Neonatal Infants Research Articles

Abstract 3802: Genetic basis of myeloid leukemogenesis in Down syndrome.

Abstract BACKGROUND Transient abnormal myelopoiesis (TAM) is known as a clonal myeloid proliferation affecting ∼10% of neonatal infants with Down syndrome (DS). Although spontaneous regression is as a rule in most cases, about 20-30% of the survived infants develop non-self-limited acute megakaryoblastic leukemia (AMKL) years after the remission. As for the molecular pathogenesis of TAM and DS-AMKL, it has been well established that GATA1 mutations are detected in virtually all TAM cases as well as DS-AMKL. However, it is still open to question whether a GATA1 mutation and trisomy 21 are sufficient for the development of TAM, what is the cellular origin of the subsequent AMKL and whether additional gene mutations are required for the progression to AMKL. METHODS To answer these questions, we performed a comprehensive analysis of somatic mutations in TAM/AMKL cases using whole genome sequencing of three trio samples sequentially obtained at the initial presentation of TAM, during remission and at the subsequent relapse phase of AMKL. Whole exome sequencing was also performed for TAM (N=15) and DS-AMKL (N=14) samples. The recurrent mutations in the discovery cohort were further screened in an extended cohort of TAM (N = 41) as well as DS-AMKL (N = 49) and other AMKL cases (N = 19). RESULTS TAM samples had significantly fewer numbers of somatic mutations compared to AMKL samples with the mean numbers of non-silent somatic mutations of 1.7 and 5.7 per sample in whole exome sequencing in TAM and AMKL cases, respectively (p=0.001). Whole genome sequencing and subsequent deep sequencing of the individual mutations revealed more complicated pictures of clonal evolutions leading to AMKL. Founding clones in TAM evolved into AMKL in two cases and, on the other hand, the direct ancestor of the AMKL clone in a remaining case could be back-traced to a more upstream branch-point of the evolution before the major TAM clone had appeared. While GATA1 was the only recurrent mutational target in the TAM phase, 8 genes were recurrently mutated in AMKL samples in whole exome sequencing, including NRAS, TP53 and other novel gene targets. The recurrent mutations found in the discovery cohort, in addition to known mutational targets in myeloid malignancies, were screened in an extended cohort of DS-associated myeloid disorders (N=90) as well as other AMKL cases, using high-throughput sequencing of hybrid-selection and/or PCR amplified targets. Secondary mutations other than GATA1 mutations were found in 6 out of 41 TAM, 38 out of 49 DS-AMKL and 10 out of 19 other AMKL cases. CONCLUSION TAM is characterized by a paucity of somatic mutations and thought to be virtually caused by a GATA1 mutation in combination with constitutive trisomy 21. We found two major clonal evolution patterns during DS-AMKL relapse. Secondary genetic hits other than GATA1 mutations were common in DS-AMKL and mutations involving genes such as tyrosine kinase and RAS pathway genes play a major role in clonal evolution into AMKL. Citation Format: Kenichi Yoshida, Tsutomu Toki, Myoung-ja Park, Yusuke Okuno, Yuichi Shiraishi, Masashi Sanada, Ayana Kon, Yasunobu Nagata, Aiko Sato-Otsubo, Yusuke Sato, RuNan Wang, Kiminori Terui, Rika Kanezaki, Norio Shiba, Kenichi Chiba, Hiroko Tanaka, Asahito Hama, Daisuke Hasegawa, Kazuhiro Nakamura, Hirokazu Kanegane, Keiko Tsukamoto, Souichi Adachi, Satoru Miyano, Seiji Kojima, Shai Izraeli, Yasuhide Hayashi, Etsuro Ito, Seishi Ogawa. Genetic basis of myeloid leukemogenesis in Down syndrome. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3802. doi:10.1158/1538-7445.AM2013-3802

True umbilical cord knot and obstetric outcome

ObjectiveTo identify risk factors for true umbilical cord knot and to evaluate its association with fetal death, premature birth, low birth weight, small-for-gestational-age (SGA) infants, low Apgar score at 1 and 5minutes, fetal venous pH of 7.15 or lower, and need for neonatal intensive care in singleton pregnancies. MethodsThe total population of women who delivered at Kuopio University Hospital, Kuopio, Finland, between January 2000 and August 2012 was reviewed. Risk factors for umbilical cord knot and its association with adverse pregnancy outcome were evaluated separately among women with and without true cord knot via logistic regression analysis. ResultsOverall, 340 (1.2%) of 27 537 singleton pregnancies were affected by umbilical cord knot, with increased incidence associated with advanced maternal age, multiparity, previous spontaneous abortion, polyhydramnios, and diabetes mellitus. Umbilical cord knot was associated with a 1.58-, 8.08-, 3.90-, 3.17-, 1.67-, and 2.00-fold increased risk of neonatal intensive care, fetal death, premature birth, SGA infants, and low Apgar score at 1 and 5minutes, respectively. ConclusionTrue umbilical cord knot is relatively common and is associated with increased incidence of SGA infants, premature birth, need for neonatal intensive care, and fetal death.

Malignant transformation of nasal chondromesenchymal hamartoma in adult: a case report and review of the literature.

Nasal chondromesenchymal hamartoma (NCMH) is an extremely rare benign tumor arising in the sinonasal tract, predominantly involving infants and children. To date, only 27 cases are reported in the international literature and there have been no reported cases of malignant transformation. We present a 40-year-old female patient with nasal obstruction and bloody rhinorrhea. Computed tomography (CT) of the nose and paranasal sinuses confirmed a heterogeneous polypoid soft-tissue mass filling the nasal cavity and extending into the maxillary and ethmoid sinus. The patient underwent a complete radical resection. Histological and immunohistochemical analyses showed a portion of the mass was consistent with typical NCMH. However, some areas of mass exhibited cytological atypia, marked mitotic activity and foci of necrosis. The atypical mesenchymal spindle cells were immunoreactive for vimentin, CD99 and smooth muscle actin (SMA) diffusely. The cartilaginous cells were immunopositive for S-100 protein. Ki-67 index was high in atypical areas, accounting for 50%. A rapid mass recurrence was observed at the original site only 3 months after surgery. The final diagnosis of NCMH with malignant transformation was made. To our knowledge, this is the first report of malignant transformation occurring in an adult with NCMH. Although NCMH commonly develops in the neonate or young infants and exhibits benign histological appearance and favorable prognosis, there is a possibility of malignant transformation in adult patients. Thoroughly histological inspections are suggested to be necessary to accurately diagnose this tumor when it is encountered in adults.

Gentamicin resistance among Escherichia coli strains isolated in neonatal sepsis

Neonatal sepsis is a significant cause of morbidity and mortality among term and preterm infants. Ampicillin and gentamicin are standard empiric therapy for early onset sepsis. Four cases of neonatal sepsis secondary to Escherichia coli (E. coli) found to be gentamicin resistant occurred within a five week period in one neonatal intensive care unit (NICU). To determine whether these cases could be tied to a single vector of transmission, and to more broadly evaluate the incidence of gentamicin resistant strains of E. coli in the neonatal population at our institution compared to other centers, we reviewed the charts of the four neonates (Infants A through D) and their mothers. The E. coli isolates were sent for Pulse Field Gel Electrophoresis (PFGE) to evaluate for genetic similarity between strains. We also reviewed all positive E. coli cultures from one NICU over a two year period. Infants A and B had genetically indistinguishable strains which matched that of urine and placental cultures of Infant B's mother. Infant C had a genetically distinct organism. Infant D, the identical twin of Infant C, did not have typing performed. Review of all cultures positive for E. coli at our institution showed a 12.9 percent incidence of gentamicin-resistance. A review of other studies showed that rates of resistance vary considerably by institution. We conclude that gentamicin-resistant E. coli is a relatively uncommon cause of neonatal sepsis, but should remain a consideration in patients who deteriorate despite initiation of empiric antibiotics.

Hospital-Based Emergency Preparedness

The objective of this study was to report an experience with a full-scale neonatal intensive care unit evacuation exercise. This was a retrospective review of lessons learned from a full-scale evacuation exercise following a simulated catastrophe. Thirty-four realistically simulated neonatal intensive care unit infants (including 12 infants who required respiratory support and 3 with very complex medical issues) were horizontally evacuated emergently to limit immediate danger, followed by a vertical evacuation down several flights of stairs to a temporary holding area. The infants were then set up for transport for ongoing care to other regional hospitals. As with a real emergency, the drill involved the hospital incident management resources plus external partners (e.g., police, public health, and fire departments). We found that effective and constant communication was critical. Essential health care personnel resources included (1) staff to physically transport patients, (2) a central communication/coordinating site, and (3) on-site triage in the holding areas. Because it is impossible to anticipate every eventuality, flexibility and creativity are essential in disaster management. Adult tracking forms, equipment, and emergency procedures were nontransferable and often inappropriate for infants. When a disaster occurs, hospital clinical staff, emergency management, and administrators may help avoid unnecessarily high morbidity and mortality among the smallest and most vulnerable patients by developing and practicing contingency plans. We learned what our rate-limiting steps are and how we would mitigate these.

Endoscopic neurosurgery in preterm and term newborn infants—a feasibility report

Neuroendoscopic procedures became essential in neurosurgical treatment of disturbed cerebrospinal fluid dynamics. While a vast number of papers report on the neuroendoscopic experience for adults and children, no series so far reported on techniques and indications for neonate infants. We present our experience for the feasibility of neuroendoscopic procedures in preterm and term newborn infants. All preterm and term infants who underwent an endoscopic neurosurgical intervention prior to the 28th day after the previously estimated date of delivery were identified by retrospective review. Surgical procedures and techniques, complications, and further follow-up data are reported. During the study period, 14 infants (median age at surgery, 36+(2)/7weeks of gestation) underwent 20 endoscopic procedures. The performed procedures included endoscopic septostomy (n = 3), endoscopic shunt placement for multiloculated hydrocephalus (n = 4), endoscopic transaqueductal stenting for isolated fourth ventricle (n = 3), and endoscopic lavage for ventriculitis (n = 4) or for intraventricular hemorrhage (n = 6). No severe complications were seen, while two patients necessitating unexpected interventions during further follow-up (10%). Despite the fragility of preterm and term newborn infants, neuroendoscopic procedures may play an important role in the treatment of disturbed cerebrospinal fluid (CSF) dynamics also in this patient population. The neuroendoscopic approach may be curative in conditions like isolated lateral ventricle, may facilitate simplified and effective CSF diversion in multiloculated hydrocephalus or isolated fourth ventricle, and may be beneficial in the course of ventriculitis and intraventricular hemorrhage. Further studies must verify our experience with a bigger cohort of patients and on a multicenter basis.

Causes of Acute Intranatal and Postnatal Hypoxia in Neonatal Infants

Objective: to study the causes of acute intranatal hypoxia and reveal a relationship of placental changes to respiratory failure (RF) in newborn infants. Subjects and methods. The investigation included 252 neonates with the complicated course of an early neonatal period. Their gestational age was 26 weeks to 40 weeks, birth weight varied from 850 g to 4100 g. 95.3% of the newborn infants were born with a low Apgar score and RF, which required mechanical ventilation immediately after birth. The neonatal status was clinically evaluated; the values of blood gas composition and acid-base balance were recorded; the pathogen was discharged from the tracheobronchial tree; chest X-ray survey and placental morphological examination were performed. Results. The main cause of neonatal respiratory failure is chronic intrauterine hypoxia caused by placental inflammatory changes and fetal-placental blood circulatory disorders, which gives rise to preterm delivery, cerebral hemodynamic disorders, and neonatal amniotic fluid aspiration. Bacteriological examination of tracheobronchial aspirations showed that no microflora growth occured in the majority of the newborns acute intranatal hypoxia. Enterococcus faecalis and Staphylococcus epidermidis were isolated in 12.3% and 8.7%, respectively. Growth of в-hemolytic streptococcus was observed in 2.8% of cases. The rate of microbial association specific only for rate premature infants with neonatal respiratory distress syndrome (NRDS) was 4.8%. Conclusion. Placental changes causing fetal-placental circulatory disorders were ascertained to be responsible for acute intranatal and postnatal neonatal hypoxia. Placental inflammatory changes occurred in the majority of cases, as confirmed by bacteriological examinations of neonatal infants. Isolation of the varying microbial flora in infants with RF to a greater extent is, indicative of the infectious process occurring in the maternal body. Key words: acute intranatal hypoxia, neonatal amniotic fluid aspiration, intrauterine infection.

Development of a Loop-Mediated Isothermal Amplification Assay for Sensitive and Rapid Detection ofCronobacter sakazakii

Cronobacter sakazakii is an emerging pathogen associated with the ingestion of contaminated reconstituted formula, which causes necrotizing enterocolitis, sepsis, and meningitis in low-birth-weight preterm neonatal infants. Sensitive and specific detection methods are needed to better control C. sakazakii infections. This study aims to develop a highly specific and sensitive loop-mediated isothermal amplification (LAMP) assay for detecting C. sakazakii in powdered infant formula (PIF). A set of four LAMP primers were designed based on the published C. sakazakii ompA gene sequence. Specificity of the assay was evaluated using a panel of 22 C. sakazakii, 27 Enterobacteriaceae family except C. sakazakii, and 25 other strains. Assay sensitivity was determined using serial dilutions of C. sakazakii American Type Culture Collection 51329 culture ranging from 10(6) colony-forming units (CFU)/mL to extinction. The assay was also tested in experimentally inoculated PIF samples. The ompA-based LAMP assay was able to detect specifically all of the 22 C. sakazakii strains without amplification from 52 non-C. sakazakii strains. The detection limit was 10(1) CFU/mL in pure culture, up to 10-fold more sensitive than that of the ompA-polymerase chain reaction (PCR). When applied to PIF, sensitivity was 10(2) CFU/mL, up to 10-fold that of the ompA-PCR. The ompA-based LAMP assay developed in this study was sensitive, specific, and low cost with great potential for future field detection of C. sakazakii in PIF.

Comparing beneficial effects of inhaled nitric oxide to l-arginine in necrotizing enterocolitis model in neonatal rats

Necrotizing enterocolitis (NEC) is a common and devastating gastrointestinal condition of neonatal infants. The pathophysiology of NEC remains poorly understood. We tried to evaluate the effectiveness of inhaled NO compared to L-arginine usage in necrotizing enterocolitis model in rats. 46 newborn pups from 4 time-mated Sprague-Dawley pregnant rats were divided equally into 4 groups as follows: NEC (subjected to NEC), NEC + L-arginine, NEC + inhaled NO and control. SOD, GSH-Px and NOx levels were significantly higher and MDA levels were significantly lower in NEC + inhaled NO group compared to NEC + L-arginine group. There was significantly lower intestinal injury and apoptosis index scoring in NEC + inhaled NO group compared to NEC + L-arginine group. We think that inhaled NO can be used as a novel therapeutic agent like L-arginine in NEC, like using in pulmonary hypertention in newborns but much more studies are needed.

1333 Clinical Manifestations of Urinary Tract Infections in Newborn Infants Admitted to Neonatal Intensive Care Unit

Background and AimsTo determine the demography, clinical manifestations and the most common organism isolated of the urinary tract infection (UTI) in the newborn infants who were admitted to the neonatal...

Growth Kinetics and Model Comparison of Cronobacter sakazakii in Reconstituted Powdered Infant Formula

Cronobacter sakazakii is a life-threatening bacterium, infrequently implicated in illnesses associated with the consumption of powdered infant formula (PIF). It can cause rare but invasive infections in neonatal infants who consume contaminated PIF. The objective of this research was to investigate the growth kinetics and develop mathematical models to predict the growth of heat-injured C. sakazakii in reconstituted PIF (RPIF). RPIF, inoculated with a 6-strain cocktail of non-heat-treated (uninjured) or heat-injured C. sakazakii, was incubated at different temperatures to develop growth models. Except for storage at 6 °C, C. sakazakii grew well at all test temperatures (10 to 48 °C). Uninjured C. sakazakii exhibited no observable lag phase, while a lag phase was apparent in heat-treated cells. A simple 3-parameter logistic equation was used to fit growth curves for non-heat-treated cells, while both Baranyi and Huang models were suitable for heat-treated C. sakazakii. Calculated minimum and maximum growth temperatures were 6.5 and 51.4 °C for non-heat-treated cells, and 6.9 and 50.1 °C for heat-treated cells of C. sakazakii in RPIF, respectively. There was no significant difference between growth rates of non-heat-treated and heat-injured cells in RPIF. For heat-treated cells of C. sakazakii, the lag phase was temperature-dependent and very short (between 25 °C and 48 °C). These results suggest that both non-heat-treated and heat-injured C. sakazakii cells may present a risk to infants if the pathogens are not completely destroyed by heat in RPIF and then exposed to subsequent temperature abuse. C. sakazakii is a life-threatening bacterium found in powdered infant formula (PIF). This study shows that the uninjured bacterium exhibits very short or no lag phase if not refrigerated and can grow well in reconstituted PIF (RPIF), while the heat-injured cells can multiply at an equivalent rate following metabolic recovery. Temperature abuse may allow C. sakazakii to grow and endanger infants fed with RPIF. Predictive models developed in this study can be used to estimate the growth and conduct risk assessments of this pathogen.

EHP Classic Paper of the Year, 2012

Environmental Health Perspectives (EHP) established the Paper of the Year in 2008 (Tilson 2008) as a way of highlighting high-quality articles published in the journal. The EHP Classic Paper of the Year is given to the most highly cited Research Article, Commentary, or Review Article over the preceding 60 months. We are proud to announce that the 2012 EHP Classic Paper of the Year is “Exposure of the U.S. Population to Bisphenol A and 4-tertiary-Octylphenol: 2003–2004” by Antonia M. Calafat, Xiaoyun Ye, Lee-Yang Wong, John A. Reidy, and the late Larry L. Needham of the Division of Laboratory Sciences, National Center for Environmental Health, Centers for Disease Control and Prevention. This article (Calafat et al. 2008) was published in the January 2008 issue of EHP; since its publication it has been cited > 40 times/year. When the paper was published, public and scientific concerns related to health and exposure to bisphenol A (BPA) had already emerged. BPA, a high production volume chemical, is used worldwide to manufacture many consumer items, such as reusable water bottles and food containers; linings of metal food cans; medical devices and impact-resistant safety equipment; and polyvinyl chloride, paper, and cardboard products. Results from animal studies suggested that exposures to BPA can lead to developmental, reproductive, and other adverse health effects. Yet, important knowledge gaps remained regarding the relevance of these findings to human health, in part, because of limited information on human exposure to BPA. Calafat et al. (2008) addressed this gap using bio-monitoring—the accurate and precise measurement of trace levels of environ-mental chemicals in a person’s body—to investigate the degree of the U.S. general population’s exposures to BPA. Calafat et al. (2008) used state-of-the-art analytical chemistry methods to measure the urinary levels of BPA in a representative sample of the U.S. population: 2,517 participants > 6 years of age in the 2003–2004 National Health and Nutrition Examination Survey (NHANES). The study demonstrated that almost 93% of the NHANES participants were exposed to BPA. Because BPA is transformed and eliminated from the body within a few hours after exposure, the high percentage of people with detectable BPA suggested frequent or almost continuous exposure of the U.S. general population to this chemical. Furthermore, using urinary levels of BPA to categorize exposures, Calafat et al. (2008) showed that exposure differed by race/ethnicity, age, sex, and household income, suggesting that exposure may be influenced by multiple factors. The authors’ findings on BPA exposure also highlighted the need for additional public health research. Calafat et al. established the framework that led the way for future studies to identify sources and routes of exposure to BPA and to evaluate potential health effects resulting from such exposures. Since the publication of the paper, our knowledge of exposure to BPA has greatly improved. For example, in addition to diet (still believed to be the main contributor to exposure for the general population), we now know that medical interventions (e.g., Calafat et al. 2009) and thermal paper products such as store receipts (e.g., Biedermann et al. 2010) can also contribute to BPA exposure. Moreover, additional high-quality biomonitoring studies of populations exposed to BPA—published since the Calafat et al. (2008) paper—have increased our understanding of the potential links between BPA exposures and human health. This exposure information will be useful for risk assessment (e.g., to set intervention and research priorities and evaluate the effectiveness of public health measures), as well as to monitor exposure trends. EHP congratulates Calafat and colleagues for their contribution to the environmental health science literature. Their work clearly illustrates the utility of human biomonitoring to estimate population-based exposures. These exposure and health effects studies will ultimately inform policy decisions regarding human exposure levels and direct appropriate public health actions.

Functional MRI of the developing neonatal brain: potential and challenges for the future

This commentary is on the original article by Lee et al. on pages 724-729 of this issue In the 20 years following its description by Ogawa et al., blood oxygen level-dependent (BOLD) contrast functional magnetic resonance imaging (fMRI) has become established as the neuroimaging tool of choice for neuroscience and psychology studies of the brain.1 The technique offers both relatively good spatial and temporal sensitivity, with whole brain visualization a major advantage, in contrast to other tools such as electrophysiology and near infrared. Moreover, the quantitative nature of the signal, relative experimental flexibility, and reproducible dynamic signal properties across different infants have made it ideal to answer detailed neuroscientific hypotheses with the application of higher level statistical testing and mathematical modelling. This has allowed investigators to map and characterize the functional organization of the brain accurately, and begin to probe more complex issues such as the underlying patterns of connectivity between different regions during particular tasks and at rest.2 These attributes, coupled with its non-invasive nature, would seemingly make fMRI extremely suitable for studying the activity of the developing human brain. Despite this apparent potential, there have only been a small number of fMRI studies in neonatal infants which have reported reliable functional responses to simple visual, auditory, and tactile stimuli.3 However, within these studies there has been prominent inconsistency as to the amplitude of the functional responses, with early studies reporting (in contrast to the typical adult response) a localized decrease in BOLD signal (termed ‘negative’ BOLD). This variation is likely to be due to the considerable challenges inherent in designing and performing an fMRI study for neonatal infants, as it is generally inappropriate to directly apply existing techniques developed for adult studies. These challenges include making necessary adaptations to the MRI acquisition parameters to account for the different magnetic properties of the developing brain; the design of appropriate and safe stimulation paradigms; understanding the effects of physiological changes on the underlying biophysics of the BOLD contrast response; and making adjustments to the analysis techniques.4 Lee et al. have performed a feasibility study of fMRI using a visual stimulus in a relatively large cohort of preterm infants.5 They have attempted to address some of the possible sources of irregularity described in previous studies, in particular the considerably longer T2* values seen in neonatal infants predominately due to the reduced synaptic density and increased water content of the immature brain.4 Despite this, functional responses were seen in just 5% of their preterm infants, suggesting that fMRI is probably not an appropriate modality for studying visual function in this population. Of note, a visual stimulation paradigm was used in the majority of previously reported neonatal fMRI studies, despite the greatest inconsistency in results occurring with this stimulus type.3 Although newborn infants behaviourally are visually attentive (e.g. showing a preference for looking at images of faces) and immature visual evoked potentials can be demonstrated in some infants as young as 24 post-menstrual weeks, the study’s findings may be in keeping with the theory that at least some early visual activity occurs via the subcortical extra-geniculo-calcarine system; with functional activity in the primary visual areas not fully established until 2 to 3 months of age.6 Although recent neonatal fMRI studies have begun to report more consistent results (and in particular positive BOLD signal responses) with auditory and sensorimotor stimuli,7,8 there remains a number of key unresolved questions; such as the effect of developmental changes on the local neurovascular coupling which underlies the BOLD response and has been shown to differ significantly in the immature rat brain.4,9 If some of these issues can be definitively resolved, then one could imagine fMRI providing a wealth of new information about the development, organization, and integration of functional activity in the newborn brain, and also important insights into the pathophysiology of central nervous system developmental abnormalities.

Heat Shock Protein 70 Expression is Increased in the Liver of Neonatal Intrauterine Growth Retardation Piglets.

Intrauterine growth retardation (IUGR) leads to the dysfunction in digestive system, as well as the alteration in the expression of some functional proteins. Heat shock protein 70 (Hsp70) could be induced by various stress factors, but whether Hsp70 expression is changed in neonatal IUGR infants has not been demonstrated. This study was conducted to explore the expression of Hsp70 in the liver by using the IUGR piglet model. Liver and plasma samples were obtained from IUGR and normal birth weight (NBW) piglets at birth. The neonatal IUGR piglets had significantly lower liver weight than their counterparts. The activities of aspartate aminotransferase and alanine aminotransferase in serum were enhanced significantly in IUGR indicating liver dysfunction. The activities of superoxide dismutase (p<0.01), glutathione peroxidase (p<0.01) and catalase (p>0.05) were lower and the level of malondialdehybe was higher (p<0.05) in IUGR liver compared with in NBW. According to the results of histological tests, fatty hepatic infiltrates and cytoplasmic vacuolization were present in the liver of IUGR piglets, but not in NBW liver. The expression of Hsp70 protein was significantly higher (p<0.05) in IUGR piglet liver than in NBW. Similar to where the hepatic injuries were observed, location of Hsp70 was mostly in the midzonal hepatic lobule indicating that oxidative stress might be responsible for the increased expression of Hsp70.

Placental Inflammatory Changes and Bacterial Infection in Premature Neonates with Respiratory Failure

Objective: to reveal a relationship of placental inflammatory changes to bacterial infection in premature neonates with respiratory failure. Material and methods. Bronchoalveolar aspirate was bacteriologically studied in 157 premature neonates with respiratory distress syndrome (NRDS); the total and differential leukocyte counts were measured in their peripheral blood. The levels of the cytokines IL-1^3, IL-4, IL-6, and TNF-a were studied in different biological fluids of mothers and their babies; the placentas were also morphologically examined. Results. An analysis of bacterial cultures from the tracheobronchial tree revealed no growth of bacterial microflora in 61.8% of cases, Enterococcus faecalis and Staphylococcus epidermidis were isolated in 6.4 and 8.3% of the infants, respectively; Staphylococcus haemolyticus, Staphylococcus capitis, Enterobacter agglomerans, and hemolytic group A Streptococcus were seen in 1.9% each; moreover, 1.3% of the newborn infants were found to have Bacillus spp., Staphylococcus aureus, Escherichia coli, Acinetobacter spp., and Serratia marcescens. Other microorganisms and a microbial association were encountered in 8.9% of cases. Placental morphological examination revealed different inflammatory changes concurrent with chronic and acute placental insufficiency. The investigation demonstrated that the maternal peripheral plasma levels of IL-1^, IL-4, IL-6, and TNF-a were within the physiological range at the end of the first period of delivery. The amniotic fluid displayed elevated IL-6 and TNF-a concentrations and normal IL-4 and IL-1e levels, suggesting that there was an intrauterine inflammatory process. Conclusion. Premature birth is associated with various placental inflammatory changes, which causes intrauterine stimulation of macrophages in the chorionic villi. Specific immune defense mechanisms that prevent the development of a fetal infectious process, i.e. the maternal infectious process, may induce preterm birth, but fail to lead to fetal and neonatal diseases. The investigation has shown that NRDS is a major disease in premature neonatal infants. Key words: intrauterine infection, premature neonates, cytokines, neonatal res piratory distress syndrome.

Analgesic trials in children: safety, efficacy and innovation

A premature newborn infant is being treated in a neonatal intensive care unit, quite ill and subject to an array of invasive procedures. We wish to do all we can to minimize that individual’s suffering. Which analgesics may be effective? Are they safe? Are they metabolized by the youngest of human beings in a predictable way? Clearly, to answer these questions it is necessary to conduct clinical trials on children within this population. But is it ethical? Is it feasible? That is the tension experienced by pediatric practitioners who wish to invoke evidence to ease children’s pain in a safe and effective manner. The magnitude of the problem may be appreciated when one examines the epidemiology of pain in children. A prospective study conducted in neonatal intensive care settings showed that over the first 14 days of admission, each premature infant experienced a median of 75 (range: 3–364) painful procedures and ten (range: 0–51) painful procedures per day of hospitalization. Among the total of 42,413 painful procedures observed, newborns were provided with pharmacologic therapy specifically targeting the procedural pain only 2.1% of the time [1]. This study, and others in the field, tells us little about other, more ongoing pain in neonates, such as disease-related and postoperative pain. Of course, beyond the neonatal period, infants and children commonly experience acute pain due to surgery or injuries. In addition to acute pain, 5–23% of school-age children experience significant recurrent pain, such as headache, chest pain, abdominal pain and limb pain [2–4]. Children also endure chronic daily pain from headache disorders, neurodegenerative diseases, inflammatory and autoimmune disease, post-traumatic neuropathic pain conditions including complex regional pain syndrome, small fiber neuropathies and pain due to malignancies and other life-limiting diseases.

Pediatric palliative care—when quality of life becomes the main focus of treatment

Pediatric palliative care (PPC) focuses on children and adolescents with life-limiting diseases. It may be initiated at various points of the disease trajectory, if possible early enough to support living with the best possible quality of life despite a limited lifespan. From birth to adolescence, children with a broad spectrum of diseases may benefit from PPC. Since 50% of deaths in childhood occur within the first year of life, PPC is just as relevant to neonatology. Causes of death in the neonate and young infant are due to perinatal conditions such as preterm birth and congenital disorders and syndromes; in older children, external causes, such as traumatic injuries, outweigh disease-related causes of death. PPC may last from a few hours or days for neonates to many years for children with complex chronic conditions. For neonates, PPC often has the character of end-of-life (EOL) care followed by bereavement care for the family. For older children, PPC can clearly be differentiated from EOL care; its indications include progress or deterioration of disease, marked instability of the child's condition, increase in the need for technical or medical support, increase in suffering, or failure of treatment. If a child's need for palliative care is established, useless and potentially harmful treatments may be withheld and informed choices can be made about treatment, care, and the remaining life of the child. Conclusion This review aims to provide knowledge for clinicians who care for children and adolescents at risk of dying from their disease. PPC can improve the child's remaining lifetime by focusing on quality of life and goals that are defined by the child and his or her family.

Two cases of severe sepsis caused by Bacillus pumilus in neonatal infants

Bacillus pumilus is an environmental contaminant that has been rarely associated with clinical infections. Here, two cases of severe sepsis caused by B. pumilus are described in two full-term neonates; one in a female infant with no factors predisposing her to infection and the other in a male infant requiring mechanical ventilation and an intravenous catheter. In both cases, the micro-organism was recovered from repeated blood cultures and was identified using biochemical assays and 16S rRNA gene sequencing. Both infants were successfully treated with vancomycin. This report reveals the potential role of B. pumilus as a bloodstream pathogen during infancy.

Neonatal periostin knockout mice are protected from hyperoxia-induced alveolar simplication.

In bronchopulmonary dysplasia (BPD), alveolar septae are thickened with collagen and α-smooth muscle actin, transforming growth factor (TGF)-β-positive myofibroblasts. Periostin, a secreted extracellular matrix protein, is involved in TGF-β-mediated fibrosis and myofibroblast differentiation. We hypothesized that periostin expression is required for hypoalveolarization and interstitial fibrosis in hyperoxia-exposed neonatal mice, an animal model for this disease. We also examined periostin expression in neonatal lung mesenchymal stromal cells and lung tissue of hyperoxia-exposed neonatal mice and human infants with BPD. Two-to-three day-old wild-type and periostin null mice were exposed to air or 75% oxygen for 14 days. Mesenchymal stromal cells were isolated from tracheal aspirates of premature infants. Hyperoxic exposure of neonatal mice increased alveolar wall periostin expression, particularly in areas of interstitial thickening. Periostin co-localized with α-smooth muscle actin, suggesting synthesis by myofibroblasts. A similar pattern was found in lung sections of infants dying of BPD. Unlike wild-type mice, hyperoxia-exposed periostin null mice did not show larger air spaces or α-smooth muscle-positive myofibroblasts. Compared to hyperoxia-exposed wild-type mice, hyperoxia-exposed periostin null mice also showed reduced lung mRNA expression of α-smooth muscle actin, elastin, CXCL1, CXCL2 and CCL4. TGF-β treatment increased mesenchymal stromal cell periostin expression, and periostin treatment increased TGF-β-mediated DNA synthesis and myofibroblast differentiation. We conclude that periostin expression is increased in the lungs of hyperoxia-exposed neonatal mice and infants with BPD, and is required for hyperoxia-induced hypoalveolarization and interstitial fibrosis.

Dietary l-arginine supplementation improves the intestinal development through increasing mucosal Akt and mammalian target of rapamycin signals in intra-uterine growth retarded piglets

Intra-uterine growth retardation (IUGR) impairs postnatal growth and development of the small intestine (SI) in neonatal pigs and infants. L-Arginine (Arg), a critical amino acid involved in promoting growth and metabolism in young mammals, is more deficient in IUGR fetuses. However, little is known whether dietary Arg supplementation would accelerate the impaired development of the SI induced by IUGR in piglets. In the present study, a total of six litters of newborn piglets were used. In each litter, one normal and two IUGR littermates were obtained. Piglets were fed milk-based diets supplemented with 0 (Normal), 0 (IUGR) and 0·60% Arg (IUGR+Arg) from 7 to 14 d of age, respectively. Compared with Normal piglets at 14 d of age, IUGR decreased (P < 0·05) the growth performance, entire SI weight, and villus height in the jejunum and ileum. IUGR piglets had lower (P < 0·05) mucosal concentrations of Arg, insulin, insulin growth factor 1, as well as phosphorylated Akt, mammalian target of rapamycin (mTOR) and p70 S6 kinase but higher (P < 0·05) enterocyte apoptosis index (AI). After Arg treatment in IUGR piglets, the growth performance, weight of entire SI and mucosa, and villus height in the jejunum and ileum were increased (P < 0·05). Diet supplemented with Arg also increased (P < 0·05) the levels of Arg, insulin, phosphorylated Akt and mTOR in SI mucosa of IUGR piglets, and decreased (P < 0·05) the AI and caspase-3 activity. In conclusion, Arg has a beneficiary effect in improving the impaired SI development in IUGR piglets via regulating cell apoptosis and activating Akt and mTOR signals in SI mucosa.