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1.  Unmyelinated White Matter Loss in the Preterm Brain Is Associated with Early Increased Levels of End-Tidal Carbon Monoxide 
PLoS ONE  2014;9(3):e89061.
Objective
Increased levels of end-tidal carbon monoxide (ETCOc) in preterm infants during the first day of life are associated with oxidative stress, inflammatory processes and adverse neurodevelopmental outcome at 2 years of age. Therefore, we hypothesized that early ETCOc levels may also be associated with impaired growth of unmyelinated cerebral white matter.
Methods
From a cohort of 156 extremely and very preterm infants in which ETCOc was determined within 24 h after birth, in 36 infants 3D-MRI was performed at term-equivalent age to assess cerebral tissue volumes of important brain regions.
Results
Linear regression analysis between cerebral ventricular volume, unmyelinated white matter/total brain volume-, and cortical grey matter/total brain volume-ratio and ETCOc showed a positive, negative and positive correlation, respectively. Multivariable analyses showed that solely ETCOc was positively related to cerebral ventricular volume and cortical grey matter/total brain volume ratio, and that solely ETCOc was inversely related to the unmyelinated white matter/total brain volume ratio, suggesting that increased levels of ETCOc, associated with oxidative stress and inflammation, were related with impaired growth of unmyelinated white matter.
Conclusion
Increased values of ETCOc, measured within the first 24 hours of life may be indicative of oxidative stress and inflammation in the immediate perinatal period, resulting in impaired growth of the vulnerable unmyelinated white matter of the preterm brain.
doi:10.1371/journal.pone.0089061
PMCID: PMC3951188  PMID: 24622422
2.  Treatment of neonatal jaundice with filtered sunlight in Nigerian neonates: study protocol of a non-inferiority, randomized controlled trial 
Trials  2013;14:446.
Background
Severe neonatal jaundice and its progression to kernicterus is a leading cause of death and disability among newborns in poorly-resourced countries, particularly in sub-Saharan Africa. The standard treatment for jaundice using conventional phototherapy (CPT) with electric artificial blue light sources is often hampered by the lack of (functional) CPT devices due either to financial constraints or erratic electrical power. In an attempt to make phototherapy (PT) more readily available for the treatment of pathologic jaundice in underserved tropical regions, we set out to test the hypothesis that filtered sunlight phototherapy (FS-PT), in which potentially harmful ultraviolet and infrared rays are appropriately screened, will be as efficacious as CPT.
Methods/design
This prospective, non-blinded randomized controlled non-inferiority trial seeks to enroll infants with elevated total serum/plasma bilirubin (TSB, defined as 3 mg/dl below the level recommended by the American Academy of Pediatrics for high-risk infants requiring PT) who will be randomly and equally assigned to receive FS-PT or CPT for a total of 616 days at an inner-city maternity hospital in Lagos, Nigeria. Two FS-PT canopies with pre-tested films will be used. One canopy with a film that transmits roughly 33% blue light (wavelength range: 400 to 520 nm) will be used during sunny periods of a day. Another canopy with a film that transmits about 79% blue light will be used during overcast periods of the day. The infants will be moved from one canopy to the other as needed during the day with the goal of keeping the blue light irradiance level above 8 μW/cm2/nm.
Primary outcome: FS-PT will be as efficacious as CPT in reducing the rate of rise in bilirubin levels. Secondary outcome: The number of infants requiring exchange transfusion under FS-PT will not be more than those under CPT.
Conclusion
This novel study offers the prospect of an effective treatment for infants at risk of severe neonatal jaundice and avoidable exchange transfusion in poorly-resourced settings without access to (reliable) CPT in the tropics.
Trial registration
ClinicalTrials.gov Identifier: NCT01434810
doi:10.1186/1745-6215-14-446
PMCID: PMC3879162  PMID: 24373547
Filtered sunlight phototherapy; Hyperbilirubinemia; Developing country; Low-cost technologies; Irradiance; Africa
3.  Expression of Biliverdin Reductase A in Peripheral Blood Leukocytes Is Associated with Treatment Response in HCV-Infected Patients 
PLoS ONE  2013;8(3):e57555.
Background and Aims
Hepatitis C virus (HCV) infection is associated with systemic oxidative stress. Since the heme catabolic pathway plays an important role in antioxidant protection, we attempted to assess the gene expression of key enzymes of heme catabolism, heme oxygenase 1 (HMOX1), heme oxygenase 2 (HMOX2), and biliverdin reductase A (BLVRA) in the liver and peripheral blood leukocytes (PBL) of patients chronically infected with HCV.
Methods
Gene expressions (HMOX1, HMOX2, BLVRA) and HCV RNA were analyzed in PBL of HCV treatment naïve patients (n = 58) and controls (n = 55), with a subset of HCV patients having data on hepatic gene expression (n = 35). Based upon the therapeutic outcome, HCV patients were classified as either responders (n = 38) or treatment-failure patients (n = 20). Blood samples in HCV patients were collected at day 0, and week 12, 24, 36, and 48 after the initiation of standard antiviral therapy.
Results
Compared to the controls, substantially increased BLVRA expression was detected in PBL (p<0.001) of therapeutically naïve HCV patients. mRNA levels of BLVRA in PBL closely correlated with those in liver tissue (r2 = 0.347,p = 0.03). A marked difference in BLVRA expression in PBL between the sustained responders and patients with treatment failure was detected at week 0 and during the follow-up (p<0.001). Multivariate analysis revealed that BLVRA basal expression in PBL was an independent predictor for sustained virological response (OR 15; 95% CI 1.05–214.2; P = 0.046). HMOX1/2 expression did not have any effect on the treatment outcome.
Conclusion
Our results suggest that patients with chronic HCV infection significantly upregulate BLVRA expression in PBL. The lack of BLVRA overexpression is associated with non-responsiveness to standard antiviral therapy; whereas, HMOX1/2 does not seem to have any predictive potential.
doi:10.1371/journal.pone.0057555
PMCID: PMC3594226  PMID: 23536765
4.  Early end-tidal carbon monoxide levels and neurodevelopmental outcome at 3 years 6 months of age in preterm infants 
Aim
Increased end-tidal carbon monoxide (ETCOc) and cytokines in preterm infants are related to bronchopulmonary dysplasia and intraventricular haemorrhages. The aim was to study the predictive value of ETCOc and cytokine levels for long-term outcome.
Methods
This study comprised 105 very preterm infants (57 males, 48 females; gestational age range 25wk 5d–31wk 4d; birthweight 610–2100g) who were admitted to a neonatal intensive care unit between 1 February and 31 December 2002. ETCOc, plasma tumour necrosis factor alpha (TNF-α) and interleukins (IL) 6 and 8, and malondialdehyde (MDA, a marker of lipid peroxidation), were measured at days 1, 3, and 5 of life and related to outcome at 3 years 6 months of age (Griffiths Mental Developmental Scales).
Results
Of the 105 infants, 69 were eligible for follow-up (37 male; 32 female; bronchopulmonary dysplasia, n=12). ETCOc at 0 to 24 hours was higher in infants with adverse outcome (Griffiths developmental quotient <85, n=15) compared with favourable outcome (2.7 SD 0.7 vs 2.0 SD 0.5; p<0.05). MDA and cytokines did not differ between groups. Regression analysis with bootstrapping of independent variables (gestational age, birthweight, ETCOc, TNF-α, IL-6, IL-8, and bronchopulmonary dysplasia) showed that ETCOc was the only parameter that correlated with outcome. The sensitivity and negative predictive value of ETCOc for adverse outcome were 93% and 85% respectively.
Interpretation
Adverse neurodevelopmental outcome is associated with increased endogenous carbon monoxide. ETCOc less than 2.0ppm during the first day indicates a favourable outcome.
doi:10.1111/j.1469-8749.2011.04110.x
PMCID: PMC3220782  PMID: 21933176
5.  Effects of Zinc Deuteroporphyrin Bis Glycol on Newborn Mice After Heme-Loading 
Pediatric research  2011;70(5):467-472.
Infants with hemolytic diseases frequently develop hyperbilirubinemia, but standard phototherapy 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 I50 (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 following heme-loading, a model analogous to a hemolytic infant. The I50 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.
doi:10.1203/PDR.0b013e31822e1675
PMCID: PMC3189293  PMID: 21785387
6.  Metalloporphyrins – An Update 
Metalloporphyrins are structural analogs of heme and their potential use in the management of neonatal hyperbilirubinemia has been the subject of considerable research for more than three decades. The pharmacological basis for using this class of compounds to control bilirubin levels is the targeted blockade of bilirubin production through the competitive inhibition of heme oxygenase (HO), the rate-limiting enzyme in the bilirubin production pathway. Ongoing research continues in the pursuit of identifying ideal metalloporphyrins, which are safe and effective, by defining therapeutic windows and targeted interventions for the treatment of excessive neonatal hyperbilirubinemia.
doi:10.3389/fphar.2012.00068
PMCID: PMC3337460  PMID: 22557967
bilirubin; heme oxygenase; hemolysis; neonatal hyperbilirubinemia
7.  HEMOLYSIS AND HYPERBILIRUBINEMIA IN ABO BLOOD GROUP HETEROSPECIFIC NEONATES 
The Journal of pediatrics  2010;157(5):772-777.
Objective
We quantified hemolysis and determined the incidence of hyperbilirubinemia in direct antiglobulin titer (DAT) positive, ABO heterospecific neonates and compared variables among O-A and O-B subgroups. Study design Plasma total bilirubin (PTB) was determined predischarge and more frequently if clinically warranted, in DAT positive, blood group A or B neonates of group O mothers. Heme catabolism (and therefore bilirubin production) was indexed by blood carboxyhemoglobin corrected for inspired carbon monoxide (COHbc). Hyperbilirubinemia was defined as any PTB concentration >95th percentile on the hour-of-life-specific bilirubin nomogram.
Results
Of 164 neonates, 111 were O-A and 53 O-B. Overall, 85 (51.8%) developed hyperbilirubinemia, which tended to be more prevalent in the O-B than O-A neonates (62.3% vs. 46.8% respectively, p=0.053). Importantly, more O-B than O-A newborns developed hyperbilirubinemia at <24 hours (93.9% vs. 48.1%, p<0.0001). COHbc values were globally higher than our previously published newborn values. Babies who developed hyperbilirubinemia had higher COHbc values than the already high values of those non-hyperbilirubinemic, and O-B newborns tended to have higher values than O-A counterparts.
Conclusions
DAT positive, ABO heterospecificity is associated with increased hemolysis and a high incidence of neonatal hyperbilirubinemia. O-B heterospecificity tends to confer even higher risk than O-A counterparts.
doi:10.1016/j.jpeds.2010.05.024
PMCID: PMC2951500  PMID: 20598320
Direct antiglobulin titer; bilirubin; ABO heterospecificity; hemolysis; hyperbilirubinemia; carboxyhemoglobin
8.  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 
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.
Method
Total plasma biirubin and unbound biirubin were measured in 1,101 extremely low birth weight infants at 5±1 day of age. Clinical criteria were used to classify infants as clinically stable or unstable. Survivors were examined at 18–22 months corrected age by certified examiners. Outcome variables were death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss, and death prior to follow-up. For all outcomes, the interaction between bilirubin variables and clinical status was assessed in logistic regression analyses adjusted for multiple risk factors.
Results
Regardless of clinical status, an increasing level of unbound bilirubin was associated with higher rates of death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss and death before follow-up. Total plasma bilirubin values were directly associated with death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss, and death before follow-up in unstable infants, but not in stable infants. An inverse association between total plasma bilirubin and death or cerebral palsy was found in stable infants.
Conclusions
In extremely low birth weight infants, clinical status at 5 days of age affects the association between total plasma and unbound bilirubin and death or adverse neurodevelopmental outcomes at 18–22 months of corrected age. An increasing level of UB is associated a higher risk of death or adverse neurodevelopmental outcomes regardless of clinical status. Increasing levels of total plasma bilirubin are directly associated with increasing risk of death or adverse neurodevelopmental outcomes in unstable, but not in stable infants.
doi:10.1111/j.1651-2227.2010.01688.x
PMCID: PMC2875328  PMID: 20105142
Plasma bilirubin; unbound bilirubin; Extremely low birth weight infants; Neurodevelopmental outcomes
9.  Diesel Engine Exhaust Initiates a Sequence of Pulmonary and Cardiovascular Effects in Rats 
Journal of Toxicology  2010;2010:206057.
This study was designed to determine the sequence of events leading to cardiopulmonary effects following acute inhalation of diesel engine exhaust in rats. Rats were exposed for 2 h to diesel engine exhaust (1.9 mg/m3), and biological parameters related to antioxidant defense, inflammation, and procoagulation were examined after 4, 18, 24, 48, and 72 h. This in vivo inhalation study showed a pulmonary anti-oxidant response (an increased activity of the anti-oxidant enzymes glutathione peroxidase and superoxide dismutase and an increase in heme oxygenase-1 protein, heme oxygenase activity, and uric acid) which precedes the inflammatory response (an increase in IL-6 and TNF-α). In addition, increased plasma thrombogenicity and immediate anti-oxidant defense gene expression in aorta tissue shortly after the exposure might suggest direct translocation of diesel engine exhaust components to the vasculature but mediation by other pathways cannot be ruled out. This study therefore shows that different stages in oxidative stress are not only affected by dose increments but are also time dependent.
doi:10.1155/2010/206057
PMCID: PMC2968117  PMID: 21052503
10.  Dermal Carbon Monoxide (CO) Excretion in Neonatal Rats During Light Exposure 
Pediatric research  2009;66(1):66-69.
Total body, head, and trunk carbon monoxide (CO) excretion rates were measured separately by gas chromatography in 1–7 day-old Wistar rat pups exposed to the dark and to mixed blue (1 Special Blue – F20T12/BB) and white (2 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 µmol/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 photo-oxidation of dermal biomolecules.
doi:10.1203/PDR.0b013e3181a7be77
PMCID: PMC2714864  PMID: 19342986
11.  Effects of Sample Dilution, Peroxidase Concentration, and Chloride Ion on the Measurement of Unbound Bilirubin in Premature Newborns 
Clinical biochemistry  2006;40(3-4):261-267.
Objectives
To assess the effects of sample dilution, peroxidase concentration, and chloride ion (Cl-) on plasma unbound bilirubin (Bf) measurements made using a commercial peroxidase methodology (UB Analyzer) in a study population of ill, premature newborns.
Design and Methods
Bf was measured with a UB Analyzer in 74 samples at the standard 42-fold sample dilution and compared with Bf measured at a 2-fold sample dilution using a FloPro Analyzer. Bf was measured at two peroxidase concentrations to determine whether the peroxidase steady state Bf (Bfss) measurements were significantly less than the equilibrium Bf (Bfeq), in which case it was necessary to calculate Bfeq from the two Bfss measurements. Bf was also measured before and after adding 100 mmol/L Cl- to the UB Analyzer assay buffer.
Results
Bfeq at the 42-fold dilution was nearly 10-fold less than but correlated significantly with Bfeq at the 2-fold dilution (mean 8.2±5.2 nmol/L versus 73.5 ±70 nmol/L, respectively, p<0.0001; correlation r=0.6). The two UB Analyzer Bfss measurements were significantly less than Bfeq in 42 of 74 (57%) samples, and Cl- increased Bfeq in 66 of 74 (89%) samples by a mean of 82±67%.
Conclusions
Bfss 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 Bfeq in undiluted plasma. Accurate Bf measurements can be made only in minimally diluted serum or plasma.
doi:10.1016/j.clinbiochem.2006.09.006
PMCID: PMC1945224  PMID: 17069786
newborn jaundice; hyperbilirubinemia; unbound bilirubin; peroxidase test; bilirubin/albumin binding; free bilirubin

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