child Health ,HMOX1 Gene ,medicine.symptom ,business ,Heme Oxygenase-1 ,Spleen - Abstract
Objective: Neonatal jaundice results from an increased bilirubin production and decreased hepatic bilirubin conjugation and excretion. Severe hyperbilirubinemia is currently treated with phototherapy or exchange transfusion; however, its prevention by inhibiting bilirubin formation is a more logical strategy. Heme oxygenase (HO), with inducible (HO-1) and constitutive (HO-2) isoenzymes, is the rate-limiting enzyme in heme catabolism, producing equimolar amounts of bilirubin and carbon monoxide (CO). Metalloporphyrins (Mps) are heme derivatives that competitively inhibit HO and thereby suppress hyperbilirubinemia. No systematic studies have been reported evaluating whether the HO isoenzymes are inhibited differentially by various Mps. Identification of Mps that selectively inhibit the inducible HO-1 without affecting the ‘housekeeping’ HO-2 isoenzyme might be desirable in the clinical setting of hemolytic disease, in which the Hmox1 gene is greatly induced. Although bilirubin production is due to the activity of both HO-1 and HO-2, the inhibition of HO-1 with a relative sparing of HO-2 activity might provide the most selective approach for the treatment of hemolytic disease. Study Design: We determined for the deutero-, proto-, meso- and bisglycol porphyrins with zinc, tin and chromium as central atoms, respectively, the concentration needed for 50% inhibition (I50) of HO-1 and HO-2 activities in rat spleen and brain tissue. Result: For a given Mp, HO-1 activity was less inhibited than that of HO-2. The order of inhibitor potency of each Mp was nearly identical for both isoenzymes. Tin mesoporphyrin was the most potent inhibitor for both isoenzymes. HO-2 selectivity was greatest for tin protoporphyrin. Conversely, the Zn compounds were least inhibitory toward HO-2. No Mp preferentially inhibited HO-1. Conclusion: Mps that produce a less inhibitory effect on HO-2, while limiting the response of the inducible HO-1, such as ZnPP, may be a useful clinical tool. Journal of Perinatology (2011) 31, S35‐S41; doi:10.1038/jp.2010.173
- Published
- 2011
41. Quantitating carbon monoxide production from heme by vascular plant preparations in vitro
- Author
-
David K. Stevenson, Hendrik J. Vreman, and Ronald J. Wong
- Subjects
Spinacia ,Chloroplasts ,Chromatography, Gas ,Physiology ,chemistry.chemical_element ,Heme ,Plant Science ,Oxygen ,Lipid peroxidation ,chemistry.chemical_compound ,Spinacia oleracea ,Genetics ,Food science ,Solanum tuberosum ,Carbon Monoxide ,biology ,fungi ,food and beverages ,Plants ,biology.organism_classification ,Heme oxygenase ,chemistry ,Biochemistry ,Spinach ,Solanum ,Plant Structures ,NADP ,Carbon monoxide - Abstract
Heme in animals is mainly degraded enzymatically, producing a predictable amount of carbon monoxide (CO). Under some conditions, alternative sources of CO production are important, such as lipid peroxidation and photo-oxidation. Less is known about CO production in plants as a reflection of enzymatic activity or coupled oxidation, but a sensitive assay for CO production in plants would be a valuable tool to explore the various sources in plants as the conditions of the reactions and mechanisms are defined. Using gas chromatography, we determined the requirements for heme-supported in vitro CO generation by exogenous reactants (NADPH, tissue supernatant, oxygen), optimum reaction conditions (time, temperature, pH, light), and effects of various cofactors and substrates using supernatants from Spinacia oleracea (spinach) leaf and Solanum tuberosa (potato) tuber homogenates. We then determined the CO production rate distribution between organ (root, stem, leaf, flower, fruit) supernatants in a number of commercially available plant species. CO production ranged from 4-65 nmol CO/h/g fresh weight and occurred in all vascular plant tissues examined, with the highest rates in chloroplast-containing tissues. In spinach leaves, CO production was concentrated (2-fold) in the particulate fraction, whereas in potato tubers, the particulate fraction accounted for50% of the rates in homogenates. We conclude that gas chromatography is uniquely suited for the determination of CO production in pigmented, heterogeneous plant tissue preparations.
- Published
- 2011
42. Understanding Neonatal Jaundice: A Perspective on Causation
- Author
-
Ronald J. Wong, Ronald S. Cohen, and David K. Stevenson
- Subjects
medicine.medical_specialty ,hyperbilirubinemia ,Bilirubin ,Carbon monoxide toxicity ,carbon monoxide ,jaundice ,Diagnosis, Differential ,Mice ,chemistry.chemical_compound ,medicine ,Animals ,Humans ,Pediatrics, Perinatology, and Child Health ,Neurologic sequelae ,Intensive care medicine ,metalloporphyrin ,Extramural ,business.industry ,Infant, Newborn ,lcsh:RJ1-570 ,lcsh:Pediatrics ,heme oxygenase ,Jaundice ,medicine.disease ,Hemolysis ,Jaundice, Neonatal ,Surgery ,chemistry ,Pediatrics, Perinatology and Child Health ,Kernicterus ,medicine.symptom ,Bilirubin levels ,business - Abstract
Neonatal jaundice can be best understood as a balance between the production and elimination of bilirubin, with a multitude of factors and conditions affecting each of these processes. When an imbalance results because of an increase in circulating bilirubin (or the bilirubin load) to significantly high levels (severe hyperbilirubinemia), it may cause permanent neurologic sequelae (kernicterus). In most infants, an increase in bilirubin production (e.g., due to hemolysis) is the primary cause of severe hyperbilirubinemia, and thus reducing bilirubin production is a rational approach for its management. The situation can become critical in infants with an associated impaired bilirubin elimination mechanism as a result of a genetic deficiency and/or polymorphism. Combining information about bilirubin production and genetic information about bilirubin elimination with the tracking of bilirubin levels means that a relative assessment of jaundice risk might be feasible. Information on the level of bilirubin production and its rate of elimination may help to guide the clinical management of neonatal jaundice.
- Published
- 2010
43. Influence of clinical status on the association between plasma total and unbound bilirubin and death or adverse neurodevelopmental outcomes in extremely low birth weight infants
- Author
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T. Michael O'Shea, David K. Stevenson, Rosemary D. Higgins, HJ Vreman, CE Ahlfors, Betty R. Vohr, JE Tyson, Dale L. Phelps, G. Jesse Bender, Ronald J. Wong, R Perritt, K. P. Van Meurs, William Oh, A Das, and BH Morris
- Subjects
Pediatrics ,medicine.medical_specialty ,Total plasma ,business.industry ,Bilirubin ,General Medicine ,medicine.disease ,Infant mortality ,Cerebral palsy ,chemistry.chemical_compound ,Low birth weight ,Corrected Age ,chemistry ,Pediatrics, Perinatology and Child Health ,Blood plasma ,Medicine ,medicine.symptom ,business ,Complication - Abstract
Objectives To assess the influence of clinical status on the association between total plasma bilirubin and unbound bilirubin on death or adverse neurodevelopmental outcomes at 18–22 months corrected age in extremely low birth weight infants.
- Published
- 2010
44. Effect of Heme Oxygenase-1 Deficiency on Placental Development
- Author
-
Hui Zhao, Flora Kalish, Nihar R. Nayak, David K. Stevenson, and Ronald J. Wong
- Subjects
Heterozygote ,medicine.medical_specialty ,Litter Size ,Nitric Oxide Synthase Type III ,Offspring ,Placenta ,Gene Expression ,Nitric Oxide Synthase Type II ,Apoptosis ,Blood Pressure ,Mice, Inbred Strains ,Biology ,Article ,Mice ,chemistry.chemical_compound ,Pregnancy ,Enos ,Internal medicine ,Basic Helix-Loop-Helix Transcription Factors ,medicine ,Animals ,Fetal Death ,Heme ,reproductive and urinary physiology ,Mice, Knockout ,Fetus ,Vascular Endothelial Growth Factor Receptor-1 ,Obstetrics and Gynecology ,Placentation ,Heterozygote advantage ,Arteries ,Organ Size ,biology.organism_classification ,Trophoblasts ,Up-Regulation ,Mice, Inbred C57BL ,Heme oxygenase ,Endocrinology ,medicine.anatomical_structure ,Fetal Weight ,Reproductive Medicine ,chemistry ,Heme Oxygenase (Decyclizing) ,embryonic structures ,Female ,Heme Oxygenase-1 ,Developmental Biology - Abstract
Heme oxygenase (HO) is the rate-limiting enzyme in the heme catabolic pathway and highly expressed in the placenta. Deficiencies in HO-1, the inducible isoform, have been associated with pregnancy disorders, such as recurrent miscarriages, intrauterine growth retardation, and pre-eclampsia. The aim of this study was to identify if a deficiency in HO-1 affects placental development using a mouse model. When HO-1 heterozygote (Het, HO-1(+/-)) mice were cross-bred, an extremely low birth rate in homozygote (Mut, HO-1(-/-)) offspring (2.4%) and small litter sizes were observed. Placentas and fetuses from Het cross-breedings were relatively smaller and weighed less than those from wild-type (WT) cross-breedings at E12.5 and E15.5. Furthermore, Het placentas had significantly less HO-1 mRNA and protein levels than WT placentas, but no significant differences in placental HO activity. Interestingly, HO-2, the constituitive HO isoform, as well as iNOS and eNOS expression were significantly upregulated in Het placentas. Histological examination showed that the junctional zone (JZ) of Het placentas were markedly thinner than those of WT placentas and appeared to be due to an increase in apoptosis. Immunohistochemistry revealed that HO-1-expressing cells were located primarily in the JZ of Het placentas, specifically in the spongiotrophoblast layer. In addition, diastolic blood pressures and plasma soluble VEGFR-1 (sFlt-1) levels were significantly elevated in pregnant Het mice. We conclude that a partial deficiency in HO-1 is associated with morphological changes in the placenta and elevations in maternal diastolic blood pressure and plasma sFlt-1 levels, despite a compensatory increase in HO-2 expression.
- Published
- 2009
45. Dermal Carbon Monoxide Excretion in Neonatal Rats During Light Exposure
- Author
-
Miu-Lan Chan, Hendrik J. Vreman, Ronald J. Wong, David K. Stevenson, and Yuri Knauer
- Subjects
Chromatography, Gas ,Light ,Photochemistry ,Riboflavin ,Article ,Excretion ,chemistry.chemical_compound ,Light source ,Animal science ,Fluorescent light ,Animals ,Rats, Wistar ,Skin ,Light exposure ,Carbon Monoxide ,Photosensitizing Agents ,Chemistry ,Anatomy ,Trunk ,Rats ,Light intensity ,Animals, Newborn ,Pediatrics, Perinatology and Child Health ,Oxidation-Reduction ,Carbon monoxide - Abstract
Total body, head, and trunk carbon monoxide (CO) excretion rates were measured separately by gas chromatography in 1- to 7-d-old Wistar rat pups exposed to the dark and to mixed blue (one Special Blue-F20T12/BB) and white (two Cool White-F20T12/CW) fluorescent light or blue light emitting diode (LED) sources. During 48-min cycled exposures to the dark and to either light source, total body CO excretion rapidly increased 1.9- and 1.4-fold, respectively, over dark control levels. When CO excretion rates from the head and trunk were measured separately during exposure to either light source, CO excretion from the head did not change significantly; however, a large mean 4.4-fold increase in CO excretion from the trunk was observed. When light intensity delivered by the blue LED source was varied, we found that trunk CO excretion increased with increasing light intensities. In the presence of riboflavin (10 micromol/kg), total body CO excretion increased 2.8- and 2.1-fold during exposure to the mixed fluorescent light and blue LED sources, respectively. We conclude that light-induced elevations in total body CO excretion may be caused by transdermally excreted CO, which is most likely produced through endogenous photosensitizer-mediated photooxidation of dermal biomolecules.
- Published
- 2009
46. Photoisomers: Obfuscating Factors in Clinical Peroxidase Measurements of Unbound Bilirubin?
- Author
-
David K. Stevenson, Hendrik J. Vreman, Ronald J. Wong, and Antony F. McDonagh
- Subjects
medicine.medical_specialty ,Bilirubin ,Serum albumin ,chemistry.chemical_compound ,Photostationary state ,Animals ,Humans ,Protein Isoforms ,Medicine ,Bovine serum albumin ,Kernicterus ,Serum Albumin ,Peroxidase ,Chromatography ,biology ,business.industry ,Albumin ,Jaundice ,Photochemical Processes ,medicine.disease ,Surgery ,chemistry ,Pediatrics, Perinatology and Child Health ,biology.protein ,Cattle ,medicine.symptom ,business ,Protein Binding - Abstract
OBJECTIVES. The objectives of the study were to measure the effect of 4Z,15E-bilirubin on peroxidase free bilirubin measurements and to review the literature on this topic.METHODS. 4Z,15E-Bilirubin was generated in situ in serum or serum albumin solution through controlled irradiation of isomerically pure 4Z,15Z-bilirubin IXα, under conditions in which the total amount of bilirubin remained constant. Reactions were monitored by difference spectroscopy, to ensure that solutions were not irradiated beyond the initial photostationary state and that concentrations of other isomers were kept to a minimum. Prepared in this way, 10% to 25% of the total bilirubin in the final solutions was in the form of the 4Z,15E-isomer. Free bilirubin in the solutions was measured with a peroxidase method, before and after irradiation. The use of bovine serum albumin as a surrogate for human albumin in in vitro studies also was investigated.RESULTS. The findings of previous studies are not altogether consistent, with a common flaw in several being the failure to measure photoisomer concentrations. For bilirubin in serum albumin solution, conversion of ∼25% of the 4Z,15Z-isomer to 4Z,15E-bilirubin led to a much smaller decrease (CONCLUSIONS. The effect of photoisomers on the accuracy and specificity of free 4Z,15Z-bilirubin measurements remains uncertain. In a clinical setting, free bilirubin measurements need to be interpreted with caution when samples contain photoisomers. Irradiated bovine albumin solutions of isomerically impure bilirubin used in previous studies are poor models for investigating the effects of phototherapy in humans and the albumin binding of photoisomers.
- Published
- 2009
47. Aggressive vs. Conservative Phototherapy for Infants with Extremely Low Birth Weight
- Author
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Rosemary D. Higgins, Waldemar A. Carlo, Cathy Grisby, Abbot R. Laptook, Seetha Shankaran, Claudia Pedroza, Brenda H. Morris, Walid A. Salhab, Ronnie Guillet, William Oh, Brenda B. Poindexter, Maynard Rasmussen, Qing Yao, Avroy A. Fanaroff, Dale L. Phelps, W. Kenneth Poole, Rebecca Perritt, David K. Stevenson, Edward F. Donovan, Betty R. Vohr, Krisa P. Van Meurs, C. Michael Cotten, Georgia E. McDavid, Barbara J. Stoll, Shahnaz Duara, Abhik Das, Richard A. Ehrenkranz, Jon E. Tyson, T. Michael O'Shea, and Michele C. Walsh
- Subjects
Male ,Pediatrics ,medicine.medical_specialty ,Bilirubin ,Developmental Disabilities ,Birth weight ,Article ,law.invention ,chemistry.chemical_compound ,Primary outcome ,Randomized controlled trial ,law ,Infant Mortality ,Birth Weight ,Humans ,Medicine ,business.industry ,Infant, Newborn ,Bayes Theorem ,Liter ,General Medicine ,Phototherapy ,Confidence interval ,Low birth weight ,Treatment Outcome ,chemistry ,Infant, Extremely Low Birth Weight ,Relative risk ,Female ,Hyperbilirubinemia, Neonatal ,medicine.symptom ,business - Abstract
It is unclear whether aggressive phototherapy to prevent neurotoxic effects of bilirubin benefits or harms infants with extremely low birth weight (1000 g or less).We randomly assigned 1974 infants with extremely low birth weight at 12 to 36 hours of age to undergo either aggressive or conservative phototherapy. The primary outcome was a composite of death or neurodevelopmental impairment determined for 91% of the infants by investigators who were unaware of the treatment assignments.Aggressive phototherapy, as compared with conservative phototherapy, significantly reduced the mean peak serum bilirubin level (7.0 vs. 9.8 mg per deciliter [120 vs. 168 micromol per liter], P0.01) but not the rate of the primary outcome (52% vs. 55%; relative risk, 0.94; 95% confidence interval [CI], 0.87 to 1.02; P=0.15). Aggressive phototherapy did reduce rates of neurodevelopmental impairment (26%, vs. 30% for conservative phototherapy; relative risk, 0.86; 95% CI, 0.74 to 0.99). Rates of death in the aggressive-phototherapy and conservative-phototherapy groups were 24% and 23%, respectively (relative risk, 1.05; 95% CI, 0.90 to 1.22). In preplanned subgroup analyses, the rates of death were 13% with aggressive phototherapy and 14% with conservative phototherapy for infants with a birth weight of 751 to 1000 g and 39% and 34%, respectively (relative risk, 1.13; 95% CI, 0.96 to 1.34), for infants with a birth weight of 501 to 750 g.Aggressive phototherapy did not significantly reduce the rate of death or neurodevelopmental impairment. The rate of neurodevelopmental impairment alone was significantly reduced with aggressive phototherapy. This reduction may be offset by an increase in mortality among infants weighing 501 to 750 g at birth. (ClinicalTrials.gov number, NCT00114543.)
- Published
- 2008
48. Regulation of Maternal and Fetal Hemodynamics by Heme Oxygenase in Mice1
- Author
-
Timothy C. Doyle, Christopher H. Contag, Hui Zhao, Hendrik J. Vreman, Ronald J. Wong, David K. Stevenson, and Nihar R. Nayak
- Subjects
medicine.medical_specialty ,Fetus ,Pregnancy ,Hemodynamics ,Vasodilation ,Cell Biology ,General Medicine ,Biology ,medicine.disease ,Heme oxygenase ,chemistry.chemical_compound ,medicine.anatomical_structure ,Endocrinology ,Reproductive Medicine ,chemistry ,Internal medicine ,Placenta ,Carboxyhemoglobin ,medicine ,Vascular resistance - Abstract
Heme oxygenase (HMOX) regulates vascular tone and blood pressure through the production of carbon monoxide (CO), a vasodilator derived from the heme degradation pathway. During pregnancy, the maternal circulation undergoes significant adaptations to accommodate the hemodynamic demands of the developing fetus. Our objective was to investigate the role of HMOX on maternal and fetal hemodynamics during pregnancy in a mouse model. We measured and compared maternal tissue and placental HMOX activity and endogenous CO production, represented by excreted CO and carboxyhemoglobin levels, during pregnancy (Embryonic Days 12.5–15.5) to nonpregnant controls. Micro-ultrasound was used to monitor maternal abdominal aorta diameters as well as blood flow velocities and diameters of fetal umbilical arteries. Tin mesoporphyrin, a potent HMOX inhibitor, was used to inhibit HMOX activity. Changes in maternal vascular tone were monitored by tail cuff blood pressure measurements. Effects of HMOX inhibition on placental structures were assessed by histology. We showed that maternal tissue and placental HMOX activity and CO production were significantly elevated during pregnancy. When HMOX in the placenta was inhibited, maternal and fetal hemodynamics underwent significant changes, with maternal blood pressures increasing. We concluded that increases in maternal tissue and placental HMOX activity contribute to the regulation of peripheral vascular resistance and therefore are important for the maintenance of normal maternal vascular tone and fetal hemodynamic functions during pregnancy. carbon monoxide, heme oxygenase, hemodynamic function, hemodynamics, placenta, pregnancy
- Published
- 2008
49. Statin treatment increases formation of carbon monoxide and bilirubin in mice: a novel mechanism of in vivo antioxidant protection
- Author
-
Mark Hsu, Henning Schröder, David K. Stevenson, Lucie Muchová, Ichiro Morioka, Jaroslav Zelenka, Libor Vítek, and Ronald J. Wong
- Subjects
Physiology ,Bilirubin ,Atorvastatin ,Pharmacology ,Antioxidants ,Lipid peroxidation ,Mice ,chemistry.chemical_compound ,Liver Function Tests ,Physiology (medical) ,medicine ,Animals ,Pyrroles ,Rosuvastatin ,Rosuvastatin Calcium ,Carbon Monoxide ,Sulfonamides ,General Medicine ,Hydroxymethylglutaryl-CoA reductase ,Fluorobenzenes ,Heme oxygenase ,Pyrimidines ,Carboxyhemoglobin ,chemistry ,Biochemistry ,Heptanoic Acids ,Heme Oxygenase (Decyclizing) ,Lipid Peroxidation ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,medicine.drug - Abstract
Heme oxygenase (HO) has a central role in cellular antioxidant defences and vascular protection, and it may mediate pleiotropic actions of drugs used in cardiovascular therapy. We investigated whether long-term use of statins upregulates HO activity and increases carbon monoxide (CO) and bilirubin levels in vivo. Adult FvB mice were given atorvastatin or rosuvastatin (5 mg/kg) daily by i.p. injections for 1, 2, or 3 weeks. HO activity, tissue CO, bilirubin, and antioxidant levels, total plasma bilirubin, and carboxyhemoglobin (COHb) were measured. Fold changes in heart HO activity significantly increased after 1, 2, and 3 weeks of atorvastatin (1.24 +/- 0.06 (p < or = 0.05); 1.29 +/- 0.26 (p < or = 0.03); 1.33 +/- 0.08 (p < 0.01), respectively) and 2 and 3 weeks of rosuvastatin (1.23 +/- 0.20 (p < or = 0.03); 1.63 +/- 0.42 (p < 0.01), respectively). Heart tissue CO and COHb levels also increased after 3 weeks with atorvastatin (1.30 +/- 0.24 (p < or = 0.05); 1.92 +/- 0.17 (p < or = 0.001), respectively) and rosuvastatin (1.47 +/- 0.13 (p < or = 0.004); 1.63 +/- 0.12 (p < or = 0.001), respectively). Significant increases in heart antioxidant levels were observed after statin treatment and corroborated by heart bilirubin content elevations. Antioxidant level increases were abolished by treatment with an HO inhibitor. These findings suggest that the induction of HO and the production of its products, CO and bilirubin, may be a mechanism by which statins exert antioxidant actions and confer cardioprotection in vivo.
- Published
- 2007
50. Effects of sample dilution, peroxidase concentration, and chloride ion on the measurement of unbound bilirubin in premature newborns
- Author
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G. Jesse Bender, Charles E. Ahlfors, David K. Stevenson, Ronald J. Wong, Hendrik J. Vreman, Brenda H. Morris, and William Oh
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Bilirubin ,Clinical Biochemistry ,Chloride ,Article ,Ion ,chemistry.chemical_compound ,Chlorides ,medicine ,Humans ,Organic chemistry ,Sample dilution ,Diagnostic Techniques and Procedures ,Chromatography ,Newborn jaundice ,biology ,Infant, Newborn ,Analytic Sample Preparation Methods ,General Medicine ,Jaundice, Neonatal ,Dilution ,Peroxidases ,chemistry ,biology.protein ,Female ,Steady state (chemistry) ,Infant, Premature ,Peroxidase ,medicine.drug - Abstract
Objectives To assess the effects of sample dilution, peroxidase concentration, and chloride ion (Cl − ) on plasma unbound bilirubin ( B f ) measurements made using a commercial peroxidase methodology (UB Analyzer) in a study population of ill, premature newborns. Design and methods B f was measured with a UB Analyzer in 74 samples at the standard 42-fold sample dilution and compared with B f measured at a 2-fold sample dilution using a FloPro Analyzer. B f was measured at two peroxidase concentrations to determine whether the peroxidase steady state B f ( B fss ) measurements were significantly less than the equilibrium B f ( B feq ), in which case it was necessary to calculate B feq from the two B fss measurements. B f was also measured before and after adding 100 mmol/L Cl − to the UB Analyzer assay buffer. Results B feq at the 42-fold dilution was nearly 10-fold less than but it correlated significantly with B feq at the 2-fold dilution (mean 8.2 ± 5.2 nmol/L versus 73.5 ± 70 nmol/L, respectively, p r = 0.6). The two UB Analyzer B fss measurements were significantly less than B feq in 42 of 74 (57%) samples, and Cl − increased B feq in 66 of 74 (89%) samples by a mean of 82 ± 67%. Conclusions B fss measured by the UB Analyzer at the standard 42-fold sample dilution using assay buffer without Cl − and a single peroxidase concentration is significantly less than the B feq in undiluted plasma. Accurate B f measurements can be made only in minimally diluted serum or plasma.
- Published
- 2007
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