Showing papers in "Frontiers in Pediatrics in 2017"

Early Childhood Caries: Prevalence, Risk Factors, and Prevention.

Abstract: “Early childhood caries (ECC) is major oral health problem, mainly in socially disadvantaged populations. ECC affect infants and preschool children worldwide. The prevalence of ECC differs according to the group examined, and a prevalence of up to 85% has been reported for disadvantaged groups”. “Early childhood caries (ECC) is the presence of one or more decayed, missing, or filled primary teeth in children aged 71 months (5 years) or younger. It begins with white-spot lesions in the upper primary incisors along the margin of the gingiva. If the disease continues, caries can progress, leading to complete destruction of the crown.” The main risk factors in the development of ECC can be categorized as microbiological, dietary and environmental risk factors. Even though it is largely a preventable condition, ECC remains one of the most common childhood diseases. The major contributing factors for the for the high prevalence of ECC are improper feeding practices, familial socioeconomic background, lack of parental education and lack of access to dental care. Oral health plays an important role in children to maintain the oral functions and are required for eating, speech development, and a positive self-image. The review will focus on the prevalence, risk factors and preventive strategies and the management of early childhood caries.

MLL-Rearranged Leukemias—An Update on Science and Clinical Approaches

Abstract: The Mixed-lineage leukemia 1 (MLL1) gene (now renamed Lysine [K]-specific MethylTransferase 2A or KMT2A) on chromosome 11q23 is disrupted in a unique group of acute leukemias. More than 80 different partner genes in these fusions have been described, although the vast majority of leukemias result from MLL1 fusions with one of about six common partner genes. Approximately 10% of all leukemias harbor MLL1 translocations. Of these, two patient populations comprise the majority of cases: patients younger than one year of age at diagnosis (primarily acute lymphoblastic leukemias), and young- to-middle-aged adults (primarily acute myeloid leukemias). A much rarer subgroup of patients with MLL1 rearrangements develop leukemia that is attributable to prior treatment with certain chemotherapeutic agents – so-called “therapy related leukemias”. In general, outcomes for all of these patients remain poor when compared to patients with non-MLL1 rearranged leukemias. In this review we will discuss the normal biological roles of MLL1 and its fusion partners, how these roles are hypothesized to be dysregulated in the context of MLL1 rearrangements, and the clinical manifestations of this group of leukemias. We will go on to discuss the progress in clinical management and promising new avenues of research which may lead to more effective targeted therapies for affected patients.

Cerebral Palsy—Trends in Epidemiology and Recent Development in Prenatal Mechanisms of Disease, Treatment, and Prevention

Abstract: Cerebral palsy (CP) is the most common motor disability in childhood. This syndrome is the manifestation of intrauterine pathologies, intrapartum complications and post-natal sequel, especially among preterm neonates. A double hit model theory is proposed suggesting that an intrauterine condition along with intrapartum or postnatal insult lead to the development of CP. Recent reports demonstrated that treatment during the process of preterm birth like magnesium sulfate and post-natal modalities such as cooling may prevent or reduce the prevalence of this syndrome. Moreover, animal model demonstrated that post-natal treatment with anti-inflammatory drugs coupled with nanoparticles may affect the course of the disease in pups with neuroinflammation. The current review would describe the changes in the epidemiology of this disease, the underlying prenatal mechanisms, and possible treatments that may reduce the prevalence of CP and alter the course of disease.

Epigenetic matters: The link between early nutrition, microbiome, and long-term health development

Abstract: Epigenetic modifications are among the most important mechanisms by which environmental factors can influence early cellular differentiation and create new phenotypic traits during pregnancy and within the neonatal period without altering the DNA sequence. A number of antenatal and postnatal factors, such as maternal and neonatal nutrition, pollutant exposure and the composition of microbiota, contribute to the establishment of epigenetic changes that can not only modulate the individual adaptation to the environment, but also have an influence on lifelong health and disease by modifying inflammatory molecular pathways and the immune response. Post-natal intestinal colonization, in turn determined by maternal flora, mode of delivery, early skin-to-skin contact and neonatal diet, leads to specific epigenetic signatures that can affect the barrier properties of gut mucosa and their protective role against later insults, thus potentially predisposing to the development of late-onset inflammatory diseases. The aim of this review is to outline the epigenetic mechanisms of programming and development acting within early life stages, and to examine in detail the role of maternal and neonatal nutrition, microbiota composition and other environmental factors in determining epigenetic changes and their short- and long-term effects.

Providing a Placental Transfusion in Newborns Who Need Resuscitation.

Abstract: Over the past decade there have been several studies and reviews on the importance of providing a placental transfusion to the newborn. Allowing a placental transfusion to occur by delaying the clamping of the umbilical cord is an extremely effective method of enhancing arterial oxygen content, increasing cardiac output and improving oxygen delivery. However, premature and term newborns that require resuscitation have impaired transitional hemodynamics and may warrant different methods to actively provide a placental transfusion while still allowing for resuscitation. In this review we will provide evidence for providing a placental transfusion in these circumstances and methods for implementation. Several factors including cord clamping time, uterine contractions, umbilical blood flow, respirations and gravity play an important role in determining placental transfusion volumes. Lastly, while many practitioners agree that a placental transfusion is beneficial it is not always straightforward to implement, and can be performed using different methods, making this basic procedure important to discuss. We will review three placental transfusion techniques: delayed cord clamping, intact umbilical cord milking and cut-umbilical cord milking. We will also review resuscitation with an intact cord and the evidence in term and preterm newborns supporting this practice. We will discuss perceived risks versus benefits of these procedures. Finally, we will provide key straightforward concepts and implementation strategies to ensure that placental-to-newborn transfusion can become routine practice at any institution.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Diagnosis and Management in Young People: A Primer.

Abstract: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disease that affects children and adolescents as well as adults The etiology has not been established While many pediatricians and other healthcare providers are aware of ME/CFS, they often lack essential knowledge that is necessary for diagnosis and treatment Many young patients experience symptoms for years before receiving a diagnosis This Primer, written by the International Writing Group for Pediatric ME/CFS provides information necessary to understand, diagnose, and man-age the symptoms of ME/CFS in children and adolescents ME/CFS is characterized by overwhelming fatigue with a substantial loss of physical and mental stamina Cardinal features are malaise and a worsening of symptoms following minimal physical or mental exertion These post-exertional symptoms can persist for hours, days, or weeks and are not relieved by rest or sleep Other symptoms include cognitive problems, unrefreshing or disturbed sleep, generalized or localized pain, light-headedness and additional symptoms in multiple organ systems While some young patients can attend school, on a full or part-time basis, many others are wheelchair dependent, housebound, or bedbound Prevalence estimates for pediatric ME/CFS vary from 01%-05% Because there is no diagnostic test for ME/CFS, diagnosis is purely clinical, based on the history and the exclusion of other fatiguing illnesses by physical examination and medical testing Co-existing medical conditions including orthostatic intolerance are common Successful management is based on determining the optimum balance of rest and activity to help prevent post-exertional symptom worsening Medications are helpful to treat pain, insomnia, orthostatic intolerance and other symptoms The published literature on ME/CFS and specifically that describing the diagnosis and management of pediatric ME/CFS is very limited Where published studies are lacking, recommendations are based on the clinical observations and practices of the authors

Primary Ciliary Dyskinesia: An Update on Clinical Aspects, Genetics, Diagnosis, and Future Treatment Strategies

Abstract: Primary ciliary dyskinesia (PCD) is an orphan disease (MIM 244400), autosomal recessive inherited, characterized by motile ciliary dysfunction. The estimated prevalence of PCD is 1:10.000 to 1:20.000 live-born children, but true prevalence could be even higher. PCD is characterized by chronic upper and lower respiratory tract disease, infertility/ectopic pregnancy and situs anomalies, that occur in ≈50% of PCD patients (Kartagener syndrome), and these may be associated with congenital heart abnormalities. Most patients report a daily year-round wet cough or nose congestion starting in the first year of life. Daily wet cough, associated with recurrent infections exacerbations, result in the development of chronic suppurative lung disease, with localized to  diffuse bronchiectasis. No diagnostic test is perfect for confirming PCD. Diagnosis can be challenging and relies on a combination of clinical data, nasal nitric oxide levels plus cilia ultrastructure and function analysis. Adjunctive tests include genetic analysis and repeated tests in ciliary culture specimens. There are currently 33 known genes associated with PCD and correlations between genotype and ultrastructural defects have been increasingly demonstrated. Comprehensive genetic testing may hopefully screen young infants before symptoms occur, thus improving survival. Recent surprising advances in PCD genetic designed a novel approach called “gene editing” to restore gene function and normalise ciliary motility, opening up new avenues for treating PCD. Currently, there are no data from randomized clinical trials to support any specific treatment, thus, management strategies are usually extrapolated from cystic fibrosis. The goal of treatment is to prevent exacerbations, slowing the progression of lung disease. The therapeutic mainstay includes airway clearance manoeuvres mainly with nebulized hypertonic saline and chest physiotherapy, and prompt and aggressive administration of antibiotics. Standardized care at specialized centers using a multidisciplinary approach that imposes surveillance of lung function and of airway biofilm composition likely improves patients outcome. Paediatricians, neonatologists, pulmonologists and ENT surgeons should maintain high awareness of PCD and refer patients to the specialized centre before sustained irreversible lung damage develops. The recent creation of a network of PCD clinical centers, focusing on improving diagnosis and treatment, will hopefully help to improve care and knowledge of PCD patients.

Feasibility of an Autism-Focused Augmented Reality Smartglasses System for Social Communication and Behavioral Coaching.

Abstract: Background: Autism Spectrum Disorder (ASD) is a childhood-onset neurodevelopmental disorder with a rapidly rising prevalence, currently affecting 1 in 68 children, and over 3.5 million people in the United States. Current ASD interventions are primarily based on in-person behavioral therapies that are both costly and difficult to access. These interventions aim to address some of the fundamental deficits that clinically characterize ASD, including deficits in social communication, and the presence of stereotypies, and other autism-related behaviors. Current diagnostic and therapeutic approaches seldom rely on quantitative data measures of symptomatology, severity, or condition trajectory. Methods: Given the current situation, we report on the Brain Power System (BPS), a digital behavioral aid with quantitative data gathering and reporting features. The BPS includes customized smartglasses, providing targeted personalized coaching experiences through a family of gamified augmented-reality applications utilizing artificial intelligence. These applications provide children and adults with coaching for emotion recognition, face directed gaze, eye contact, and behavioral self-regulation. This preliminary case report, part of a larger set of upcoming research reports, explores the feasibility of the BPS to provide coaching in two boys with clinically diagnosed ASD, aged 8 and 9 years. Results: The coaching intervention was found to be well tolerated and rated as being both engaging and fun. Both males could easily use the system, and no technical problems were noted. During the intervention, caregivers reported improved non-verbal communication, eye contact, and social engagement during the intervention. Both boys demonstrated decreased symptoms of ASD, as measured by the Aberrant Behavior Checklist at 24 hours’ post-intervention. Specifically, both cases demonstrated improvements in irritability, lethargy, stereotypy, hyperactivity/noncompliance, and inappropriate speech. Conclusions: Smartglasses using augmented reality may have an important future role in helping address the therapeutic needs of children with ASD. Quantitative data-gathering from such sensor-rich systems may allow for digital phenotyping and the refinement of social communication constructs of the Research Domain Criteria (RDoC). This report provides evidence for the feasibility, usability, and tolerability of one such specialized smartglasses system.

Echocardiographic Evaluation of Pericardial Effusion and Cardiac Tamponade.

Abstract: Pericardial effusion is defined by an increase in the physiological amount of fluid within the pericardial space. It can appear following different medical conditions, mainly related to inflammation and cardiac surgery. Cardiac tamponade is a critical condition that occurs after sudden and/or excessive accumulation of fluid in the pericardial space that restricts appropriate filling of the cardiac chambers disturbing normal hemodynamics and ultimately causing hypotension and cardiac arrest. It is; therefor, a life-threatening condition that must be diagnosed as soon as possible for correct treatment and management. Echocardiographic evaluation of pericardial effusion is paramount for timely and appropriate diagnosis and management. A structured echocardiographic approach including two-dimensional, M-mode and Doppler echocardiographic evaluation assessing: i) quantity and quality of pericardial fluid, ii) collapse of cardiac chambers, iii) respiratory variation of the ventricular diameters, iv) inferior vena cava collapsibility and iv) flow patterns in atrioventricular valves should give the bedside clinician the necessary information to appropriately manage pericardial effusion. Here, we review these key echocardiographic signs that will ensure an appropriate assessment of a patient with pericardial effusion and/or cardiac tamponade.

The Nose and the Lung: United Airway Disease?

Abstract: Epidemiologic, pathophysiological and clinical evidence recently revealed the link between upper and lower airways, changing the global pathogenic view of respiratory allergy. The aim of this review is to highlight the strong interaction between the upper and lower respiratory tract diseases, in particular allergic rhinitis and asthma.

Pregnancy: An Underutilized Window of Opportunity to Improve Long-term Maternal and Infant Health—An Appeal for Continuous Family Care and Interdisciplinary Communication

Abstract: Physiologic adaptations during pregnancy unmask a woman’s predisposition to diseases. Complications are increasingly predicted by first-trimester algorithms, amplify a pre-existing maternal phenotype and accelerate risks for chronic diseases in the offspring up to adulthood (Barker hypothesis). Recent evidence suggests that vice versa, pregnancy diseases also indicate maternal and even grandparent’s risks for chronic diseases (reverse Barker hypothesis). Pub-Med and Embase were reviewed for Mesh-terms „fetal programming” „and „pregnancy complications combined with maternal disease” until January 2017. Studies linking pregnancy complications to future cardiovascular, metabolic and thrombotic risks for mother and offspring were reviewed. Women with a history of miscarriage, fetal growth restriction, pre-eclampsia, preterm delivery, obesity, excessive gestational weight gain, gestational diabetes, subfertility and thrombophilia more frequently demonstrate with echocardiographic abnormalities, higher fasting insulin, lipids, or deviating clotting factors and show defective endothelial function. Thrombophilia hints to thrombotic risks in later life. Pregnancy abnormalities correlate with future cardiovascular and metabolic complications and earlier mortality. Conversely, women with a normal pregnancy have lower rates of subsequent diseases than the general female population creating the term: “Pregnancy as a window for future health”. Although the placenta works as a gatekeeper, many pregnancy complications may lead to sickness and earlier death in later life when the child becomes an adult. The epigenetic mechanisms and the mismatch between pre- and postnatal life have created the term “fetal origin of adult disease”. Up to now, the impact of cardiovascular, metabolic or thrombotic risk profiles has been investigated separately for mother and child. In this manuscript, we strive to illustrate the consequences for both, fetus and mother within a cohesive perspective and thus try to demonstrate the complex interrelationship of genetics and epigenetics for long-term health of societies and future generations. Maternal-fetal medicine specialists should have a key role in the prevention of non-communicable diseases by implementing a framework for patient consultation and interdisciplinary networks. Health care providers and policy makers should increasingly invest in a stratified primary prevention and follow-up to reduce the increasing number of manifest cardiovascular and metabolic diseases and to prevent waste of health care resources.

Effect of Fetal Sex on Maternal and Obstetric Outcomes

Abstract: Fetal sex plays an important role in modifying the course and complications related to pregnancy and may also have an impact on maternal health and well-being both during and after pregnancy. The goal of this article is to review and summarize the findings from published research on physiologic and pathologic changes that may be affected by fetal sex and the effect of these changes on the maternal and obstetrical outcomes. This will help create awareness that fetal sex is not just a random chance event but an interactive process between the mother, the placenta and the fetus. The reported effects of male sex on the course of pregnancy and delivery include: higher incidence of preterm labor in singletons and twins, failure of progression in labor, true umbilical cord knots, cord prolapse, nuchal cord, higher cesarean section rate, higher heart rate variability with increased frequency and duration of decelerations without acidemia and increased risk of gestational diabetes mellitus (GDM) through the poor beta cells function. Similarly, female fetal sex has been reported to modify pregnancy and delivery outcomes including: altered fetal cardiac hemodynamics, increased hypertensive diseases of pregnancy, higher vulnerability of developing type 2 DM after pregnancy possibly because of influences on increased maternal insulin resistance. Placental function is also influenced by fetal sex. Vitamin D metabolism in the placenta varies by fetal sex; and the placenta of a female fetus is more responsive to the relaxing action of magnesium sulfate. Male and female feto-placental units also vary in their responses to environmental toxin exposure. The association of fetal sex with stillbirths is controversial with many studies reporting higher risk of stillbirth in male fetuses; although some smaller and limited studies have reported more stillbirths with female fetus pregnancies. Maternal status such as BMI may in turn also affect the fetus and the placenta in a sex specific manner. There is probably a sex specific maternal-placental-fetal interaction that has significant biological implications of which the mechanisms may be genetic, epigenetic or hormonal. Determination of fetal sex may therefore be an important consideration in management of pregnancy and childbirth.

Monitoring Cerebral Oxygenation in Neonates: An Update.

Abstract: Cerebral oxygenation is not always reflected by systemic arterial oxygenation. Therefore, regional cerebral oxygen saturation (rScO2) monitoring with near-infrared spectroscopy (NIRS) is of added value in neonatal intensive care. rScO2 represents oxygen supply to the brain, while cerebral fractional tissue oxygen extraction, which is the ratio between rScO2 and systemic arterial oxygen saturation, reflects cerebral oxygen utilization. The balance between oxygen supply and utilization provides insight in neonatal cerebral (patho-)physiology. This review highlights the potential and limitations of cerebral oxygenation monitoring with NIRS in the neonatal intensive care unit.

Meckel–Gruber Syndrome: An Update on Diagnosis, Clinical Management, and Research Advances

Abstract: Meckel-Gruber syndrome (MKS) is a lethal autosomal recessive congenital anomaly syndrome caused by mutations in genes encoding proteins that are structural or functional components of the primary cilium. Conditions that are caused by mutations in ciliary genes are collectively termed the ciliopathies, and MKS represents the most severe condition in this group of disorders. The primary cilium is a microtubule-based organelle, projecting from the apical surface of vertebrate cells. It acts as an "antenna" that receives and transduces chemosensory and mechanosensory signals, but also regulates diverse signaling pathways, such as Wnt and Shh, that have important roles during embryonic development. Most MKS proteins localize to a distinct ciliary compartment called the transition zone (TZ) that regulates the trafficking of cargo proteins or lipids. In this review, we provide an up-to-date summary of MKS clinical features, molecular genetics, and clinical diagnosis. MKS has a highly variable phenotype, extreme genetic heterogeneity, and displays allelism with other related ciliopathies such as Joubert syndrome, presenting significant challenges to diagnosis. Recent advances in genetic technology, with the widespread use of multi-gene panels for molecular testing, have significantly improved diagnosis, genetic counseling, and the clinical management of MKS families. These include the description of some limited genotype-phenotype correlations. We discuss recent insights into the molecular basis of disease in MKS, since the functions of some of the relevant ciliary proteins have now been determined. A common molecular etiology appears to be disruption of ciliary TZ structure and function, affecting essential developmental signaling and the regulation of secondary messengers.

Obesity-Related Hypertension in Children.

Abstract: Obesity and hypertension have both been on the rise in children Each is associated with increased cardiovascular disease risk and both track into adulthood, increasing the prevalence of heart disease and related morbidity and mortality All children should be screened for hypertension, but children with comorbid obesity may not only particularly benefit from the screening but may also prove the most challenging to screen Increased arm circumference and conical arm shape are particularly problematic when attempting to obtain an accurate blood pressure (BP) measurement This review focuses on the unique aspects of hypertension evaluation and management in the child with comorbid obesity Specific traditional and non-traditional risk factors that may contribute to elevated BP in children with obesity are highlighted Current proposed pathophysiologic mechanisms by which obesity may contribute to elevated BP and hypertension is reviewed, with focus on the role of the sympathetic nervous system and the renin-angiotensin-aldosterone system This review also presents a targeted treatment approach to children with obesity-related hypertension, providing evidence for the recommended therapeutic lifestyle change that should form the basis of any antihypertensive treatment plan in this population of at-risk children Advantages of specific pharmacologic agents in the treatment of obesity-related hypertension are also reviewed

The Microbiome and Blood Pressure: Can Microbes Regulate Our Blood Pressure?

Abstract: The surfaces of the human body are heavily populated by a highly diverse microbial ecosystem termed the microbiota. The largest and richest among these highly heterogeneous populations of microbes is the gut microbiota. The collection of microbes and their genes, called the microbiome, has been studied intensely through the past few years using novel metagenomics, metatranscriptomics and metabolomics approaches. This has enhanced our understanding of how the microbiome affects our metabolic, immunologic, neurologic and endocrine homeostasis. Hypertension is a leading cause of cardiovascular disease worldwide; it contributes to stroke, heart disease, kidney failure, premature death and disability. Recently, studies in humans and animals have shown that alterations in microbiota and its metabolites are associated with hypertension and atherosclerosis. In this review, we compile the recent findings and hypotheses describing the interplay between the microbiome and blood pressure, and we highlight some prospects by which utilization of microbiome-related techniques may be incorporated to better understand the pathophysiology and treatment of hypertension.

The Role of Carrageenan and Carboxymethylcellulose in the Development of Intestinal Inflammation

Abstract: Although the exact pathophysiology remains unknown, the development of inflammatory bowel disease (IBD) is influenced by the interplay between genetics, the immune system, and environmental factors such as diet. The commonly used food additives carrageenan and carboxymethylcellulose (CMC) are used to develop intestinal inflammation in animal models. These food additives are excluded from current dietary approaches to induce disease remission in Crohn’s disease such as exclusive enteral nutrition using a polymeric formula. By reviewing the existing scientific literature, this review aims to discuss the role that carrageenan and CMC may play in the development of IBD. Animal studies consistently report that carrageenan and CMC induce histopathological features that are typical of IBD while altering the microbiome, disrupting the intestinal epithelial barrier, inhibiting proteins that provide protection against microorganisms, and stimulating the elaboration of pro-inflammatory cytokines. Similar trials directly assessing the influence of carrageenan and CMC in humans are of course unethical to conduct, but recent studies of human epithelial cells and the human microbiome support the findings from animal studies. Carrageenan and CMC may trigger or magnify an inflammatory response in the human intestine but are unlikely to be identified as the sole environmental factor involved in the development of IBD or in disease recurrence after treatment. However, the widespread use of carrageenan and CMC in foods consumed by the pediatric population in a ‘Western’ diet is on the rise alongside a corresponding increase in IBD incidence, and questions are being raised about the safety of frequent usage of these food additives. Therefore, further research is warranted to elucidate the role of carrageenan and CMC in intestinal inflammation, which may help identify novel nutritional strategies that hinder the development of the disease, or prevent disease relapse post exclusive enteral nutrition treatment.

Review of Pediatric Pheochromocytoma and Paraganglioma

Abstract: Pheochromocytoma and paraganglioma are rare chromaffin cell tumors which secrete catecholamines and form part of the family of neuroendocrine tumors. Although a rare cause of secondary hypertension in pediatrics, the presentation of hypertension in these patients is characteristic and treatment is definitive. The gold standard for diagnosis is via measurement of plasma free metanephrines, with imaging studies performed for localization, identification of metastatic lesions and for surgical resection. Pre-operative therapy with alpha-blocking agents, beta-blockers and potentially tyrosine hydroxylase inhibitors aid in a safe pre, intra and post-operative course. Pheochromocytoma and paraganglioma are inherited in as much as 80% of pediatric cases and all patients with mutations should be followed closely given the risk of recurrence and malignancy. While the presentation of chromaffin cell tumors has been well described with MEN, NF1 and VHL syndromes, the identification of new gene mutations leading to chromaffin cell tumors at a young age is changing the landscape of how clinicians approach such cases. The Paraganglioma-Pheochromocytoma syndromes (SDHx) comprise familial gene mutations, of which the SDHB gene mutation carries a high rate of malignancy. Since the inheritance rate of such tumors is higher than previously described, genetic screening is recommended in all patients and life-long follow-up for recurrent tumors is a must. A multidisciplinary team approach allows for optimal healthcare delivery in such children. This review serves to provide an overview of pediatric pheochromocytoma and paraganglioma, including updates on the preferred methods of imaging, guidelines on gene testing as well as management of hypertension in such patients.

Regulatory T Cells in Allergy and Asthma.

Abstract: The immune system correct functioning requires a sophisticated equilibrium between response to continuous microbial challenges, and tolerance to harmless antigens, like self-antigens, food antigens, commensal microbes, allergens, etc When this equilibrium is altered, it can guide to inflammatory disorders, tumor growth, autoimmunity, and allergy/asthma The objective of this review is to show the existing data on the importance of regulatory T cells (Tregs) on this balance and to underline how intrauterine and early life environmental exposures influence the maturation of the human immune system Genetic and environmental factors during embryo development and/or early life will result in a proper or, by contrary, inadequate immune maturation with either beneficial or deleterious effects on health We have focus here in Tregs as a reflection of the maturity of the immune system We explain the types, origins and the mechanisms of action of these cells discussing their role in allergy and asthma predisposition A better understanding of the role of Tregs in counteracting dysregulated immunity would provide approaches to diminish asthma and other related diseases in infants

Cerebral Autoregulation, Brain Injury, and the Transitioning Premature Infant.

Abstract: Improvements in clinical management of the preterm infant have reduced the rates of the two most common forms of brain injury, severe intraventricular hemorrhage (IVH) and white matter injury (WMI), both of which are contributory factors in the development of cerebral palsy. Nonetheless, they remain a persistent challenge and are associated with a significant increase in the risk of adverse neurodevelopment outcomes. Repeated episodes of ischemia-reperfusion represent a common pathway for both forms of injury, arising from discordance between systemic blood flow and the innate regulation of cerebral blood flow in the germinal matrix and periventricular white matter. Nevertheless, establishing firm hemodynamic boundaries, as a part of neuroprotective strategy, has challenged researchers. Existing measures either demonstrate inconsistent relationships with injury, as in the case of mean arterial blood pressure, or are not feasible for long term monitoring, such as cardiac output estimated by echocardiography. These challenges have led some researchers to focus on the mechanisms which control blood flow to the brain, known as cerebrovascular autoregulation. Historically, the function of the cerebrovascular autoregulatory system has been difficult to quantify, however the evolution of bedside monitoring devices, particularly near-infrared spectroscopy (NIRS), have enabled new insights into these mechanisms and how impairment of blood flow regulation may contribute to catastrophic injury. In this review, we first seek to examine how technological advancement has changed the assessment of cerebrovascular autoregulation in premature infants. Next, we explore how clinical factors, including hypotension, vasoactive medications, acute and chronic hypoxia, and ventilation alter the hemodynamic state of the preterm infant. Additionally, we examine how developmentally-linked or acquired dysfunction in cerebral autoregulation contributes to preterm brain injury. In conclusion, we address exciting new approaches to the measurement of autoregulation and discuss the feasibility of translation to the bedside.

Assessment of Sensory Processing Characteristics in Children between 3 and 11 Years Old: A Systematic Review.

Abstract: The assessment of sensory perception, discrimination, integration, modulation, praxis and other motor skills, such as posture, balance and bilateral motor coordination, is necessary to identify the sensory and motor factors influencing the development of personal autonomy. The aim of this work is to study the assessment tools currently available for identifying different patterns of sensory processing. There are fifteen tests available that have psychometric properties, primarily for the US population. Nine of them apply to children in preschool and up to grade 12. The assessment of sensory processing is a process that includes the use of standardized tests, administration of caregiver questionnaires, and clinical observations. The review of different studies using PRISMA criteria or Osteba Critical Appraisal Cards reveals that the most commonly used tools are the Sensory Integration and Praxis Test, the Sensory Processing Measure and the Sensory Profile.

The Role of Mucosal Immunity in the Pathogenesis of Necrotizing Enterocolitis.

Abstract: Necrotizing enterocolitis (NEC) is the most devastating gastrointestinal disease of prematurity. Although the precise cause is not well understood, the main risk factors thought to contribute to NEC include prematurity, formula feeding, and bacterial colonization. Recent evidence suggests NEC develops as a consequence of intestinal hyper-responsiveness to microbial ligands upon bacterial colonization in the preterm infant, initiating a cascade of aberrant signaling events and a robust pro-inflammatory mucosal immune response. We now have a greater understanding of important mechanisms of disease pathogenesis, such as the role of cytokines, immunoglobulins, and immune cells in NEC. In this review, we will provide an overview of the mucosal immunity of the intestine and the relationship between components of the mucosal immune system involved in the pathogenesis of NEC, while highlighting recent advances in the field that have promise as potential therapeutic targets. First, we will describe the cellular components of the intestinal epithelium and mucosal immune system and their relationship to NEC. We will then discuss the relationship between the gut microbiota and cell signaling that underpins disease pathogenesis. We will conclude our discussion by highlighting notable therapeutic advancements in NEC that target the intestinal mucosal immunity.

Cesarean Section, Formula Feeding, and Infant Antibiotic Exposure: Separate and Combined Impacts on Gut Microbial Changes in Later Infancy.

Abstract: Established during infancy, our complex gut microbial community is shaped by medical interventions and societal preferences, such as cesarean section, formula-feeding and antibiotic use. We undertook this study to apply the Significance Analysis of Microarrays (SAM) method to quantify changes in gut microbial composition during later infancy following the most common birth and postnatal exposures affecting infant gut microbial composition. Gut microbiota of 166 full-term infants in the Canadian Healthy Infant Longitudinal Development birth cohort were profiled using 16S high-throughput gene sequencing. Infants were placed into groups according to mutually-exclusive combinations of birth mode (vaginal/cesarean birth), breastfeeding status (yes/no) and antibiotic use (yes/no) by 3 months of age. Based on repeated permutations of data and adjustment for the false discovery rate, the SAM statistic identified statistically significant changes in gut microbial abundance between 3 months and 1 year of age within each infant group. We observed well-known patterns of microbial phyla succession in later infancy (declining Proteobacteria; increasing Firmicutes and Bacteroidetes) following vaginal birth, breastfeeding and no antibiotic exposure. Genus Lactobacillus, Roseburia and Faecalibacterium species appeared in the top 10 increases to microbial abundance in these infants. Deviations from this pattern were evident among infants with other perinatal co-exposures; notably, the largest number of microbial species with unchanged abundance was seen in gut microbiota following early cessation of breastfeeding in infants. With and without antibiotic exposure, the absence of a breast milk diet by 3 months of age following vaginal birth yielded a higher proportion of unchanged abundance of Bacteroidaceae and Enterobacteriaceae in later infancy, and a higher ratio of unchanged Enterobacteriaceae to Alicaligenaceae microbiota. Gut microbiota of infants born vaginally and exclusively formula-fed became less enriched with family Veillonellaceae and Clostridiaceae, showed unchanging levels of Ruminococcaceae and exhibited a greater decline in the Rikenellaceae/ Bacteroideceae ratio compared to their breastfed, vaginally-delivered counterparts. These changes were also evident in cesarean-delivered infants to a lesser extent. The clinical relevance of these trajectories of microbial change is that they culminate in taxon-specific abundances in the gut microbiota of later infancy, which we and others have observed to be associated with food sensitization.

Echocardiographic Evaluation of Patent Ductus Arteriosus in Preterm Infants.

Abstract: Patent ductus arteriosus (PDA) is part of the typical morbidity profile of the preterm infant, with a high incidence of 80¬–90% in extremely low birth weight infants born before 26 weeks of gestation. Whereas spontaneous closure of the ductus arteriosus (DA) is likely in term infants, it is less so in preterm ones. PDA is associated with increased mortality and various comorbidities including cardiac failure, need for respiratory support, bronchopulmonary dysplasia, pulmonary or intracranial hemorrhage and necrotizing enterocolitis; however, there is no proven causality between these morbidities and the presence of DA. Thus, the indication to close PDA remains highly controversial. This paper focuses on echocardiographic evaluation of PDA in the preterm infant and particularly on the echocardiographic signs of hemodynamic significance.

Oxidative Stress and Bronchial Asthma in Children—Causes or Consequences?

Abstract: Bronchial asthma is one of the most common chronic inflammatory diseases of the airways. In the pathogenesis of this disease, the interplay among the genes, intrinsic and extrinsic factors is crucial. Various combinations of the involved factors determine and modify the final clinical phenotype/endotype of asthma. Oxidative stress results from imbalance between the production of reactive oxygen and nitrogen species and the capacity of anti-oxidant defense mechanisms. It was shown that oxidative damage of biomolecules is strongly involved in the asthmatic inflammation. It is evident that asthma is accompanied by oxidative stress in the airways and also at systemic circulation. During the acute exacerbation or allergen challenge, the oxidative stress is more pronounced. On the other hand, the genetic variations in the genes for anti-oxidative and pro-oxidative enzymes is variably associated with various asthmatic subtypes. Whether oxidative stress is the consequence of, or the cause for, chronic changes in asthmatic airways is still being discussed. Contribution of oxidative stress to asthma pathology remains at least partially controversial, since antioxidant interventions have proven rather unsuccessful. According to current knowledge, the relationship between oxidative stress and asthmatic inflammation is bi-directional and genetic predisposition could modify the balance between these two positions – oxidative stress as a cause for or consequence of asthmatic inflammation.

Mental Health Problems in Parents of Children with Congenital Heart Disease

Abstract: This review will provide a concise description of mental health problems in parents of children with a (non-syndromic) congenital heart disease (CHD) during different stressful periods. Predictors of these problems and also implications for clinical practice will be mentioned. Having a child with CHD can be very stressful for parents, who have to face overwhelming emotions and also extra physical, financial, and other practical challenges. Parental distress has been reported in 30-80% of parents and appears not to be related to severity of CHD. Parental mental health, parenting, the parent-child relationship, and parental quality of life can all be affected. Parents, and especially mothers, are at risk of psychological distress, anxiety, depression, somatization, hopelessness, and posttraumatic stress symptoms, which in turn may influence mother's responsiveness. In the long term, the majority of parents adapt successfully to living with a child with CHD, but approximately 40% report a need for psychosocial care. These families may be helped by early psychosocial interventions to alleviate stress and reduce children's emotional and behavioral problems. A holistic approach to early psychosocial interventions should aim at improving coping and enhance parenting. During routine medical checkups, medical professionals should ask about parental stress, family functioning, and psychosocial functioning of the child and, when needed, adequate psychosocial care should be provided.

Anastomotic Strictures after Esophageal Atresia Repair: Incidence, Investigations, and Management, Including Treatment of Refractory and Recurrent Strictures.

Abstract: Improved surgical techniques, as well as preoperative and postoperative care have dramatically changed survival of children with esophageal atresia (EA) over the last decades Nowadays, we are increasingly seeing EA patients experiencing significant short- and long-term gastrointestinal morbidities Anastomotic stricture (AS) is the most common complication following operative repair An esophageal stricture is defined as an intrinsic luminal narrowing in a clinically symptomatic patient, but no symptoms are sensitive or specific enough to diagnose an AS This review aims to provide a comprehensive view of AS in EA children Given the lack of evidence-based data, we critically analyzed significant studies on children as well as adults, including comments on benign strictures with other etiologiesDespite there is no consensus about the goal of the luminal diameter based on the patient’s age, esophageal contrast study and/or endoscopy are recommended to assess the degree of the narrowing A high variability in incidence of ASs is reported in literature, depending on different definitions of AS and on a great number of pre-, intra- and postoperative risk factor influencing the anastomosis outcome The presence of a long gap between the two esophageal ends, with consequent anastomotic tension, is determinant for stricture formation as well as its response to treatment The cornerstone of treatment is endoscopic dilation, whose primary aims are to achieve symptom relief, allow age-appropriate capacity for oral feeding and reduce the risk of pulmonary aspiration No clear advantage of either balloon or bougie dilator has been demonstrated, therefore the choice is based on operator experience and comfort with the equipment Retrospective evidences suggest that selective dilatations (performed only in symptomatic patients) results in significantly less number of dilatation sessions than routine dilations (performed to prevent symptoms) with equal long-term outcomes The response to dilation treatment is variable, and some patients may experience recurrent and refractory ASs Adjunctive treatments have been used, including local injection of steroids, topical application of Mitomycin-C and esophageal stenting, but long-term studies are needed to prove their efficacy and safety Stricture resection or esophageal replacement with an interposition graft remain options for AS refractory to conservative treatments

Dynamic Akt/mTOR Signaling in Children with Autism Spectrum Disorder.

Abstract: Autism Spectrum disorder (ASD) is a behaviorally defined disorder affecting 1 in 68 children. Currently, there is no known cause for the majority of ASD cases nor are there physiological diagnostic tools or biomarkers to aid behavioral diagnosis. However, sibling concordance suggests a strong genetic component to this disorder. Whole-genome linkage studies, genome wide association studies, copy number variation screening and SNP analyses have identified several ASD candidate genes, but which vary greatly among individuals and family clusters, suggesting that a variety of genetic mutations may result in a common pathology or alter a common mechanistic pathway. Among the most highly associated single gene mutations in ASD are those in the Akt/mTOR pathway, including FMR1 (Fragile X), TSC1 or TSC2 (Tuberous Sclerosis), PTEN (Cowden’s Syndrome), and NF1 (Neurofibromatosis type 1). The Akt/mTOR pathway is involved in many cellular processes including synaptic plasticity and immune function that can alter neurodevelopment. We also tested the hypothesis that primary T cell could be useful as a relatively non-invasive test to assess dynamic Akt/mTOR signaling that would not be capable in post-mortem tissues. To address this, we examined activity of the Akt/mTOR pathway in primary cells isolated from young children with ASD and typically developing controls of the same age. Phosphorylation levels of insulin receptor substrate-1 (IRS1), phosphatase and tensin homolog (PTEN), tuberin (TSC2), Akt, glycogen synthase kinase 3 (GSK3)α, GSK3β, mammalian target of rapamycin (mTOR), p70S6 kinase (p70S6K), ribosomal protein S6 (RPS6), and extracellular receptor kinase (ERK) were measured in all subjects. We observed higher activity of mTOR, ERK, p70S6K, as well as lower activity of GSK3α (p=0.050) and TSC2 in cells from children with ASD, which suggests higher activity in the Akt/mTOR pathway. ASD subjects also exhibited higher activity of the Akt/mTOR pathway than controls after 15 minutes and 45 minutes of cellular activation. In this article, we describe a phosphorylation pattern in the general/idiopathic ASD population of high Akt/mTOR pathway activity, which had been previously described for known ASD associated mutations, and may suggest a common pathological pathway of interest for ASD.

Oxygen Use in Neonatal Care: A Two-edged Sword.

Abstract: In the neonatal period, the clinical use of oxygen should be taken into consideration for its beneficial and toxicity effects. Oxygen toxicity is due to the development of reactive oxygen species (ROS) such as OH• that is one of the strongest oxidants in nature. Of note, generation of ROS is a normal occurrence in human and it is involved in a myriad of physiological reactions. Anyway an imbalance between production of oxidant species and antioxidant defenses, called oxidative stress, could affect various aspect of organisms' physiology and it could determine pathological consequences to living beings. Neonatal oxidative stress is essentially due to decreased antioxidants, increased ROS, or both. Studies have demonstrated that antioxidant capacity is lower in preterm newborns than term babies. This well-known deficiency of antioxidant factors is only a piece of a cohort of factors, which can be involved in the neonatal oxidative stress and the increased production of ROS may be a main factor. Mechanisms of ROS generation are: mitochondrial respiratory chain, free iron and Fenton reaction, inflammation, hypoxia and/or ischemia, reperfusion, and hyperoxia. Oxidative stress following hyperoxia has been recognized to be responsible for lung, central nervous system, retina, red blood cell injuries, and possibly generalized tissue damage. When supplemental oxygen is needed for care, it would be prudent to avoid changes and fluctuations in SpO2. The definition of the safest level of oxygen saturations in the neonate remains an area of active research. Currently, on the basis of the published evidences, the most suitable approach would be to set alarm limits between 90 and 95%. It should allow to avoid SpO2 values associated with potential hypoxia and/or hyperoxia. Although the usefulness of antioxidant protection in the neonatal period is still under investigation, the risk of tissue damage due to oxidative stress in perinatal period should not be underestimated.

Alterations in Cerebral Blood Flow after Resuscitation from Cardiac Arrest.

Abstract: Greater than 50% of patients successfully resuscitated from cardiac arrest have evidence of neurological disability. Numerous studies in children and adults, as well as in animal models have demonstrated that cerebral blood flow is impaired after cardiac arrest. Stages of cerebral perfusion post-resuscitation include early hyperemia, followed by hypoperfusion, and finally either resolution of normal blood flow or protracted hyperemia. At the level of the microcirculation the blood flow is heterogeneous, with areas of no flow, low flow, and increased flow. Cerebral blood flow directed therapies in animal models of cardiac arrest improved neurological outcome, and therefore the alterations in cerebral blood flow after cardiac arrest likely contribute to the development of hypoxic ischemic encephalopathy. Current intensive care after cardiac arrest is centered upon maintaining systemic oxygenation, normal blood pressure values for age, maintaining general homeostasis, and avoiding hyperthermia, Assessment of cerebral blood flow and oxygenation is not routinely performed after cardiac arrest. Currently available and underutilized techniques to assess cerebral perfusion include transcranial doppler, near infrared spectroscopy, and arterial spin label magnetic resonance imaging. Limited clinical studies established the role of cerebral blood flow and oxygenation monitoring in prognostication after cardiac arrest and few studies suggest that guiding critical care post-resuscitation to mean arterial pressures above the minimal autoregulatory range might improve outcome. Important knowledge gaps thus remain in cerebral monitoring and cerebral blood flow and oxygen goal-directed therapies post-resuscitation from cardiac arrest.