Rapid clearance of a structural isomer of bilirubin during phototherapy.

During phototherapy for neonatal jaundice, bilirubin is converted into a variety of photoproducts. Determination of the relative importance of these photoproducts to the elimination of bilirubin requires knowledge of their rates of excretion. We have measured the rate at which the structural isomer of bilirubin, lumirubin, disappeared from the serum of nine jaundiced premature infants after the cessation of phototherapy. In all patients studied, the decline in serum lumirubin could be approximated by a first-order rate equation with a half-life of 80 to 158 min. This rate of disappearance is much faster than that previously determined for the other major bilirubin photoproducts. In samples of bile aspirated from the duodenum of infants undergoing phototherapy, lumirubin was the principal bilirubin photoproduct found. These results indicate that formation and excretion of lumirubin is an important route for bilirubin elimination during phototherapy.

Thiol suppression of human immunodeficiency virus type 1 replication in primary cord blood monocyte-derived macrophages in vitro.

We investigated the effects of glutathione (GSH), the major naturally occurring thiol, and a pharmacologic thiol precursor of GSH, N-acetyl cysteine (NAC), on the expression of human immunodeficiency type 1 (HIV-1) in primary cord blood and adult donor monocyte-derived macrophages (MDM). HIV-1 infection of cord blood and adult MDM was accomplished after incubating 10-15-d-old cultures for 4 h with a monocyte-tropic strain of HIV-1 (Bal). After 1 wk in culture cell supernatants were tested for reverse transcriptase (RT) activity. MDM were exposed to 5, 10 and 20 mM concentrations of both GSH and NAC before infection, during infection, and after infection was established. GSH and NAC suppressed the replication of HIV-1 in both primary cord blood and adult donor MDM in a concentration dependent fashion. These suppressive effects were more pronounced in cord-derived cells than in adult-derived cells. In cells treated with GSH or NAC before infection, there was no significant rise in RT activity as compared with controls. Similarly, when cells were treated with GSH and NAC and simultaneously infected, there was also no significant rise in RT activity after 1 wk in culture. In cells treated after infection was established, RT values were suppressed 80-90% that of untreated controls. This effect persisted for 1-2 wk after exposure to GSH and NAC. Untreated controls demonstrated syncytium formation and lost characteristics of spreading and elongation 2 wk after HIV-1 infection, whereas most of the treated cells remained free of syncytium and retained cytoplasmic spreading, adherence, and elongation. These data are consistent with other studies of thiol suppression of HIV-1 replication and demonstrate a similar observation for primary cultured cord MDM. These results may offer new approaches toward cellular protection after infection with HIV-1.

Infant mortality in the United States.

The infant mortality rate (IMR) of 6.0 per 1000 live births in the United States in 2013 is nearly the highest among developed countries. Moreover, the IMR among blacks is >twice that among whites-11.11 versus 5.06 deaths per 1000 live births.This higher IMR and racial disparity in IMR is due to a higher preterm birth rate (11.4% of live births in 2013) and higher IMR among term infants. The United States also ranks near the bottom for maternal mortality and life expectancy among the developed nations-despite ranking highest in the proportion of gross national product spent on health care. This suggests that factors other than health care contribute to the higher IMR and racial disparity in IMR. One factor is disadvantaged socioeconomic status. All of the actionable determinates that negatively impact health-personal behavior, social factors, heath-care access and quality and the environment-disproportionately affect the poor. Addressing disadvantaged socioeconomic status by improving access to quality health care and increasing social expenditures would have the greatest impact on the USA's IMR and racial disparity in IMR.

Enhancement in vitro of the low interferon-gamma production of leukocytes from human newborn infants.

Interferon-gamma (IFN-gamma), a lymphokine produced by lymphocytes with the help of monocytes, is essential for host resistance to intracellular pathogens. Leukocytes from normal term newborn infants cannot produce IFN-gamma in vitro in response to stimulation by antigen or mitogens in vitro or in vivo. We investigated the production of IFN-gamma in vitro using endotoxin from Salmonella typhimurium as a stimulus. In contrast to those from adults, mononuclear cells derived from the cord blood of newborn infants did not produce IFN-gamma in response to this endotoxin. We investigated the contribution of the functional immaturity of cord blood monocytes to this relative inability to produce IFN-gamma. Aging of the monocytes for 2 weeks in vitro or treatment of freshly isolated cord blood monocytes with conditioned medium (from cultures of mononuclear cells from healthy adults) greatly enhanced IFN-gamma production stimulated by endotoxin. Furthermore, recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF), or IFN-gamma was able to substitute in part for the conditioned medium from adult cells. Thus correction of the functional immaturity of monocytes derived from newborn infants can result in enhanced production of IFN-gamma in vitro.

Decreased fibronectin biosynthesis by human cord blood mononuclear phagocytes in vitro.

Cultured cord blood monocytes synthesize significantly less fibronectin than cultured monocyte-macrophages from adult peripheral blood. Biosynthesis of the second component of complement in vitro is similar for both cell systems. The monocyte-macrophages from neonates and adults have similar functional and morphologic properties in long-term cultures. The decreased monocyte-macrophage biosynthesis of fibronectin observed in vitro may be in part related to the reduced plasma fibronectin concentrations and reticuloendothelial system hypofunction which occur in newborn infants.

Fibronectin and complement secretion by monocytes and peritoneal macrophages in vitro from patients undergoing continuous ambulatory peritoneal dialysis.

We investigated the role of the opsonic glycoprotein fibronectin in the host defense of the peritoneum in patients undergoing continuous ambulatory peritoneal dialysis (CAPD). Fibronectin concentration in peritoneal dialysate from high infection rate CAPD patients (greater than 1.50 episodes peritonitis per year) was significantly less than from low infection rate CAPD patients (less than 0.55 episodes peritonitis per year). In vitro secretion of fibronectin by cultured peritoneal macrophages from patients with high infection rate was less than from low infection rate patients (P less than 0.05) and controls (P less than 0.01). In vitro secretion of the second component of complement, however, was similar in both high and low infection rate patients. Plasma fibronectin concentration and in vitro fibronectin secretion by cultured peripheral blood monocytes was not different between high infection rate patients and low infection rate patients, but was less than normals. Decreased fibronectin secretion by peritoneal macrophages is associated with a higher incidence of peritonitis among CAPD patients.

Early radiologic evidence of severe respiratory distress syndrome as a predictor of nasal continuous positive airway pressure failure in extremely low birth weight newborns.

OBJECTIVE: To determine whether early radiologic evidence of severe respiratory distress syndrome (RDS) is predictive of nasal continuous positive airway pressure (CPAP) failure in extremely low birth weight (ELBW) infants during the first 72 h of age. STUDY DESIGN: Retrospective analysis of 235 consecutively inborn ELBW infants who received initial support with CPAP. CPAP success (n=151) and CPAP failure (n=84) groups were designated according to outcome within the first 72 h of age. We assessed the ability of radiologic evidence of severe RDS in the initial chest radiograph, alone and in combination with other variables available in the first hours of life, to predict CPAP failure. RESULT: Severe RDS had a positive predictive value (PPV) of 0.81 (95% confidence interval (CI) 0.64, 0.92) for CPAP failure. The combination of severe RDS and gestational age (GA) ⩽ 26 weeks had a PPV of 0.92 (95% CI 0.68, 0.96). CONCLUSION: Early radiologic evidence of severe RDS is predictive of CPAP failure, especially in infants with GA ⩽ 26 weeks.

Fibronectin turnover in the premature neonate measured with [15N]glycine.

Fibronectin is a large-molecular-weight glycoprotein present on most cell surfaces and in plasma. Plasma fibronectin concentrations in neonates are lower than those in adults and a direct relationship exists between plasma concentration and gestational age. We determined the half-life and fractional synthetic rate (FSR) of plasma fibronectin in the premature infant. Infants and adults received a loading dose of [15N]glycine followed by a constant infusion [15N]glycine incorporation into plasma fibronectin and urine hippurate was determined by gas chromatography-mass spectrometry. The plasma fibronectin FSR in the preterm neonates was 15.5 +/- 9.9%/d(means +/- SD) and the half-life was 5.55 +/- 2.25 d. Birth weight correlated inversely with plasma fibronectin half-life. In the adults the plasma fibronectin FSR ranged from 20 to 87%/d and half-life ranged between 0.79 and 3.47 d. These data suggest that decreased plasma fibronectin levels in preterm infants are due to reduced FSRs rather than to greater turnover of a relatively small plasma pool.

Half-dose immunization for diphtheria, tetanus, pertussis: response of preterm infants.

The American Academy of Pediatrics currently recommends administering full-dose diphtheria, tetanus, pertussis, (DTP) vaccine to preterm infants, beginning at 2 months' chronologic age. Many physicians, however, continue to administer DTP vaccine at a reduced dosage in an attempt to lessen side effects. This study was designed to quantitate the immune response of 20 preterm infants immunized with half-dose DTP vaccine and to determine the nature and extent of side effects. Control subjects were 25 preterm infants immunized with full-dose vaccine. Although 96% of infants who received a full dose were able to mount a serologic response to pertussis after a second dose of DTP, 45% of infants who received a half dose were unable to mount a similar immune response to pertussis even after a third dose of DTP and required a full-dose (fourth dose of DTP) vaccine to better ensure protection. Serologic responses to diphtheria and tetanus were similar in the two groups. The incidence of side effects in preterm infants receiving both full-dose and half-dose DTP was less than that seen in a full-term population. Thus, the physician caring for the preterm infant should adhere to the American Academy of Pediatrics' recommendation for the immunization of preterm infants and offer full-dose DTP vaccine at the routine time intervals of 2, 4, 6, and 15 or 18 months' chronologic age to ensure adequate protection.

Bilirubin photoisomerization in premature neonates under low- and high-dose phototherapy.

Photoisomerization of native bilirubin to more polar configurational isomers (Z,E-bilirubin) and structural isomers (lumirubin) was studied in 20 premature infants with physiologic jaundice to determine the effect of low-dose (6 microW/cm2/nm) v high-dose (12 microW/cm2/nm) phototherapy. Patients were assigned prospectively to receive either low- or high-dose treatment. Study groups were comparable with regard to birth weight, gestational age, and total bilirubin prior to the initiation of phototherapy. Treatment was administered with white light produced by a commercially available halogen-tungsten lamp. Dose was measured periodically during the study to ensure a uniform distribution of irradiance and constant exposure. Sera for photoisomers were obtained before initiation of treatment and at two, four, and eight hours. Photoisomers expressed as a percent of total bilirubin were determined using high-pressure liquid chromatography. Serum proportion of both configurational and structural isomers increased with the duration of phototherapy in both treatment groups. There was no significant difference between the percent of configurational isomers in low- and high-dose phototherapy groups. However, high-dose treatment produced a significantly higher proportion of the structural isomer lumirubin after four hours (0.7% low dose v 1.3% high dose, P less than .05). These data confirm that phototherapy results in both configurational and structural isomerization of bilirubin in vivo. Furthermore, the previously described "dose" effect of phototherapy may be attributed to the production of the structural isomer, lumirubin.

Decreased plasma fibronectin in neonatal sepsis.

Fibronectin is a large opsonic glycoprotein which promotes reticuloendothelial system clearance of bacteria, immune complexes, collagenous debris, and damaged platelets. The concentration of plasma fibronectin is decreased in the newborn infant; however, the role of fibronectin in the onset and course of neonatal sepsis is unknown. Serial plasma fibronectin levels were determined in 19 neonates with documented bacterial sepsis. Plasma fibronectin concentrations decreased significantly (P less than .001) in all study infants concurrent with the development of septicemia. Recovery of plasma fibronectin to normal levels occurred by day 5 in premature neonates and by days 7 to 10 in term neonates. Fibronectin deficiency and resultant reticuloendothelial system impairment may decrease the ability of newborn infants to resist or clear bacterial infections. An acute reduction in the concentration of plasma fibronectin may be a valuable marker for neonatal sepsis.

Sickle cell anemia in the newborn.

The clinical presentation of homozygous sickle cell disease is unusual in the neonatal period. Recently, we have encountered a newborn infant whose disease was apparent at birth and who died at 5 days of age. The findings at autopsy suggested a sickle cell crisis with multisystem involvement that was present prior to birth. Laboratory findings confirmed homozygous sickle cell disease without the presence of elevated levels of hemoglobin S. The cause of the unusually severe clinical course of the disease in our patient is the object of the discussion.

Natural history of neonatal colonization with group B streptococci.

Thirteen percent of the newborns in our study group were colonized with group B streptococci on day 3. This colonization rate appeared constant during the first two weeks of life and then decreased to 5%. Of the babies colonized on day 3, 59% and 91% were culture-negative on days 14 and 42, respectively. Sixty-five percent of the babies carrying group B streptococci on day 14 acquired this microorganism following discharge (day 3). Babies colonized with staphylococci or Escherichia coli were found to have decreased probability of colonization with group B streptococci.

Survivors of extracorporeal membrane oxygenation at 1 year of age: the relationship of primary diagnosis with health and neurodevelopmental sequelae.

OBJECTIVE: Although extracorporeal membrane oxygenation (ECMO) has been responsible for the improved survival of infants with cardiorespiratory failure, its use over the last decade has raised concern as to the health of the survivors and the severity of neurodevelopmental sequelae. Though infants meeting ECMO criteria have a variety of reasons prompting the use of this therapy, most studies to date have simply reported outcome on the entire population that has survived without regard to the original nature of the child's illness. The purpose of this study was to determine the type and extent of health-related problems and neurodevelopmental sequelae in infants requiring ECMO therapy and the association of these findings with the infants' primary diagnosis. METHODS: Eighty-two neonates required ECMO therapy between May 1990 and December 1993. The most common diagnosis prompting ECMO therapy included 26% with meconium aspiration syndrome, 34% with congenital diaphragmatic hernia (CDH), 16% with persistence of the fetal circulation, and 9% with sepsis. Information concerning the hospital course was obtained through chart review, and the infants were seen at 6 and 12 months of age for medical and neurodevelopmental follow-up. Data were analyzed using descriptive statistics and Fisher's exact test, t-tests, and analysis of variance where appropriate. Assessment of hospital course and discharge data focused on the four main diagnostic groups, whereas follow-up data were further limited to the two most frequently encountered groups (meconium aspiration syndrome and CDH). RESULTS: Overall survival was 79%. Significant differences in survival were noted based on primary diagnostic category. Those with CDH fared the worst, with an overall survival rate of 68% and a more complicated hospital course with a longer duration of ECMO. At discharge, the CDH group demonstrated a greater incidence of bronchopulmonary dysplasia, gastroesophageal reflux, feeding dysfunction, and hypotonia. No significant differences were noted in the incidence of intraventricular hemorrhage, cerebral infarction, extra-axial fluid collection, or seizures. Hearing loss was uncommon. During the first year of life, although no differences were noted in growth rate, infants in the CDH group continued to experience a higher incidence of gastroesophageal reflux (43%) and feeding dysfunction, with 36% of this group requiring tube feedings for nourishment. Although 40% of the entire ECMO population was diagnosed with bronchopulmonary dysplasia before initial discharge, by 1 year of age, 50% of those with CDH versus 17% of those with meconium aspiration syndrome continued to be clinically symptomatic. Although the ECMO population as a whole scored in the normal range developmentally, CDH infants had significantly lower motor and slightly lower cognitive scores at 1 year of age. Despite finding abnormal muscle tone in a high percentage of the entire ECMO population at discharge, most demonstrated resolution by 1 year of age. Of the CDH infants, however, 75% continued to evidence some degree of hypotonicity, which affected acquisition and quality of gross motor skills. CONCLUSION: Despite the impact that ECMO has had on the survival of infants with severe respiratory failure, the efficacy of ECMO cannot be assessed accurately without an analysis of the extent and morbidity in the surviving population. Most centers are reporting relatively low morbidity for the entire ECMO population. However, upon separating this population into primary diagnostic categories, we found that the CDH population encountered a greater number of neurodevelopmental, respiratory, and feeding abnormalities during the first year of life. The reasons for these differences are unclear but may be related to the severity of the primary illness itself or the variables associated with prolonged ECMO therapy. Stratifying outcome by primary diagnosis gives the health care provider more information to improve

Neonatal sepsis. Progress in diagnosis and management.

Despite the rarity of proven neonatal bacterial sepsis (1 to 5 cases/1000 live births) systemic bacterial infections during the first month of life remain a major cause of morbidity and mortality. Most neonatal bacterial infections occur during the first week of life (early onset sepsis) and result from the spread of micro-organisms colonising the maternal genital tract into the amniotic cavity. Susceptible infants either inhale or swallow contaminated amniotic fluid and develop generalised sepsis. During the last decade, however, improvements in neonatal intensive care have permitted the survival of a population of very low birthweight infants, who remain hospitalised for many months, and who are at increased risk of developing nosocomial infections. The primary objective of the clinician caring for infants at risk for neonatal infection is to identify all potential cases of bacterial disease quickly and begin antibiotic therapy promptly. It is equally important, however, to determine which of these cases represent true infection, and therefore require a full course of antibiotics, and which do not. This paper reviews the epidemiology of bacterial infections in neonates, and critically evaluates current recommendations for the diagnosis and treatment of neonatal sepsis.

Sepsis screen in neonates with evaluation of plasma fibronectin.

Two hundred twenty neonates with suspected early onset sepsis were prospectively studied to evaluate the ability of a sepsis screen to discriminate infected from noninfected newborn infants. A positive sepsis screen consisted of positive findings in two or more of the following tests: total white blood cell count; immature/total neutrophil ratio; C-reactive protein; micro-erythrocyte sedimentation rate; or plasma fibronectin. For proved sepsis a four-part screen excluding fibronectin yielded a sensitivity of 100%, specificity of 83%, positive predictive value of 27% and negative predictive value of 100%. In contrast the sensitivity of white blood cell count and immature/total neutrophil ratio was only 46%. Adding fibronectin to the four-part screen provided equal sensitivity and negative predictive value but decreased specificity and positive predictive value. While plasma fibronectin may play an important role in the pathogenesis of neonatal sepsis, it is not useful as a marker for infection. The screens did not identify preterm infants with late onset nosocomial sepsis. Although clinical judgment should be the primary factor in the decision to institute antibiotic therapy, a simple four-part sepsis screen provides valuable presumptive information for excluding the diagnosis of early onset neonatal sepsis.

Effect of bacterial flora on staphylococcal colonisation of the newborn.

The umbilical and nasopharyngeal flora of newborn infants was examined on days 3, 14, and 42 of life. An analysis of the bacteriological findings suggests that colonisation by either Staphylococcus aureus or Staph. epidermidis prevents colonisation by the other staphylococcus. Similarly, colonisation by Gram-negative bacteria prevents colonisation by staphylococci. Further, this bacterial interference lasts for as long as 42 days, which suggests the possibility of artificially colonising newborns with nonpathogens to prevent subsequent colonisation and disease by virulent microorganisms.

Hepatic metabolic alterations in rats treated with low-dose endotoxin and aspirin: an animal model of Reye's syndrome.

The administration of a sublethal dose of endotoxin (LPS) followed one hour later by a low dose of aspirin (LPS + ASA) to fasted rats leads to biochemical perturbations similar to Reye's syndrome. In this study hepatic energy metabolism was assessed in freeze-clamped liver samples (12 hours posttreatment) obtained from (250 to 300 g Sprague-Dawley) rats. The administration of aspirin alone to fasted rats did not significantly alter the hepatic levels of adenine nucleotides, total ketones, or acyl-CoA thioesters as compared to controls. In contrast, in both LPS and LPS + ASA samples, there were declines in ATP/ADP ratio (P less than .005), total ketones (P less than .001) and acetyl CoA (P less than .005) compared to their respective controls. A striking alteration in acyl-CoA thioesters was observed in LPS + ASA-treated animals. Unlike control, aspirin, or LPS-treated animals, LPS + ASA-treated animals accumulated relatively large amounts of unusual CoA esters, including propionyl-CoA, (iso)butyryl-CoA, beta-methylcrotonyl-CoA, and isovaleryl-CoA, metabolites of the branch chain amino acid and odd-chain fatty acid oxidation pathways. The acyl-CoA profile is similar to that obtained in patients with Reye's syndrome. Like human patients with Reye's syndrome, these rats showed hyperammonemia, compromised fatty acid oxidation, and accumulation of branched chain amino acid oxidation metabolites. Accumulation of these intermediates with LPS + ASA is a possible mechanism for the potentiation of Reye's syndrome by aspirin. These findings provide biochemical evidence that sublethal doses of LPS + ASA administered to fasted rats produces an animal model of Reye's syndrome.

Amniotic fluid fibronectin concentrations with advancing gestational age.

Fibronectin, a large-molecular-weight glycoprotein present on cell surfaces and in human plasma, promotes cell adhesion and may modulate reticuloendothelial clearance of particulate debris and bacteria. Amniotic fluid is known to contain a heavily glycosylated variety of fibronectin, and cells derived from amniotic fluid synthesize and secrete fibronectin in tissue culture. The purpose of this study was to determine the relationship between the concentration of fibronectin in amniotic fluid and gestational age. Amniotic fluid samples, obtained from 54 women whose pregnancies ranged in gestation from 15-40 weeks, demonstrated a significant decrease in fibronectin levels with increasing duration of pregnancy (r = -0.70). Diminished concentrations of amniotic fluid fibronectin in the latter stages of pregnancy may represent either decreasing synthesis by amniocytes or a dilutional effect from fetal urine.

Use of umbilical cord blood culture for detection of neonatal bacteremia.

Rapid and accurate detection of neonatal bacteremia is an important part of the management of the neonate with suspected sepsis. This study compared the incidence of positive umbilical cord blood cultures (UCBCs) to the incidence of positive peripheral venous blood cultures and determined whether a meticulous UCBC technique prevented contamination of culture specimens. Six UCBCs of the 200 sampled were positive. Three cultures exhibited delayed growth (more than 48 hours) and were not considered clinically significant. In 2 of the 3 remaining positive cultures were organisms considered contaminants; the third culture correlated to the infant's peripheral venous blood culture (alpha-hemolytic streptococcus), showing evidence of bacteremia. From these data the authors conclude that 1) meticulous and fastidious collection of UCBCs prevents contamination of culture specimens, and 2) the UCBC may prove to be a satisfactory alternative to the postnatal peripheral venous blood culture for detection of neonatal bacteremia.