Immature Babies Research Articles

The Intricate Connection between Bacterial α-Diversity and Fungal Engraftment in the Human Gut of Healthy and Impaired Individuals as Studied Using the In Vitro SHIME® Model.

From the estimated 2.2 to 3.8 million fungal species existing on Earth, only a minor fraction actively colonizes the human gastrointestinal tract. In fact, these fungi only represent 0.1% of the gastrointestinal biosphere. Despite their low abundance, fungi play dual roles in human health-both beneficial and detrimental. Fungal infections are often associated with bacterial dysbiosis following antibiotic use, yet our understanding of gut fungi-bacteria interactions remains limited. Here, we used the SHIME® gut model to explore the colonization of human fecal-derived fungi across gastrointestinal compartments. We accounted for the high inter-individual microbial diversity by using fecal samples from healthy adults, healthy babies, and Crohn's disease patients. Using quantitative Polymerase Chain Reaction and targeted next-generation sequencing, we demonstrated that SHIME®-colonized mycobiomes change upon loss of transient colonizers. In addition, SHIME® reactors from Crohn's disease patients contained comparable bacterial levels as healthy adults but higher fungal concentrations, indicating unpredictable correlations between fungal levels and total bacterial counts. Our findings rather link higher bacterial α-diversity to limited fungal growth, tied to colonization resistance. Hence, while healthy individuals had fewer fungi engrafting the colonic reactors, low α-diversity in impaired (Crohn's disease patients) or immature (babies) microbiota was associated with greater fungal abundance. To validate, antibiotic-treated healthy colonic microbiomes demonstrated increased fungal colonization susceptibility, and bacterial taxa that were negatively correlated with fungal expansion were identified. In summary, fungal colonization varied individually and transiently, and bacterial resistance to fungal overgrowth was more related with specific bacterial genera than total bacterial load. This study sheds light on fungal-bacterial dynamics in the human gut.

Caffeine Therapy for Apnea of Prematurity: Role of the Circadian CLOCK Gene Polymorphism.

Standard-dose caffeine citrate has been routinely prescribed for apnea of prematurity (AOP) management; however, some preterm infants respond well to the therapy while others do not. The AOP phenotype has been attributed solely to the immature control of the respiratory system consequent to preterm birth, but there are also important genetic influences. Based on our previous report, we tested the hypothesis that the human circadian locomotor output cycles kaput (CLOCK) gene polymorphisms play a role in the response to caffeine citrate therapy in preterm infants. We also studied the interactions of the circadian clock with aryl hydrocarbon receptor (AHR) signaling pathways in preterm babies who received caffeine citrate. This single-center study collected data from 112 preterm infants (<35 weeks gestational age) between July 2017 and July 2018, including apnea-free (n = 48) and apneic (n = 64) groups. Eighty-eight candidate single nucleotide polymorphisms (SNPs) were tested using the MassARRAY system. Association analysis was performed using the PLINK Whole Genome Data Analysis Toolset and SNPStats software. Linkage disequilibrium (LD) and haplotype analyses were performed using Hapview software. No significant intergroup differences in allele distributions or genotype frequencies of CYP1A2, CYP3A4, CYP3A5, and CYP3A7 were detected in our study on preterm babies. Two more SNPs in AHR were found to be associated with determining the response to caffeine citrate therapy in our pediatric patients. Of the 46 candidate SNPs in the CLOCK gene, 26 were found to be associated with determining the response to caffeine treatment in these babies. Interestingly, a significant association was retained for 18 SNPs in the CLOCK gene after false discovery rate correction. Moreover, strong LD formed in those variants in AHR, ADORA2A, and CLOCK genes was confirmed to be significantly associated with a better response to standard-dose caffeine therapy. In summary, CLOCK gene polymorphisms play a role in determining the response to caffeine therapy in premature neonates with AOP. However, whether the AHR and CLOCK signaling pathways crosstalk with each other during caffeine treatment remains largely unclear. Future clinical studies including more immature babies and basic research are needed to explore the mechanism by which circadian rhythms affect the response to caffeine therapy.

Mapping of Paediatric Cochlear Implant Using Neural Response Threshold (NRT) and Behavioural Observation Audiometry (BOA).

To measure the correlation between neural response threshold (NRT) and most comfortable level for behaviouralresponse (MCLB) whichever is better for rehabilitation purpose and to calculate the impedance of the electrode in cochlear implant recipient. Mapping may be done by various methods here we did by NRT and behavioral observation audiometry (BOA). NRT is technique by which we measure the response from the auditory nerve using the hi-resolution bionic ear system. Neural response measurement depends on the-neural tissue, stimulus used and recording technique. BOA is used for observing motor response on presenting sound to the implanted child. Most comfortable level for behaviouralresponse (MCLB) is calculated for behavioural response. It measures the useful information about low frequency hearing, it provides more information about the hearing of neurologically immature babies giving indication of uncomfortable loudness levels. The NRT and MCLB is calculated for 2nd, 6th, and 11th electrode for all patients in our study. Auditory response threshold is better for rehabilitations then behavioural observation audiometry for Cochlear implant patients. Mean value and standard deviation of neural response threshold (NRT) (qu) are 10.23, 3.67; 11.27, 4.39; 10.71, 3.88 at 2nd, 6th, and 11th electrode respectively. Mean value and standard deviation of Most comfortable level for behavioral response (qu) are 20.49, 7.08; 21.26, 7.31; 21.01, 6.03 at 2nd, 6th and 11th electrode respectively. NRT is better for post-operative rehabilitations and MCL and threshold vary with different electrode and in different patients.

Chemical Effects and Predictive Factors in Premature Birth

Premature birth is considered to be the consequence of independent alterations in the cervix and in the uterus. During labor, for full-term birth, as well as for premature birth, the cervix changes, from firm, long and closed, to soft and pliable, through a biochemical process characterized by the reshaping of the extracellular matrix and a growth of the tissue concentration of inflammatory mediators; the uterus proves an increase in contractility and sensitivity to endogenic hormones, such as oxytocin. Premature labor is associated with the premature activation of the release of cytokines in the decidua (mucosa lining uterus walls) and cervix. Interleukins IL-1 beta, IL-6, IL-8 and the alpha tumoral necrosis factor increase the production and activation of matrix metalloproteinases (MMP-1, MMP-3 and MMP-9) and of cathepsin S, which digests the collagen from the extracellular matrix of the cervix, causing the wiping and softening of the cervix. These cytokines are released by leukocytes in the myometer, leading to the production of prostaglandins and oxytocin, which stimulate uterine contractions. Therefore, the cervical shortening represented by ultrasound is believed to represent premature cervical softening. The obstetrical approach of aspects related to premature birth are based, considerably, on the prognosis expected by the obstetrician regarding the survival of the premature new-born baby, as well as the therapeutic variants to be followed. And not only survival is important, of equal importance is also the quality of life of underweight, immature new-born babies, who are considerably affected both physically, and intellectually.

A different perspective: anesthesia for extreme premature infants: is there an age limitation or how low should we go?

To put in perspective, the various challenges that faces pediatric anesthesiologists because of the recently lowered limits with regards to the viability of a fetus. Both medical and ethical considerations will be highlighted. Issues related to: who should anesthetize these tiny babies; can we provide adequate and legal monitoring during the anesthetic; does these immature babies need hypnosis and amnesia and the moral/ethical implications associated with being involved with care of doubtful long-term outcome are reviewed. There does currently not exist sufficient research data to provide any evidence-based guidelines for the anesthetic handling of extreme premature infants. Current practice relies on extrapolations from other patient groups and from attempting to preserve normal physiology. Thus, focused research initiatives within this specific field of anesthesia should be a priority. Furthermore, in-depth multiprofessional ethical discussions regarding long-term outcome of aggressive care of extremely premature babies are urgently needed, including the new concepts of disability-free survival and number-need-to-suffer.

Mercury in breast milk from women in the Federal District, Brazil and dietary risk assessment for breastfed infants

Mercury is a toxic metal, ubiquitous in nature; it is excreted in breast milk from exposed mothers and may affect infant neuro-development. In this study, 224 breast milk samples provided by eight human milk banks in the Federal District of Brazil were analyzed for total mercury (THg), of which 183 were also analyzed for methyl mercury (MeHg), the most relevant form of this metal for the breastfed infants. Samples were acid digested in a microwave oven and THg determined by atomic fluorescence spectrometry (LOQ of 0.76 μg/L). Samples were lyophilized, ethylated and MeHg determined in a MERX automated system (LOQ of 0.10 μg/L). Inorganic mercury (IHg) levels were estimated from the THg and MeHg determined in the samples. Most of the samples were collected 1–2 months postpartum, with 38% during the first month. Over 80% of the samples had THg values above the LOQ, reaching a maximum of 8.40 μg/L, with a mean of 2.56 μg/L. On average, MeHg accounted for 11.8% of THg, with a maximum of 97.4%. Weekly intakes were estimated individually, considering the baby’s age and body weight at the time of milk collection. Mean weekly intake for MeHg was 0.16 ± 0.22 μg/kg bw, which represented 10% of the PTWI; in only one case, the intake exceeded 100% of the PTWI (1.90 μg/kg bw, 119% of PTWI). Mean intake for IHg was 2.1 ± 1.5 μg/kg bw, corresponding to 53% PTWI. These results indicate no health concern for the breastfed babies, a conclusion that can be extended to the consumers of breast milk donated to the milk banks, primarily immature and low weight babies.

Skin antisepsis in the neonate: what should we use?

Neonates in intensive care are more susceptible to sepsis. Infection is commonly acquired via the transcutaneous portal. It is necessary to identify the most effective yet safest topical antiseptics for use in neonates to reduce nosocomial sepsis. Recent national surveys indicate that a wide range of topical antiseptic preparations are used in the neonatal nursery. There are very few comparative studies in neonates and no robust evidence in favour of any particular antiseptic. There are significant safety and potential toxicity issues for neonates with all the commonly used antiseptics, particularly in very small immature babies. There are no convincing roles for routine application of emollient creams on the skin, topical antiseptics on the umbilical stump, or maternal vaginal washes with chlorhexidine for the prevention of neonatal infection. Large multicentre trials are needed to determine the optimal antiseptic to use for neonates undergoing intensive care, especially for extremely preterm infants.

MRI of animal models of developmental disorders and translation to human imaging

In order to understand the pathophysiological mechanisms leading to the specific brain alterations observed in immature newborn babies, preclinical studies on animal models mimicking clinical reality are mandatory and are ideally coupled with imaging modalities transferable to the human scenario. The availability of MRI techniques on both clinical and animal scanners allows this methodological transfer from bench to bedside. The aim of this review is to give an overview of the recent findings in MRI of animal models of developmental disorders and emphasize what we can learn from MRI on these models. Progress in newborn medicine has allowed the survival of increasingly immature newborns that is often associated with specific morbidities. The brain in particular shows developmentally linked vulnerability leading to specific brain injury and subsequent developmental disorders. MRI delivers a large amount of anatomical, microstructural and functional information and has been widely used to monitor cerebral development and characterize the specificity of brain lesions in the immature brain in humans and animal models. In this review, we will present the different animal models assessed by magnetic resonance techniques and the histopathological correlations observed, as well as the implications for human imaging.

Effect of thyroxine on brain microstructure in extremely premature babies: magnetic resonance imaging findings in the TIPIT study

In order to assess relationships between thyroid hormone status and findings on brain MRI, a subset of babies was recruited to a multi-centre randomised, placebo-controlled trial of levothyroxine (LT4) supplementation for babies born before 28 weeks' gestation (known as the TIPIT study, for Thyroxine supplementation In Preterm InfanTs). These infants were imaged at term-equivalence. Forty-five TIPIT participants had brain MRI using diffusion tensor imaging (DTI) to estimate white matter development by apparent diffusion coefficient (ADC), fractional anisotropy (FA) and tractography metrics of number and length of streamlines. We made comparisons between babies with the lowest and highest plasma FT4 concentrations during the initial 4 weeks after birth. There were no differences in DTI metrics between babies who had received LT4 supplementation and those who had received a placebo. Among recipients of a placebo, babies in the lowest quartile of plasma-free thyroxine (FT4) concentrations had significantly higher apparent diffusion coefficient measurements in the posterior corpus callosum and streamlines that were shorter and less numerous in the right internal capsule. Among LT4-supplemented babies, those who had plasma FT4 concentrations in the highest quartile had significantly lower apparent diffusion coefficient values in the left occipital lobe, higher fractional anisotropy in the anterior corpus callosum and longer and more numerous streamlines in the anterior corpus callosum. DTI variables were not associated with allocation of placebo or thyroid supplementation. Markers of poorly organised brain microstructure were associated with low plasma FT4 concentrations after birth. The findings suggest that plasma FT4 concentrations affect brain development in very immature infants and that the effect of LT4 supplementation for immature babies with low FT4 plasma concentrations warrants further study.

314 Hyperoxia Changes the Balance of the Thioredoxin/Peroxiredoxin System in the Neonatal Rat Brain

Background and AimAs demonstrated previously, oxygen contributes to the pathogenesis of neonatal brain damage and leading to neurocognitive impairment of prematurely born infants in later life.Reactive oxygen species (ROS) and...

No advanced retinopathy of prematurity stages 4 or 5 in a large high-risk German cohort

BackgroundRetinopathy of prematurity (ROP) remains a major cause of juvenile blindness. As screening recommendations are refined, decreasing gestational age (GA) and birth weight (BW) constitute an increasing risk for ROP....

Update on risk factors and future perspectives for preterm infants

Abstract Purpose To give an update on risk factors for retinopathy of prematurity with special focus on postnatal growth and growth factors Methods The relationship between birth weight, serum levels of IGF‐I as well as postnatal longitudinal growth and ROP will be presented. Preventive measures will be discussed. Results Birth weight data on 451 infants demonstrated initially a significant difference in BW between different ROP stages but when taking gestational age and sex into account the significance was eliminated. Recently, a new diagnostic tool based on weekly neonatal measurements of body weight and serum insulin‐like growth factor 1 (IGF‐I) levels, was shown to be predictive for ROP development. The algorithm “Weight IGF‐I Neonatal ROP” (WINROP™) predicted early (mean 10 weeks) all infants who later developed proliferative ROP requiring treatment. The WINROP algorithm was then taken one step further using only serial weight measurements (n=700), excluding blood sampling for measuring IGF‐I. With this approach WINROP predicted all infants who later developed proliferative ROP requiring treatment (100% sensitivity) and correctly identified 75% of those who did not develop proliferative ROP, and thus would not need any ophthalmologic screening. We have also shown a close relationship between postnatal growth, severe ROP and poor brain development. Conclusion For decades, neonatal intensive care has focused on survival of the most immature babies. Time has come to find methods to ameliorate the nutrition for the children born very preterm. It is known that IGF‐I is essential for growth and development of the immature vasculature of the eye. Intervention with substitution of IGF‐I to the very preterm babies to raise IGF‐I up to normal intrauterine levels might be beneficial. Commercial interest

Effet du NO inhalé sur le poumon et le cerveau en développement

With the advent of prenatal steroids, postnatal exogenous surfactant and less aggressive respiratory support, premature infants can develop chronic lung disease without even acute respiratory distress. This "new bronchopulmonary dysplasia" could be the result of impaired postnatal growth. Several experimental studies have suggested a possible role of the vascular endothelial growth factor/nitric oxide (VEGF/NO) pathway in restoring pulmonary angiogenesis and enhancing distal lung growth. The results of the clinical studies are, however, inconclusive, and it is currently unclear which subsets of premature infants might benefit from inhaled nitric oxide. Besides, severe intracranial haemorrhage and/or cystic periventricular leukomalacia may affect the most immature babies, many of whom are spared from severe initial respiratory disease. Recently, inhaled nitric oxide was shown to significantly decrease the incidence of these neurological events, and to improve the long-term outcome in a few clinical trials. At times neuroprotective, at times neurotoxic, nitric oxide is capable of divergent effects depending upon the extent of cerebral damage, the redox state of the cell, and the experimental model used. Recently, inhaled nitric oxide had recognized to have dramatic remote effects including angiogenesis and maturation on the developing brain in rodent pups. Therefore, the developmental consequences of inhaled NO should be further investigated to ensure its safety on the developing brain and to test its potential neurprotective effect.

Actualización en Presentación y Patogénesis de la Displasia Broncopulmonar

Bronchopulmonary dysplasia (BPD) remains as the most frequent chronic lung disease seen among babies with very low birth weight, contributing to their morbidity and mortality. An increase in the survival of very immature babies due to improvement in pre and post natal care, has resulted in an increase in the number of newborns with BDP, although there have been no changes in the actual incidence of the disease. Objective: Lo describe the evolution of DBP in recent decades, the current definition, and to describe and analyze the risk factors involved in the pathogenesis of this disease. Until a few years ago, the terms BPD and chronic lung disease were used as synonyms. After the workshop sponsored by the National Institute of Health in the United States in 2001, it was recommended that the term BPD be used to describe the pulmonary sequelae of immature babies. Classic severe as described by Northway et al over forty years ago, has evolved into milder forms of chronic pulmonary damage, the so-called BPD, characterized by impairment of alveolarizacion and vascularization of the immature lung in response to multiple injuries. BPD is a multifactorial disease where major risk factors are related to pulmonary immaturity, hyperoxia, baro/volutrauma, as well as inflamation and infection. Genetic susceptibility has recently been shown to be another important risk factor. Conclusion: Bronchopulmonary Dysplasia continues to be the most frequent sequelae affecting low birth weight infants. In the past four decades, the disease has been better defined, and new pathogenetic risk factors have been established.

Inhaled nitric oxide to prevent bronchopulmonary dysplasia in preterm neonates

Bronchopulmonary dysplasia is a chronic lung disease that affects premature infants and contributes to their morbidity and mortality. With the advent of prenatal steroids and postnatal exogenous surfactant and less aggressive respiratory support, premature infants can develop chronic oxygen dependency without even acute respiratory distress. This 'new bronchopulmonary dysplasia' could be the result of impaired postnatal growth. Several experimental studies have suggested a possible role of the vascular endothelial growth factor/nitric oxide (VEGF/NO) pathway in restoring pulmonary angiogenesis and enhancing distal lung growth. The results of the clinical studies are, however, inconclusive, and it is currently unclear which subsets of premature infants might benefit from inhaled nitric oxide. Besides, severe intracranial haemorrhage and/or cystic periventricular leucomalacia may affect the most immature babies, many of whom are spared from severe initial respiratory disease. Recently, inhaled nitric oxide was shown to significantly decrease the incidence of these neurological events, and to improve the long-term outcome in a few clinical trials. At times neuroprotective, at times neurotoxic, nitric oxide is capable of divergent effects depending upon the extent of cerebral damage, the redox state of the cell, and the experimental model used. Recently, our group found that inhaled nitric oxide had remote effects including angiogenesis and maturation on the developing brain in rodent pups. Thus, we await the results of the recently completed randomised clinical trial of inhaled nitric oxide to prevent bronchopulmonary dysplasia (the European Nitric Oxide or 'EUNO' trial) where, besides the primary endpoint of chronic oxygen dependency reduction at 36 weeks' postconceptional age, long-term lung and brain will be followed-up until 7 years of age.

Extremely low birthweight infants – the interplay between outcomes and ethics

Extremely low birthweight infants – the interplay between outcomes and ethics

Neurological outcomes following preterm birth

Neonatal survival continues to improve; for many years, including throughout the 1990s there have been anxieties that this was at the cost of additional morbidity, most particularly in terms of neurosensory impairments. Recent evidence suggests that rates of neuromotor morbidity, in particular cerebral palsy, may be declining for all but the most immature babies. Severe sensory impairment has a low, but relatively static incidence. High prevalence, low severity motor problems and their inter-relationship with developmental co-ordination disorder, executive dysfunction and cognitive impairment are increasingly recognised and correlated with reduced school performance. Because of difficulties in comparing outcomes across different populations, validated motor and manual function classifications have been developed for children with cerebral palsy and can help to standardise outcome measures. Improved neuro-imaging is helping us understand the types and consequences of neonatal brain injury. The possibility of using composite measures of early motor movement quality, longitudinal use of motor classification systems and volumetric magnetic resonance imaging (MRI) imaging to understand developmental processes needs to be explored.

Lack of effect of antenatal glucocorticoid therapy in the fetal baboon on cerebral cortical glucose transporter proteins

Maternal antenatal glucocorticoid therapy is used to accelerate lung maturation of immature babies at risk of preterm delivery. It acutely affects brain activity of the human fetus and reduces the immunoreactivity of neurocytoskeletal and synaptic proteins in the fetal baboon brain. These effects might be based on cerebral energy failure due to a decreased neuronal glucose uptake that has been shown in vitro. Glucose uptake into the brain is selectively facilitated by GLUT1 expressed in the blood-brain barrier and GLUT3 expressed in the neuronal membrane. Immunohistochemical distribution of GLUT1 and GLUT3 were examined in the frontal neocortex of the fetal baboon brain at 0.73 gestation (i.e. similar to 28 weeks of human gestation) after maternal betamethasone administration, mimicking the clinical dose regimen. Betamethasone did not alter GLUT1 and GLUT3 immunoreactivity. The results suggest that inhibition of glucose uptake is not the mechanism for the cerebral effects of antenatal glucocorticoids.

Suppressive effect of alpha2 Heremans-Schmid glycoprotein on in vitro calcification of osteogenesis

alpha(2) Heremans-Schmid glycoprotein (alpha(2)HS glycoprotein) is predominantly found in bone. To date, we have investigated plasma alpha(2)HS levels in immature babies and neonates as well as the histological distribution in various neonatal tissues in order to clarify its physiological significance. In an effort to understand the physiological function of alpha(2)HS glycoprotein in bones, we studied the effects of alpha(2)HS glycoprotein in cultured osteogenesis model using rat marrow cells. We added different concentrations of alpha(2)HS glycoprotein to cultured marrow cells, including osteoblasts in the presence of dexamethasone, in an attempt to elucidate the effects of alpha(2)HS glycoprotein on osteoblast growth and bone calcification in vitro. The results showed that total DNA content was significantly increased with 0.2-20 nM (f.c.) alpha(2)HS glycoprotein, but was neither suppressed nor increased with 200 nM (f.c.) alpha(2)HS glycoprotein. Although ALP activity increased with 0.2 or 2 nM (f.c.) alpha(2)HS glycoprotein, it decreased with 20 or 200 nM (f.c.) alpha(2)HS glycoprotein. While 0.2 nM (f.c.) alpha(2)HS glycoprotein had no effect on calcium or osteocalcin content, 2 nM (f.c.) alpha(2)HS glycoprotein decreased both calcium content and osteocalcin content by about half, and no calcium or osteocalcin was observed with 20 or 200 nM (f.c.). Calcium staining of cultured marrow cells revealed that the number of stained cell tubercles decreased in a concentration-dependent manner. These findings suggest that alpha(2)HS glycoprotein regulates the growth of osteoblasts and acts as an inhibitory factor in the regulation of bone calcification.

The sequelae of periventricular haemorrhage

<h2>Summary</h2> Periventricular haemorrhage (PVH) is a common condition in very immature babies. It has attracted much attention because it is easy to diagnose using real-time ultrasound and, as a result, its prominence in causing subsequent severe neurodevelopmental problems has been overestimated. The majority of babies with PVH are not damaged, but a number of sequelae of this condition can predict adverse outcome in later years if the baby survives. The distinction between PVH and other forms of neuropathology that affect the immature brain makes disentangling the effects of haemorrhage alone difficult. This review attempts to separate out the significance of PVH from other lesions such as periventricular leukomalacia.