Showing papers in "Pediatric Research in 2004"
TL;DR: The “developmental origins of disease” paradigm is a reflection of the persistence of such mechanisms in humans who now live in very different environments from those within which they evolved and have major implications for addressing the increasing burden of metabolic and cardiovascular disease.
Abstract: Fetal growth is determined by the interaction between the environment and the fetal genome. The fetal environment, in turn, is determined by the maternal environment and by maternal and placental physiology. There is evidence that the interaction between the fetal environment and genome can determine the risk of postnatal disease, as well as the individual's capacity to cope with the postnatal environment. Furthermore, the role of various forms of maternal constraint of fetal growth in determining the persistence of these responses is reviewed. A limited number of biologic processes can contribute to the mechanistic basis of these phenomena. In addition to immediate homeostatic responses, the developing organism may make predictive adaptive responses of no immediate advantage but with long-term consequences. An evolutionary perspective is provided, as well as a review of possible biologic processes. The "developmental origins of disease" paradigm is a reflection of the persistence of such mechanisms in humans who now live in very different environments from those within which they evolved. The developmental origins paradigm and its underlying mechanistic and evolutionary basis have major implications for addressing the increasing burden of metabolic and cardiovascular disease.
508 citations
TL;DR: It is suggested that placental insufficiency with IUGR have specific structural and functional consequences on cerebral cortical brain development and Behavioral assessment at term showed a significantly less mature score in the subsystem of attention-interaction availability in IUU infants.
Abstract: Placental insufficiency with fetal intrauterine growth restriction (IUGR) is an important cause of perinatal mortality and morbidity and is subsequently associated with significant neurodevelopmental impairment in cognitive function, attention capacity, and school performance. The underlying biologic cause for this association is unclear. Twenty-eight preterm infants (gestational age 32.5 +/- 1.9 wk) were studied by early and term magnetic resonance imaging (MRI). An advanced quantitative volumetric three-dimensional MRI technique was used to measure brain tissue volumes in 14 premature infants with placental insufficiency, defined by abnormal antenatal Doppler measurements and mean birth weights <10(th) percentile (1246 +/- 299 g) (IUGR) and in 14 preterm infants matched for gestational age with normal mean birth weights 1843 +/- 246 g (control). Functional outcome was measured at term in all infants by a specialized assessment scale of preterm infant behavior. Premature infants with IUGR had a significant reduction in intracranial volume (mean +/- SD: 253.7 +/- 29.9 versus 300.5 +/- 43.5 mL, p < 0.01) and in cerebral cortical gray matter (mean +/- SD: 77.2 +/- 16.3 versus 106.8 +/- 24.6 mL, p < 0.01) when measured within the first 2 wk of life compared with control premature infants. These findings persisted at term with intracranial volume (mean +/- SD: 429.3 +/- 47.9 versus 475.9 +/- 53.4 mL, p < 0.05) and cerebral cortical gray matter (mean +/- SD: 149.3 +/- 29.2 versus 189 +/- 34.2 mL, p < 0.01). Behavioral assessment at term showed a significantly less mature score in the subsystem of attention-interaction availability in IUGR infants (p < 0.01). Cerebral cortical gray matter volume at term correlated with attention-interaction capacity measured at term (r = 0.45, p < 0.05). These results suggest that placental insufficiency with IUGR have specific structural and functional consequences on cerebral cortical brain development. These findings may provide insight into the structural-functional correlate for the developmental deficits associated with IUGR.
454 citations
TL;DR: It is suspected that high levels of prenatal stress exposure, particularly early in the pregnancy, may negatively affect the brain development of the fetus, reflected in the lower general intellectual and language abilities in the toddlers.
Abstract: Prenatal maternal stress has been shown to impair functioning in nonhuman primate offspring Little is known about the effects of prenatal stress on intellectual and language development in humans because it is difficult to identify sufficiently large samples of pregnant women who have been exposed to an independent stressor We took advantage of a natural disaster (January 1998 ice storm in Quebec, Canada) to determine the effect of the objective severity of pregnant women's stress exposure on general intellectual and language development of their children Bayley Mental Development Index (MDI) scores and parent-reported language abilities of 58 toddlers of mothers who were exposed to varying levels of prenatal stress were obtained at 2 y of age The hierarchical multiple regression analyses indicated that the toddlers' birth weight and age at testing accounted for 120% and 148% of the variance in the Bayley MDI scores and in productive language abilities, respectively More importantly, the level of prenatal stress exposure accounted for an additional 114% and 121% of the variance in the toddlers' Bayley MDI and productive language abilities and uniquely accounted for 173% of the variance of their receptive language abilities The more severe the level of prenatal stress exposure, the poorer the toddlers' abilities The level of prenatal stress exposure accounted for a significant proportion of the variance in the three dependent variables above and beyond that already accounted for by non-ice storm-related factors We suspect that high levels of prenatal stress exposure, particularly early in the pregnancy, may negatively affect the brain development of the fetus, reflected in the lower general intellectual and language abilities in the toddlers
446 citations
TL;DR: In infants ≤28 wks GA, BPD may be initiated by inflammatory mediators in amniotic fluid, but brain injury may involve variations in the systemic inflammatory response.
Abstract: Recent evidence strongly implicates the inflammatory response to intrauterine infection in the pathogenesis of neonatal brain and lung injury. We hypothesized that lung and brain injury in preterm infants occurs during a common developmental window of vulnerability as the result of an inflammatory response in different compartments. To determine whether inflammatory markers in these compartments are associated with bronchopulmonary dysplasia (BPD) or cranial ultrasound (CUS) abnormalities in infants /=17 pg/mL was associated with an abnormal CUS in infants >28 wk GA (OR 3.36, p = 0.023) but not /=6.5 pg/mL and TNF-alpha >/=3 pg/mL were associated with abnormal CUS in infants /=28 wk GA. These data suggest that in infants
238 citations
TL;DR: Infants of diabetic mothers suspected to have BID demonstrated impaired neonatal auditory recognition memory and lower psychomotor developmental scores at 1 y of age than IDMs with BIS, which map onto areas of the developing brain known to be vulnerable to iron deficiency.
Abstract: Infants of diabetic mothers (IDMs) are at risk for perinatal brain iron deficiency that may target the developing hippocampus. The objective of this study was to evaluate hippocampally based recognition memory and infant development in IDMs with suspected brain iron deficiency (BID; cord ferritin ≤34 μg/L) compared with IDMs with sufficient brain iron stores (BIS; cord ferritin >34 μg/L) using event-related potentials (ERPs). ERPs assessed neonatal auditory cortical responses to sounds and auditory recognition memory in response to the mother's voice compared with a stranger's voice. Thirty-two newborn IDMs had cord serum ferritin concentrations and provided neonatal ERP data (n = 23) and/or blinded 1 y developmental assessments (n = 28). Auditory cortical responses to speech and nonspeech sounds were similar in the BID and BIS groups. In the maternal voice recognition paradigm, peak latencies were shorter in the BID group than in the BIS group. Infants in the BIS group displayed a significant negative slow wave for the strangers' voices compared with the mothers' voices, whereas the BID group did not. Higher cord ferritin concentrations were correlated with larger negative slow waves at the right temporal (T4) electrode site. At 1 y of age, motor development was slower in the BID group than in the BIS group. IDMs suspected to have BID demonstrated impaired neonatal auditory recognition memory and lower psychomotor developmental scores at 1 y of age than IDMs with BIS. These impairments map onto areas of the developing brain known to be vulnerable to iron deficiency.
233 citations
TL;DR: A significant temporal relationship was established between early colonization by Clostridium and the later development of NEC and the use of molecular techniques based on the study of bacterial 16S rRNA genes allowed the recognition of C. perfringens species in the first 2 wk of life of three infants who later displayed symptoms of NEC.
Abstract: Necrotizing enterocolitis (NEC) is among the most severe conditions that can affect preterm infants. Although the etiology of NEC remains unknown, initial bacterial colonization could play a pivotal role in the development of NEC. To further explore the putative relationship between pathogen microorganisms and NEC, we conducted a prospective case-control study in 12 preterm infants with a new approach based on molecular techniques. Over an inclusion period of 24 mo, 12 neonates of <34 wk gestational age admitted to the neonatal unit were enrolled. The group included three cases of NEC, and nine control infants without evidence of NEC who were matched for gestational age and birth weight. Stool samples were collected at weekly intervals from all infants. PCR and temporal temperature gradient gel electrophoresis of 16S ribosomal DNA were used to detect the establishment of bacterial communities in the digestive tract. A salient feature of the bacteriological pattern was observed only in the three infants who later developed NEC: A band corresponding to the Clostridium perfringens subgroup could be detected in early samples, before diagnosis. There was no evidence for this specific band in any of the nine controls. To our knowledge, the current report is the first to demonstrate that the use of molecular techniques based on the study of bacterial 16S rRNA genes allowed the recognition of C. perfringens species in the first 2 wk of life of three infants who later displayed symptoms of NEC. A significant temporal relationship was thus established between early colonization by Clostridium and the later development of NEC. Compared with conventional bacteriological culturing methods, the use of this new molecular approach to analyze the gastrointestinal ecosystem should therefore allow a more complete and rapid assessment of intestinal flora. Although the current data do not constitute definitive proof that the identified bacterial species was a causative agent in the development of NEC, they outline the promise of this new technique based on molecular biology, and suggest that large-scale studies on a much wider population at high risk for NEC may be warranted.
218 citations
TL;DR: It is concluded that neonates who carry the 211 and 388 variants in the UGT1A1 and OATP 2 genes, respectively, as well as feed with breast milk are at high risk to develop severe hyperbilirubinemia.
Abstract: The incidence of severe neonatal hyperbilirubinemia is higher in Asians than in whites. A case-control study was designed to investigate the effects of eight known risk factors [breast feeding, ABO incompatibility, premature birth, infection, cephalohematoma, asphyxia, glucose-6-phosphate dehydrogenase (G6PD) deficiency, and variant UDP-glucuronosyltransferase 1A1 (UGT1A1) gene] and a suspicious analog [organic anion transporter 2 (OATP 2) gene] on severe hyperbilirubinemia in Taiwanese neonates. The 72 study subjects and 100 hospital control subjects consisted of neonates with peak serum bilirubin levels > or =342 microM and <256.5 microM, respectively. The PCR-restriction fragment length polymorphism method was applied to detect the UGT1A1, OATP 2, and G6PD genes. The results of multivariate logistic regressions, adjusted for covariates, revealed odds ratios (ORs) of 4.64 [95% confidence interval (CI): 2.25-9.57; p < 0.001], 3.36 (95% CI: 1.54-7.35; p=0.002), and 3.02 (95% CI: 1.30-6.99; p=0.010) for neonates who were fed with breast milk, and carry the variant UGT1A1 gene at nucleotide 211 and the variant OATP 2 gene at nucleotide 388, respectively. The ORs, adjusted for covariates, for the other six risk factors were not statistically significant. The ORs in neonates who had one, two, and three significant risk factors were 8.46 (95% CI: 2.75-34.48; p < 0.001), 22.0 (95% CI: 5.50-88.0; p < 0.001), and 88.0 (95% CI: 12.50-642.50; p < 0.001), respectively. In conclusion, neonates who carry the 211 and 388 variants in the UGT1A1 and OATP 2 genes, respectively, as well as feed with breast milk are at high risk to develop severe hyperbilirubinemia.
218 citations
TL;DR: The unique pediatric aspects of SARS are examined, the epidemiology of the SARS-CoV in regard to future epidemics is reviewed, and the Sars experience is used as a model for future pandemics are used.
Abstract: SARS (severe acute respiratory syndrome) was a new disease in the fall of 2002, which first occurred in Guangdong Province, China and spread to 29 countries with 8422 cases and 916 fatalities (1–3). After an unprecedented global public health effort, the epidemic was controlled within 7 mo of its original occurrence (4). The scientific effort demonstrated unusual international cooperation and was facilitated by electronic communication. Media coverage was incredibly accurate and provided worldwide pictures to augment scientific data. As of March 1, 2004, there were 1695 citations related to SARS in the medical literature. Of interest, however, is that of these citations only 0.1% are related to pediatric experiences. The purpose of this mini-review is to examine the unique pediatric aspects of SARS, to review the epidemiology of the SARS-CoV in regard to future epidemics, and to use the SARS experience as a model for future pandemics.
198 citations
TL;DR: Oligosaccharides and, in particular, acidic oligosac charides may influence lymphocyte maturation in breast-fed newborns and affect the cytokine production and activation of cord blood derived T cells in vitro.
Abstract: Human milk contains large amounts of free oligosaccharides (HMOs). HMOs have been shown to exert antiinflammatory properties, and evidence for their immunomodulatory effects is increasing. The purpose of this study was to evaluate influences of two human breast milk-derived oligosaccharide samples (neutral and acidic oligosaccharides), and of a low-molecular-weight fucoidan on cytokine production and activation of cord blood mononuclear cells. Cord blood mononuclear cells from randomly chosen healthy newborns were co-cultured with the oligosaccharide samples. By means of flow cytometry, intracellular cytokine production (d 20) and surface marker expression of T cells (d 5) were measured. In vitro-induced Ig levels were quantified nephelometrically (total IgG1) and by ELISA (total IgE) in the supernatant of cell cultures. The acidic oligosaccharide fraction increased the percentage of interferon-gamma producing CD3+CD4+ and CD3+CD8+ cells (p < 0.05) and the IL-13 production in CD3+CD8+ cells (p < 0.05). In acidic oligosaccharide cultures, CD25+ expression on CD3+CD4+ cells was significantly elevated (p < 0.05). Low-molecular-weight fucoidan induced IL-4 production in CD3+CD4+ T cells (p < 0.05) and IL-13 production in CD3+CD8+ T cells (p < 0.05), whereas interferon-gamma production remained unaffected in both T-cell populations. Ig production (total IgE and total IgG1) remained unaffected. Human milk-derived oligosaccharides and plant-derived oligosaccharides affect the cytokine production and activation of cord blood derived T cells in vitro. Therefore, oligosaccharides and, in particular, acidic oligosaccharides may influence lymphocyte maturation in breast-fed newborns.
197 citations
TL;DR: In neonatal rats FFCAS induces epithelial apoptosis that serves as an underlying cause for subsequent gross tissue necrosis, and supplementation of formula with 8 boc-aspartyl(OMe)-fluoromethylketone, a pan-caspase inhibitor, significantly reduced the incidences of apoptosis and experimental NEC.
Abstract: The histopathology of necrotizing enterocolitis (NEC) is characterized by destruction of the mucosal layer in initial stages and by transmural necrosis of the intestinal wall in advanced stages of the disease. To test the hypothesis that enhanced epithelial apoptosis is an initial event underlying the gross histologic changes, we analyzed epithelial apoptosis and tissue morphology in an animal model of NEC and evaluated the effect of caspase inhibition on the incidence of experimental NEC in this model. Apoptosis was analyzed with terminal deoxynucleotidyltransferase-mediated dUTP-FITC nick end labeling (TUNEL) staining in intestinal sections and by measuring caspase 3 activity from intestinal lysates of neonatal rats subjected to formula feeding and cold/asphyxia stress (FFCAS) and from mother-fed (MF) controls. Morphologic evaluation was based on hematoxylin and eosin staining of intestinal sections. FFCAS resulted in histologic changes consistent with NEC, which were absent from MF animals. FFCAS was also associated with a significantly increased rate of nuclear DNA fragmentation in the small intestinal epithelium compared with MF. Elevated tissue caspase 3 activity confirmed the presence of apoptosis in samples with increased DNA fragmentation. Analysis of the coincidence of morphologic damage and apoptosis in corresponding tissue sections indicated that apoptosis precedes gross morphologic changes in this model. Furthermore, supplementation of formula with 8 boc-aspartyl(OMe)-fluoromethylketone, a pan-caspase inhibitor, significantly reduced the incidences of apoptosis and experimental NEC. These findings indicate that in neonatal rats FFCAS induces epithelial apoptosis that serves as an underlying cause for subsequent gross tissue necrosis.
189 citations
TL;DR: Preliminary results showed short-term heat inactivation below 72°C was less harmful in reducing the activity of marker enzymes than Holder pasteurization, and CMV-RNA more directly reflects infectious CMV in human milk samples.
Abstract: Breast-feeding mothers frequently transmit cytomegalovirus (CMV) to preterm infants of very low birth weight. Current recommendations for prevention of virus transmission are based on data published 20 y ago in the context of human milk banking. Two recent clinical trials examined storage of breast milk at -20 degrees Celsius to reduce virus transmission. However, in both studies, CMV transmission occurred. Using sensitive tools like quantitative PCR, CMV pp67 late mRNA assay, and a high-speed, centrifugation-based microculture assay for quantification of CMV infectivity, we reassessed the virological and biochemical characteristics of freeze-storing breast milk at -20 degrees Celsius, compared it with traditional Holder pasteurization (30 min at 62.5 degrees Celsius), and a new short-term pasteurization (5 s at 72 degrees Celsius) based on the generation of a milk film. Both heat treatment procedures were able to destroy viral infectivity and pp67 RNA completely. Preliminary results showed short-term heat inactivation below 72 degrees Celsius was less harmful in reducing the activity of marker enzymes than Holder pasteurization. Freezing breast milk preserved the biochemical and immunologic quality of the milk; however, late viral RNA and viral infectivity was also preserved. Compared with viral DNA, CMV-RNA more directly reflects infectious CMV in human milk samples. Further studies are necessary to evaluate short-term heat treatment below 72 degrees Celsius as an effective tool for prevention of CMV transmission.
TL;DR: The absence of similar inflammation in other pediatric cholestatic conditions suggests that the portal tract inflammation in biliary atresia is not a secondary response to cholESTasis but rather indicates a specific immune response involved in the pathogenesis of biliaryAtresia.
Abstract: A proposed mechanism in the pathogenesis of biliary atresia involves an initial virus-induced, progressive T cell–mediated inflammatory obliteration of bile ducts. The aim of this study was to characterize the inflammatory environment present within the liver of infants with biliary atresia to gain insight into the role of a primary immune-mediated process versus a nonspecific secondary response to biliary obstruction. Frozen liver tissue obtained from patients with biliary atresia, neonatal giant cell hepatitis, total parenteral nutrition (TPN)–related cholestasis, choledochal cysts, and normal control subjects was used for fluorescent immunohistochemistry studies of cellular infiltrates, cytokine mRNA expression, and in situ hybridization for localization of cytokine-producing cells. Immunohistochemistry revealed increases in CD8+ and CD4+ T cells and Kupffer cells (CD68+) in the portal tracts of biliary atresia. Reverse transcription–PCR analysis of biliary atresia tissue showed a Th1-type cytokine profile with expression of IL-2, interferon-γ, tumor necrosis factor-α, and IL-12. This profile was not seen in normal, neonatal hepatitis or choledochal cyst livers but was present in TPN-related cholestasis. In situ hybridization revealed that the Th1 cytokine–producing cells were located in the portal tracts in biliary atresia and in the parenchyma of TPN-related cholestasis. A distinctive portal tract inflammatory environment is present in biliary atresia, involving CD4+ Th1 cell–mediated immunity. The absence of similar inflammation in other pediatric cholestatic conditions suggests that the portal tract inflammation in biliary atresia is not a secondary response to cholestasis but rather indicates a specific immune response involved in the pathogenesis of biliary atresia.
TL;DR: It is indicated that the course of aEEG patterns adds to the prognostic value of a EEG monitoring in asphyxiated infants, and spontaneous recovery of severely abnormal aEEGs is not uncommon.
Abstract: Amplitude-integrated EEG (aEEG) is used to select patients for neuroprotective therapy after perinatal asphyxia because of its prognostic accuracy within several hours after birth. We aimed to determine the natural course of aEEG patterns during the first 72 h of life, in relation to neurologic outcome, in a group of severely asphyxiated term infants. Thirty infants, admitted to our neonatal intensive care unit from October 1998 until February 2001, were studied retrospectively. The aEEG traces obtained during the first 72 h after birth were assessed by pattern recognition: continuous normal voltage (CNV), discontinuous normal voltage (DNV), burst suppression (BS), continuous low voltage, and flat trace. Epileptic activity was also determined. The course of aEEG patterns was examined in relation to neurologic findings at 24 mo. Initially, 17 of 30 infants had severely abnormal aEEG patterns (BS or worse), which changed spontaneously to normal voltage patterns (CNV, DNV) in 7 within 48 h. The sooner the abnormalities on aEEG disappeared, the better the prognosis. The likelihood ratio of BS or worse for adverse outcome was 2.7 (95% confidence interval 1.4-5.0) between 0 and 6 h and increased to a highest value of 19 (95% confidence interval 2.8-128) between 24 and 36 h; after 48 h, it was not significant. Normal voltage patterns (CNV and DNV) up to 48 h of life were predictive for normal neurologic outcomes (negative likelihood ratios <0.3). Our findings indicate that the course of aEEG patterns adds to the prognostic value of aEEG monitoring in asphyxiated infants. Spontaneous recovery of severely abnormal aEEG patterns is not uncommon.
TL;DR: In this article, the diagnostic utilities of neutrophil CD64 expression for the identification of early-onset clinical infection and pneumonia in term infants and to define the optimal cutoff value so that it may act as a reference with which future studies can be compared.
Abstract: This prospective study aimed to evaluate the diagnostic utilities of neutrophil CD64 expression for the identification of early-onset clinical infection and pneumonia in term infants and to define the optimal cutoff value so that it may act as a reference with which future studies can be compared. Term newborns in whom infection was suspected when they were <72 h of age were recruited into the study. C-reactive protein (CRP) and expression of CD64 on neutrophils were measured at 0 h (at the time of sepsis evaluation) and 24 h. The sensitivity, specificity, positive predictive value, and negative predictive value (NPV) of CRP, CD64, and the combination of these two markers for predicting neonatal sepsis were determined. A total of 338 infants with suspected clinical sepsis were investigated, 115 of whom were found to be clinically infected. CRP and CD64 in infected infants were both significantly elevated at 0 and 24 h compared with noninfected infants (p < 0.001). The calculated optimal cutoff value for CD64 was 6136 antibody-phycoerythrin molecules bound/cell. CD64 has a very high sensitivity (96%) and NPV (97%) at 24 h. The addition of CRP only marginally enhanced the sensitivity and NPV (97 and 98%, respectively). In conclusion, neutrophil CD64 is a very sensitive diagnostic marker for the identification of early-onset clinical infection and pneumonia in term newborns. The results strongly suggest that measurement of neutrophil CD64 may allow neonatal clinicians to discontinue antibiotic treatment at 24 h in infants who are clinically stable and whose CD64 expressions are below the optimal cutoff level.
TL;DR: Higher IQs in children who were born preterm are related to poorer development of the caudate relative to the rest of the brain, independent of other lesions, and abnormal brain development after perinatal injury or postnatal nutritional deficits is responsible for cognitive deficits in preterm children.
Abstract: Children who survive very preterm birth without major disability have a high prevalence of learning difficulty, attention deficit, and minor motor impairment (MMI). To determine whether these difficulties are associated with structural brain abnormalities, we studied 105 preterm children (<32 wk) at 7 y with tests of IQ and MMI (Movement ABC) and detailed magnetic resonance brain scans. Scans were assessed qualitatively for visible cerebral lesions. Volume measurements of the caudate nuclei and hippocampal formations were made. Total brain volume (TBV) was estimated from the head circumference. Qualitative assessment of the scans showed evidence of cerebral lesions in 20 (19%), which were associated with lower IQ and more frequent MMI. IQ correlated with right and left caudate volume (Spearman's rho 0.304 and 0.349; p < 0.01). This association persisted (except for verbal IQ) when caudate volume was expressed as a percentage of estimated TBV to allow for overall brain size. No significant correlations with hippocampal volumes were observed. These differences persisted when only scans from children without visible lesions on scan were considered. MMI was significantly associated only with TBV and was more common in children with evidence of thinning of the posterior corpus callosum, although most children with MMI have a normal corpus callosum. Lower IQs in children who were born preterm are related to poorer development of the caudate relative to the rest of the brain, independent of other lesions. These findings suggest abnormal brain development after perinatal injury or postnatal nutritional deficits is responsible for cognitive deficits in preterm children.
TL;DR: Elevated inflammatory cytokines were associated with impaired cerebral oxidative metabolism, but not with detectable MRI changes in the neonatal period, and understanding the link between elevated cytokines and outcome would inform novel strategies of cerebral protection.
Abstract: In term neonatal encephalopathy, little is known about the relationship between early inflammatory markers, neonatal brain injury, and long-term neurodevelopmental outcome. Our goal was to determine whether neonatal serum cytokine levels are associated with cerebral metabolism assessed by proton magnetic resonance spectroscopy (MRS), with magnetic resonance imaging (MRI) abnormalities, and with neurodevelopmental outcome at 30 mo of age. Levels of seven cytokines [IL-1 beta, IL-6, IL-8, IL-9, IL-12, IL-13, and tumor necrosis factor (TNF)-alpha] were measured in dried neonatal blood by immunoaffinity chromatography in a prospective cohort of 62 term newborns at risk of neonatal encephalopathy. MR images (n = 61) were scored and lactate/choline and N-acetyl-aspartate (NAA)/choline were measured by MRS (n = 42) on median day of life 6 in the deep gray nuclei (DGN) and in the watershed/cortical zone (WS). Neurodevelopmental outcome (n = 54) was considered abnormal if the infant died or if cognitive delay and/or functional motor deficit were detected at 30 mo. IL-1 beta, IL-6, IL-8 and TNF-alpha were significantly associated with lactate/choline in the DGN (p = 0.03, 0.02, 0.03, and 0.01 respectively), but not in the WS (all p > 0.1). Cytokines were not associated with NAA/choline in any region or with MRI scores. Children with abnormal neurodevelopmental outcome had higher neonatal levels of IL-1 beta, IL-6, IL-8, and lower levels of IL-12 (p = 0.04, 0.03, 0.01, 0.03 respectively). Elevated inflammatory cytokines were associated with impaired cerebral oxidative metabolism, but not with detectable MRI changes in the neonatal period. Understanding the link between elevated cytokines and outcome would inform novel strategies of cerebral protection.
TL;DR: HBP was superior to CBP in predicting ABPM, but neither CBP nor HBP detected hypertension with enough sensitivity or specificity to replace ABPM.
Abstract: Ambulatory blood pressure monitoring (ABPM) provides superior information for diagnosis and treatment of pediatric hypertension, but for reasons of practicality, clinic blood pressure measurements (CBP) are still the primary diagnostic tool. Regular home blood pressure measurements (HBP) may be an alternative to ABPM, but this technique awaits validation in practice. We analyzed the concordance of ABPM, CBP and HBP in 118 pediatric patients (3-19 y) with chronic renal failure. HBP readings (10.5 +/- 5.4 per patient) were averaged for one week around the day of ABPM and CBP. Mean arterial pressure (MAP) measured by HBP (84.0 +/- 10 mm Hg) was significantly lower than both CBP (86.1 +/- 14.1 mm Hg, P< 0.05) and daytime ABPM (90.3 +/- 10.4 mm Hg, P< 0.05). HBP detected hypertensive patients with greater specificity (82 versus 70%), but lower sensitivity (52 versus 70%) than CBP. The fraction of patients rated erroneously hypertensive was 23% with CBP, but only 14% with HBP. The 95% limits of agreement with ABPM were narrower for HBP (-23 to10 mm Hg) than for CBP (-30 to 21 mm Hg). CBP, but not HBP measurements, were less precise in the upper BP range. The accuracy of HBP measurements did not change with use over a six months time period. In conclusion, HBP was superior to CBP in predicting ABPM, but neither CBP nor HBP detected hypertension with enough sensitivity or specificity to replace ABPM. The greater specificity of HBP compared with CBP makes it a more suitable tool for diagnosis, rather than screening, of hypertension in children.
TL;DR: The morphology of blood vessels in the GM, gray matter, and white matter was determined and maturational changes in the morphology of these vessels as a function of gestational age were examined to help understand the pathogenesis of GM hemorrhage and also of periventricular leukomalacia.
Abstract: The germinal matrix (GM) located in the thick subependymal cell layer of the thalamostriate groove is a major site of cerebral hemorrhage in premature infants. Comparing the morphology of vasculature among GM, gray and white matter of the brain may help in understanding the pathogenesis of GM hemorrhage and also of periventricular leukomalacia. The objective of the present study was to determine the morphology of blood vessels in the GM, gray matter, and white matter and to examine maturational changes in the morphology of these vessels as a function of gestational age. We measured vessel density, percentage of blood vessel area, mean surface area, length, breadth, perimeter, radius, and shape of blood vessels in coronal sections of the GM, gray matter, and white matter in postmortem human brain samples for 17 fetuses and premature infants of gestational age 16-40 wk and 2 adults. We performed immunohistochemical staining using anti-laminin primary antibody, confocal microscopy to acquire images, and analysis using Metamorph version 6.1. Vessel density and the percentage of blood vessel area increased as a function of gestational age in the GM, gray matter, and white matter (p < 0.001 each). The blood vessel density and the percentage of blood vessel area were largest in the GM followed by gray matter and then white matter in all of the gestational age categories (p < 0.001 for all comparisons). Increased vascularity of the GM compared with gray and white matter may play a role in GM hemorrhage, whereas a relatively low vascularity of white matter may increase the propensity for the occurrence of periventricular leukomalacia in premature infants
TL;DR: The molecular definition of these rare primary immune deficiency disorders has shed light on the complex events leading to the production of high-affinity, antigen-specific antibodies of different isotypes.
Abstract: The hyper IgM syndromes (HIGM) are a group of primary immune deficiency disorders characterized by defective CD40 signaling by B cells affecting class switch recombination and somatic hypermutation. As a consequence, patients with HIGM have decreased concentrations of serum IgG and IgA and normal or elevated IgM, leading to increased susceptibility to infections. The most common HIGM syndrome is X-linked and due to mutations of CD40 ligand (CD40L) expressed by activated CD4(+) T lymphocytes. Four other genes, expressed by B cells, have been associated with the HIGM phenotype. Mutations of CD40, the receptor for CD40L, cause a rare autosomal form of HIGM with a clinical phenotype similar to CD40L deficiency. Mutations of Activation-Induced Cytidine Deaminase (AICDA) and Uracil (DNA) Glycosylase (UNG), both expressed by follicular B lymphocytes, lead to defective class switch recombination and somatic hypermutation. Mutations of Nuclear Factor kappa B Essential Modulator (NEMO), an X-chromosome associated gene, result in hypohidrotic ectodermal dysplasia and immune deficiency. Thus, the molecular definition of these rare primary immune deficiency disorders has shed light on the complex events leading to the production of high-affinity, antigen-specific antibodies of different isotypes.
TL;DR: The data suggest that the human infant is under oxidative stress early in infancy and further study may be warranted to assess the potential benefits of antioxidant supplementation for either the mother or the infant.
Abstract: We hypothesized that early infancy would be a time of oxidative stress due to the difficulty of adapting to ambient oxygen. Therefore, we measured levels of products of lipid peroxidation (F2-isoprostanes), antioxidant enzyme activity (catalase (CAT) and superoxide dismutase (SOD)), and ability to resist oxidative stress (ferric reducing ability of plasma (FRAP)) in full-term infants (38-42 wk) fed human milk from birth. Seventy-seven infants were followed at 1, 3.5, 6, and 12 mo of age. F2-isoprostanes in plasma declined significantly (p < 0.05) from 1 to 6 mo (160 +/- 43; 90 +/- 33; 41 +/- 27 pg/mL (mean +/- SD)). FRAP values (775 +/- 196, 723 +/- 133, 697 +/- 126, 669 +/- 145 microM) 1, 3.5, 6, and 12, respectively) declined (p = 0.06) from 1 to 3.5 mo and from 3.5 to 6 mo of age. RBC-SOD (2.7 +/- 2, 3.2 +/- 2.8, 2.1 +/- 1.8, 2.5 +/- 1.8 U, 1, 3.5, 6, 12 mo, respectively) declined from 3.5 to 6 mo. RBC-CAT (76 +/- 23, 94 +/- 28, 81 +/- 22, 85 +/- 31 U, 1, 3.5, 6, 12 mo, respectively) also declined between 3.5 and 6 mo, after a significant increase between 1 and 3.5 mo. These data suggest that the human infant is under oxidative stress early in infancy and further study may be warranted to assess the potential benefits of antioxidant supplementation for either the mother or the infant.
TL;DR: The present results indicate that antipoliovirus response can be triggered with a fermented formula that is able to favor intestinal bifidobacteria.
Abstract: To determine whether the size of the intestinal bifidobacterial population can influence the immune response to poliovirus vaccination in infants, we set up a randomized, placebo-controlled trial. From birth to 4 mo, infants were given a fermented infant formula (FIF) or a standard formula (placebo). Bifidobacteria were quantified monthly in infant stools. Antipoliovirus IgA response to Pentacoq® was assessed before and 1 mo after the second vaccine injection. Thirty infants were randomized, and 20 completed the study (nine in the placebo group and 11 in the FIF group). Fecal bifidobacterial level was significantly higher with the FIF group at 4 mo of age (p = 0.0498). Furthermore, B. longum/B. infantis carriage was higher at 4 mo in the FIF group (p = 0.0399). Antipoliovirus IgA titers increased after Pentacoq® challenge (p < 0.001), and the rise was significantly higher in the FIF group (p < 0.02). Antibody titers correlated with bifidobacteria, especially with B. longum/B. infantis and B. breve levels (p < 0.002). Infants who harbored B. longum/B. infantis also exhibited higher levels of antipoliovirus IgAs (p < 0.002). In conclusion, the present results indicate that antipoliovirus response can be triggered with a fermented formula that is able to favor intestinal bifidobacteria. Whether this effect on the immune system is achieved through the bifidogenic effect of the formula (mainly through B. longum/B. infantis and B. breve stimulation) or directly linked to compounds (i.e. peptides) produced by milk fermentation remains to be investigated.
TL;DR: Applying PEEP during resuscitation of very premature infants might be advantageous and merits further investigation.
Abstract: Positive end expiratory pressure (PEEP) is important for neonatal ventilation but is not considered in guidelines for resuscitation. Our aim was to investigate the effects of PEEP on cardiorespiratory parameters during resuscitation of very premature lambs delivered by hysterotomy at approximately 125 d gestation (term approximately 147 d). Before delivery, they were intubated and lung fluid was drained. Immediately after delivery, they were ventilated with a Drager Babylog plus ventilator in volume guarantee mode with a tidal volume of 5 mL/kg. Lambs were randomized to receive 0, 4, 8, or 12 cm H(2)O of PEEP. They were ventilated for a 15-min resuscitation period followed by 2 h of stabilization at the same PEEP. Tidal volume, peak inspiratory pressure, PEEP, arterial pressure, oxygen saturation, and blood gases were measured regularly, and respiratory system compliance and alveolar/arterial oxygen differences were calculated. Lambs that received 12 cm H(2)O of PEEP died from pneumothoraces; all others survived without pneumothoraces. Oxygenation was significantly improved by 8 and 12 cm H(2)O of PEEP compared with 0 and 4 cm H(2)O of PEEP. Lambs with 0 PEEP did not oxygenate adequately. The compliance of the respiratory system was significantly higher at 4 and 8 cm H(2)O of PEEP than at 0 PEEP. There were no significant differences in partial pressure of carbon dioxide in arterial blood between groups. Arterial pressure was highest with 8 cm H(2)O of PEEP, and there was no cardiorespiratory compromise at any level of PEEP. Applying PEEP during resuscitation of very premature infants might be advantageous and merits further investigation.
TL;DR: The increased sepsis rate of homozygous IL6-174G carriers was especially related to an increase in Gram-positive infections, and was not observed in VLBW infants who received prophylaxis with teicoplanin.
Abstract: Mutations of genes involved in the innate immune system have been reported to be associated with an increased sepsis rate in adults. We determined the -159T mutation of the CD14 gene, the 896G mutation of the toll-like receptor 4 gene, the 3020insC mutation of the NOD2 gene (NOD2-3020insC), the IL-6 174G/C promoter polymorphism (IL6-174G/C), and the mannose-binding lectin genotype and their association to the subsequent development of neonatal sepsis in a large cohort of very low birth weight (VLBW) infants. Fifty (14%) of 356 VLBW infants developed blood culture-proven sepsis during their stay in the hospital. VLBW infants carrying the NOD2-3020insC allele (n =15) and the IL6-174G allele (n =121) had a significantly higher rate of blood culture-proven sepsis (33% and 19.8%, respectively) than VLBW infants without these genotypes (p = 0.046 and 0.035, respectively). In a multivariate logistic regression analysis, gestational age less than 28 wk (odds ratio, 3.2; 95% confidence interval, 1.7-6.0; p < 0.001) and the homozygous IL6-174G allele (odds ratio, 1.9; 95% confidence interval, 1.0-3.9; p = 0.039) were predictive for the development of sepsis, whereas the NOD2-3020insC allele was only of borderline significance (odds ratio, 3.2; 95% confidence interval, 1.0-10.4; p = 0.052). VLBW infants with repeated episodes of sepsis had higher frequencies of the NOD2-3020insC and IL6-174G allele. The increased sepsis rate of homozygous IL6-174G carriers was especially related to an increase in Gram-positive infections, and was not observed in VLBW infants who received prophylaxis with teicoplanin (frequency of Gram-positive sepsis in homozygous IL6-174G carriers without prophylaxis 16.5% versus 2.4% in homozygous IL6-174G carriers with prophylaxis; p = 0.033).
TL;DR: The data show increased MMP-2 activity at both gene and protein levels, accompanied with cerebral leakage of glycerol, presumably triggered by augmented oxidative stress, in newborn piglets that underwent global hypoxia and subsequent resuscitation with 21 or 100% O2.
Abstract: Perinatal asphyxia is a major cause of immediate and postponed brain injury in the newborn. We hypothesized that resuscitation with 100% O2 compared with ambient air is detrimental to the cerebral tissue. We assessed cerebral injury in newborn piglets that underwent global hypoxia and subsequent resuscitation with 21 or 100% O2 by extracellular glycerol, matrix metalloproteinase (MMP) expression levels, and oxidative stress. Extracellular glycerol was sampled by cerebral microdialysis. MMP levels were analyzed in cerebral tissue by gelatin zymography, broad matrix degrading capacity, and real-time PCR. Total endogenous antioxidant capacity was measured by the oxygen radical absorbance capacity assay. Extracellular glycerol increased 50% after resuscitation with 100% O2 compared with 21% O2. Total MMP activity was doubled in resuscitated animals at endpoint compared with baseline (p=0.018), and the MMP-2 activity was significantly increased in piglets that were resuscitated with 21% O(2) (p=0.003) and 100% O2 (p=0.001) compared with baseline. MMP-2 mRNA level was 100% increased in piglets that were resuscitated with 100% O2 as compared with 21% O2 (p < 0.05). Oxygen radical absorbance capacity values in piglets that were resuscitated with 100% O2 were considerably reduced compared with both baseline (p=0.001) and piglets that were resuscitated with 21% O2 (p=0.001). In conclusion, our data show increased MMP-2 activity at both gene and protein levels, accompanied with cerebral leakage of glycerol, presumably triggered by augmented oxidative stress. Our findings suggest that resuscitation of asphyxiated piglets with 100% O2 is detrimental to the piglet brain compared with resuscitation with 21% O2.
TL;DR: It is suggested that VEGF and its receptor, KDR, genes contributed to the development of CAL in KD patients, with the highest odds ratio among several clinical parameters.
Abstract: We analyzed the genetic polymorphisms of vascular endothelial growth factor (VEGF) and its receptors [Fms-related tyrosine kinase-1, kinase insert domain receptor (KDR)] in Japanese patients with Kawasaki disease (KD) and normal control subjects to examine whether these genes would contribute to the KD occurrence and/or the development of coronary artery lesion (CAL) in KD. We found that the frequency of G allele of VEGF g.-634 G>C single-nucleotide polymorphism in the promoter region was significantly higher in KD patients with CAL than in those without CAL (p = 0.012) or control subjects (p = 0.021) because of a significantly higher frequency of the GG genotype in KD patients with CAL. In addition, the frequency of the A1 allele with 11 AC repeats of KDR g.+4422(AC)11-14 dinucleotide repeat polymorphism in intron 2 was significantly higher in KD patients with CAL than in those without CAL (p = 0.013) or control subjects (p = 0.040) as a result of a significantly higher frequency of the A1A1 genotype in KD with CAL patients. The multivariate analysis of clinical features and genotypes of the two polymorphisms showed that the A1A1 genotype of KDR g.+4422(AC)11-14 polymorphism was an independent risk factor for the development of CAL with the highest odds ratio among several clinical parameters (odds ratio 6.76; 95% confidence interval 1.05-43.48). Dual luciferase assay demonstrated that the A1 allele with KDR g.+4422(AC)11 repeats showed a weaker silencer function than the A2 allele with 12 AC repeats. These findings suggested that VEGF and its receptor, KDR, genes contributed to the development of CAL in KD patients.
TL;DR: Subcutaneous and intra-abdominal adipose tissue compartments may be under different regulatory control during intrauterine life in infants born at or near term.
Abstract: Regional differences in adipose tissue distribution are associated with differences in adipocyte metabolism and obesity-related morbidities. Intrauterine growth restriction appears to place individuals at greater risk of obesity associated morbidities in later life. Despite this, little is known regarding the quantity and distribution of adipose tissue in infants during early development. The aim of this study was to compare total and regional adipose tissue content in appropriate-for-gestational-age (AGA) and growth-restricted (GR) newborn infants born at or near term. Whole body adipose tissue magnetic resonance imaging (MRI) was performed as soon as possible after birth. Total and regional adipose tissue depots were quantified. A total of 35 infants (10 GR; 25 AGA) were studied. Mean (SD) total percentage adipose tissue was lower in GR infants than AGA infants [GR: 17.70% (2.17); AGA: 23.40% (3.85); p = 0.003]. This difference arose from differences in subcutaneous adipose tissue mass [mean (SD) percentage subcutaneous adipose tissue mass, GR: 16.13% (2.20); AGA: 21.44% (3.81); p = 0.004], but not intra-abdominal adipose tissue mass [mean (SD) percentage intra-abdominal adipose tissue, GR: 0.42% (0.22); AGA: 0.61% (0.31); p = 0.45]. In contrast to subcutaneous adipose tissue, intra-abdominal adipose tissue is not reduced in infants with intrauterine growth restriction. This suggests that subcutaneous and intra-abdominal adipose tissue compartments may be under different regulatory control during intrauterine life.
TL;DR: This history reviews developments in the field through the centuries and is writen so that it does not overlap the contribution to this series by Baker and Katz entitled ‘Childhood Vaccine Development in the United States.
Abstract: The history of Pediatric Infectious Diseases closely parallels the history of Pediatrics at least until the last century, because historically infections comprised the major causes of childhood morbidity and mortality, as they still do in the developing world. This history reviews developments in the field through the centuries and is written so that it does not overlap the contribution to this series by Baker and Katz entitled 'Childhood Vaccine Development in the United States.' Remarkable descriptions of selected pediatric infections existed long before the invention of printing, and early pediatric texts included many chapters devoted to various infections. Coincident with the establishment of pediatric organizations in America in the late 19th and early 20th Centuries, major attention was focused on diphtheria, infant diarrheal illnesses, tuberculosis, streptococcal infections and their complications, and other pediatric infections, and substantial progress was made. The American Pediatric Society (1888), the American Academy of Pediatrics (1930), the Society for Pediatric Research (1931), and the American Board of Pediatrics (1933) all contributed to the evolution of the discipline of Pediatric Infectious Disease, and numerous leaders of these organizations had significant infectious diseases interests. The establishment of the Pediatric Infectious Diseases Society, the Pediatric Infectious Diseases sub-board, and an accreditation process for training programs, as well as sub-specialty textbooks and journal, further validated the development of this specialty, particularly in North America. The many remaining challenges related to infectious diseases in children (including HIV, emerging infections, antimicrobial resistance, opportunistic infections, and infections in the developing world) insure the future of the specialty. The genomic era of medicine and the tools of molecular biology will lead to new insights into pathogenesis, diagnosis, and treatment of infections. Pediatric Infectious Diseases physicians can celebrate the past triumphs of the discipline and future achievements, all contributing to improved health for children.
TL;DR: Observations show that an intrauterine inflammatory stimulus can cause large increases in Th1 cytokines within the fetal brain, and the placenta can produce selected cytokines but fails to produce IFN-γ, suggesting that the fetal immune system produces this cytokine in response to the authors' stimulus.
Abstract: Intrauterine infection is a risk factor for developmental brain injuries in childhood. A variety of cytokines known to be toxic to developing brain cells have been isolated from mothers or children at risk for developmental disabilities, and these cytokines have been proposed as mediators of these injuries. We have developed a model of intrauterine inflammation that damages the developing white matter and we now hypothesize that selected cytokines are increased after our experimental inflammatory stimulus. Timed-pregnant Fischer 344 and Lewis rats were injected with 0.1 mg/kg of lipopolysaccharide (LPS) into the cervix at E15. Tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), IL-6, and IL-10 were measured in homogenates of fetal brain and placenta at serial time periods within the first 24 h after the inflammatory stimulus. TNF-alpha was increased 20-fold in the placenta and more than 5-fold in the fetal brain after the stimulus. IFN-gamma was only increased within the fetal brain (20-fold) and IL-6 was only increased in the placenta (10-fold). IL-10 was mildly increased in the placenta and was decreased slightly in the fetal brain. Our observations show that an intrauterine inflammatory stimulus can cause large increases in Th1 cytokines within the fetal brain. The placenta can produce selected cytokines but fails to produce IFN-gamma, suggesting that the fetal immune system produces this cytokine in response to our stimulus. By studying placental and brain cytokine responses in models such as ours, the mechanisms responsible for the damage to developing white matter can be determined.
TL;DR: Despite reducing the number of spontaneous seizures after SE, the ketogenic diet resulted in severe impairment in visual-spatial memory and decreased brain growth, with no effect on mossy fiber sprouting.
Abstract: The ketogenic diet (KD) is a high-fat, low-carbohydrate, and low-protein diet that is widely used to treat epilepsy in children. Although the KD has been shown to be efficacious in the treatment of childhood epilepsy, the long-term effects of the KD on brain development are not clear. The objective of this study was to examine the long-term effects of the KD on visual-spatial memory, activity level, and emotionality in immature rats after status epilepticus (SE). Weanling rats were subjected to lithium/pilocarpine-induced SE or saline injections and were then randomized to either the KD or regular rat diet, both fed ad libitum. One month later, rats were evaluated for visual-spatial memory in the water maze, activity level in the open field test, and emotionality with the handling test. Spontaneous recurrent seizures were measured using videotaping, and seizure susceptibility was tested with flurothyl inhalation. Brains were weighed and examined for mossy fiber sprouting and cell loss. Although rats treated with the KD were active and seemed healthy, their weight gain was substantially lower than that in rats that received regular rat diet. The KD reduced the number of spontaneous seizures but had no discernible effect on flurothyl seizure susceptibility. KD-fed rats, with or without SE, had significantly impaired visual-spatial learning and memory compared with rats that were fed regular diet. The KD had minimal effects on activity level and emotionality. Rats that were treated with the KD had significantly impaired brain growth. No differences in pathology scores between the KD and regular diet groups were seen after SE. Despite reducing the number of spontaneous seizures after SE, the KD resulted in severe impairment in visual-spatial memory and decreased brain growth, with no effect on mossy fiber sprouting. This study raises concerns about the long-term effects of the KD on brain development.
TL;DR: The broad difference positivity at 1 y of age may indicate atypical cortical auditory processing and an increased risk for cognitive dysfunction, and whether cognitive dysfunction can be predicted by these findings needs to be assessed in a study with extended follow-up.
Abstract: We assessed auditory event-related potentials in small-for-gestational-age (SGA; 850 ± 258 g, 28.9 ± 3.3 gestational wk; n = 15) and appropriate for gestational age (AGA; 1014 ± 231 g, 26.9 ± 1.9 gestational wk; n = 20) preterm infants and healthy term infants (n = 22). An oddball paradigm was used with a harmonic tone of 500-Hz frequency as the standard and of 750-Hz frequency as the deviant stimulus. The preterm infants were studied at 40 gestational wk and at 6 and 12 mo of corrected age, and the control subjects were studied at 2–4 d and at 3, 6, 9, 12, and 15 mo of age. The peaks of interest were the main positive peak (P350), the negative peaks at 250 ms (N250) and 650 ms (Nc), and the mismatch negativity at 200 ms (MMN). At term, the P350 in the preterm infants was similar to that of the newborn control subjects. In response to the deviant, the Nc was smaller in the SGA than in the AGA (P < 0.02) and control (P < 0.005) infants. The N250 amplitude was also lower in the SGA infants. At 12 mo, the MMN was observed in the control but not in the preterm infants, whose broad difference positivity correlated with the Bayley developmental index. The decreased Nc and N250 peaks in the SGA infants may suggest an increased risk for cognitive dysfunction. The broad difference positivity at 1 y of age may indicate atypical cortical auditory processing. Whether cognitive dysfunction can be predicted by these findings needs to be assessed in a study with extended follow-up.