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Abstract: Mitochondria are highly-dynamic, membrane-bound organelles that generate most of the chemical energy needed to power the biochemical reactions in eukaryotic cells. These orga-nelles also communicate with the nucleus and other cellular structures to help maintain somatic homeostasis, allow cellular adaptation to stress, and help maintain the developmental trajectory. Mitochondria also perform numerous other functions to support metabolic, energetic, and epigenet-ic regulation in our cells. There is increasing information on various disorders caused by defects in intrinsic mitochondrial or supporting nuclear genes, on different organ systems. In this review, we have summarized the ultrastructural morphology, structural components, our current understanding of the evolution, biogenesis, dynamics, function, clinical manifestations of mitochondrial dysfunc-tion, and future possibilities. The implications of deficits in mitochondrial dynamics and signaling for embryo viability and offspring health are also explored. We present information from our own clinical and laboratory research in conjunction with information collected from an extensive search in the databases PubMed, EMBASE, and Scopus.

Abstract: The understanding of necrotizing enterocolitis (NEC) etiopathogenesis is incomplete, contributing to the lack of early biomarkers and therapeutic options. Micro RNAs (miRNAs) are a class of RNAs that can alter gene expression and modulate various physiological and pathological processes. Several studies have been performed to evaluate the role of miRNA in the pathogenesis of NEC. In this article, we review the information on miRNAs that have been specifically identified in NEC or have been noted in other inflammatory bowel disorders that share some of the histopathological abnormalities seen frequently in NEC. This review highlights miRNAs that could be useful as early biomarkers of NEC and suggests possible approaches for future translational studies focused on these analytes. It is a novel field with potential for immense translational and clinical relevance in preventing, detecting, or treating NEC in very premature infants. Impact: • Current information categorizes necrotizing enterocolitis (NEC) as a multifactorial disease, but microRNAs (miRNAs) may influence the risk of occurrence of NEC. • MiRNAs may alter the severity of the intestinal injury and the clinical outcome of NEC. • The literature on intestinal diseases of adults suggests additional miRNAs that have not been studied in NEC yet but share some features and deserve further exploration in human NEC, especially if affecting gut dysbiosis, intestinal perfusion, and coagulation disorders.

Varicella-zoster virus (VZV) is a human pathogen of the α-herpesvirus family. Some fetuses infected in utero around 8-20 weeks of pregnancy show signs of congenital varicella syndrome (CVS). Infants born to mothers who develop varicella within 5 days before and 2 days after delivery can experience severe disease with increased mortality. The best diagnostic modality is polymerase chain reaction (PCR), which can be done using vesicular swabs or scrapings, scabs from crusted lesions, tissue from biopsy samples, and cerebrospinal fluid. The prevention and management of varicella infections include vaccination, anti-VZV immunoglobulin, and specific antiviral drugs. In this article, we have reviewed the characteristics of VZV, clinical manifestations, management of perinatal infections, and short- and long-term prognosis.

Enteroviruses (EVs) are major pathogens in young infants. These viruses were traditionally classified into the following four subgenera: polio, coxsackie A and B, and echoviruses. Now that poliomyelitis seems to be controlled in most parts of the world, coxsackie and echoviruses are gaining more attention because (i) the structural and pathophysiological similarities and (ii) the consequent possibilities in translational medicine. Enteroviruses are transmitted mainly by oral and fecal-oral routes; the clinical manifestations include a viral prodrome including fever, feeding intolerance, and lethargy, which may be followed by exanthema; aseptic meningitis and encephalitis; pleurodynia; myopericarditis; and multi-system organ failure. Laboratory diagnosis is largely based on reverse transcriptase-polymerase chain reaction, cell culture, and serology. Prevention and treatment can be achieved using vaccination, and administration of immunoglobulins and antiviral drugs. In this article, we have reviewed the properties of these viruses, their clinical manifestations, and currently available methods of detection, treatment, and prognosis.

Abstract: The etiopathogenesis of necrotizing enterocolitis (NEC) remains unclear, but increasing information suggests that the risk and severity of NEC may be influenced by single nucleotide polymorphisms in many genes. In this article, we have reviewed gene variations that have either been specifically identified in NEC or have been noted in other inflammatory bowel disorders with similar histopathological abnormalities. We present evidence from our own peer-reviewed laboratory studies and data from an extensive literature search in the databases PubMed, EMBASE, and Scopus. To avoid bias in the identification of existing studies, search keywords were short-listed both from our own studies and from PubMed’s Medical Subject Heading (MeSH) thesaurus.

Lipids are a major source of energy during the fetal/neonatal period. Most are received from the mother, either transplacentally during the intrauterine period or via maternal milk after birth. However, in addition to the known nutritional role(s), lipids are now known to bind a variety of cellular receptors to regulate specific patterns in metabolism and gene expression. The expression of these receptors is regulated by various genetic and environmental stimuli, and ligation can activate positive-feedback loops both in the expression and the activity of downstream signaling pathways. In this review, we summarize the role of lipid ligands, cognate receptors, epigenetic regulation, and downstream signaling. Further study of lipid metabolism and downstream signaling pathways can enable specific, disease-focused translational studies.

Short bowel syndrome (SBS) of infancy is a cause of prolonged morbidity with intolerance to enteral feeding, specialized nutritional needs, and partial/total dependence on parenteral nutrition. These infants can benefit from individualized nutritional strategies to support and enhance the process of intestinal adaptation. Early introduction of enteral feeds during the period of intestinal adaptation is crucial, even though the enteral feedings may need to be supplemented with an effective, safe, and nutritionally adequate parenteral nutritional regimen. Newer generation intravenous lipid emulsions can be effective in preventing and treating intestinal failure-associated liver disease. Prevention of infection(s), pharmaceutical interventions to enhance bowel motility and prevent/mitigate bacteria overgrowth, and specialized multidisciplinary care to minimize the injury to other organs such as the liver, kidneys, and the brain can assist in nutritional rehabilitation and lower the morbidity in SBS.

In both fetal and neonatal physiologic and pathologic processes in most organs, endothelial cells are known to play critical roles. Although the endothelium is one of the most ubiquitous cell type in the body, the tight adherence to the blood vessel wall has made it difficult to study their diverse function and structure. In this article, we have reviewed endothelial cell origins and explored their heterogeneity in terms of structure, function, developmental changes, and their role in inflammatory and infectious diseases. We have also attempted to evaluate the untapped therapeutic potentials of endothelial cells in neonatal disease. This article comprises various peer-reviewed studies, including ours, and an extensive database literature search from EMBASE, PubMed, and Scopus.

Background: The pathophysiology of necrotizing enterocolitis (NEC) is not clear, but increasing information suggests that the risk and severity of NEC may be influenced by abnormalities in the enteric nervous system (ENS). Objective: The purpose of this review was to scope and examine the research related to ENS-associated abnormalities that have either been identified in NEC or have been noted in other inflammatory bowel disorders (IBDs) with histopathological abnormalities similar to NEC. The aim was to summarize the research findings, identify research gaps in existing literature, and disseminate them to key knowledge end-users to collaborate and address the same in future studies. Methods: Articles that met the objectives of the study were identified through an extensive literature search in the databases PubMed, EMBASE, and Scopus. Results: The sources identified through the literature search revealed that: (1) ENS may be involved in NEC development and post-NEC complications, (2) NEC development is associated with changes in the ENS, and (3) NEC-associated changes could be modulated by the ENS. Conclusions: The findings from this review identify the enteric nervous as a target in the development and progression of NEC. Thus, factors that can protect the ENS can potentially prevent and treat NEC and post-NEC complications. This review serves to summarize the existing literature and highlights a need for further research on the involvement of ENS in NEC.

Nearly 10% of premature and critically ill infants receive fresh-frozen plasma (FFP) transfusions to reduce their high risk of bleeding. The authors have only limited data to identify relevant clinical predictors of bleeding and to evaluate the efficacy of FFP administration. There is still no consensus on the optimal use of FFP in infants who have abnormal coagulation parameters but are not having active bleeding. The aims of this review are to present current evidence derived from clinical studies focused on the use of FFP in neonatology and then use these data to propose best practice recommendations for the safety of neonates receiving FFP.

The prognosis in surgical necrotizing enterocolitis (NEC) has focused on the total length of the resected bowel; the relative impact of small intestinal vs colonic resection is not well studied.We hypothesized that intestinal resections may reduce mortality and length of hospital stay (LOS) more likely in infants who have NEC extending into the colon than in those with disease limited to the small intestine. We also investigated the relationship between gestational maturation and NEC-related mortality.A retrospective study of 153 patients compared demographic, clinical, and histopathological information in infants who had NEC limited to the small intestine vs disease with colonic involvement.Our 153 infants had a mean (±standard deviation) gestational age of 27.4 ± 3.4 weeks and a birth weight of 987 ± 505 g. NEC was limited to the small intestine in 103 (67.3%) infants and extended into the colon in 50 (32.7%). Infants with small intestinal NEC needed shorter bowel resections of 28 ± 31.9 cm than 42.2 ± 40.7 cm in those with colonic involvement (Bowel resections may be more likely associated with shorter LOS in surgical NEC that involves both the small bowel and colon, even when longer segments of the gastrointestinal tract are removed, than in disease limited to the small intestine.

The incomplete understanding of the etiopathogenesis of necrotizing enterocolitis (NEC) contributes to the lack of timely diagnosis and limited therapeutic options. Non-coding RNAs (ncRNAs) have emerged as key regulators of gene expression in various pathways that can modulate various physiological and pathological processes. Despite several studies revealing the role of ncRNAs in intestinal inflammatory diseases in adults, these remain largely unexplored in NEC. In this article, we review the information on ncRNAs that have been specifically identified in NEC or have been noted in other inflammatory bowel disorders that share some of the histopathological abnormalities seen frequently in NEC. We have assimilated the most current research findings on ncRNAs in intestinal diseases. This is an attempt to explore a novel field that has immense potential for future translational and clinical research in preventing, detecting, and treating NEC.

The association between red blood cell (RBC) transfusions and necrotizing enterocolitis (NEC), so-called transfusion-associated NEC (ta-NEC), was first described in 1987. However, further work is needed to confirm a causal relationship, elucidate underlying mechanisms, and develop possible strategies for prevention. We performed an extensive literature search in the databases PubMed, EMBASE, and Scopus.Although multiple retrospective human studies have strongly suggested an association between blood transfusions and subsequent occurrence of NEC, meta-analyses of randomized controlled trials (RCTs) testing RBC transfusion thresholds or the use of recombinant erythropoiesis-stimulating growth factors did not confirm an association of anemia with ta-NEC. These conflicting data necessitated the development of an animal model to elucidate mechanisms and causal factors. Data from this recent mouse model of ta-NEC highlighted the importance of sequential exposure to severe anemia followed by transfusion for development of ta-NEC.This review summarizes current human and experimental data, highlights open questions, and suggests avenues for further research aimed at preventing ta-NEC in preterm infants. Further studies are required to delineate whether there is a tipping point, in terms of the level and duration of anemia, and to develop an effective strategy for blood management and the quality of RBC transfusions.

Anemia of prematurity (AOP) is a common condition with a well-described chronology, nadir hemoglobin levels, and timeline of recovery. However, the underlying pathophysiology and impact of prolonged exposure of the developing infant to low levels of hemoglobin remains unclear. Phlebotomy losses exacerbate the gradual decline of hemoglobin levels which is insidious in presentation, often without any clinical signs. Progressive anemia in preterm infants is associated with poor weight gain, inability to take oral feeds, tachycardia and exacerbation of apneic, and bradycardic events. There remains a lack of consensus on treatment thresholds for RBC transfusion which vary considerably. This review elaborates on the current state of the problem, its implication for the premature infant including association with subphysiologic cerebral tissue oxygenation, necrotizing enterocolitis, and retinopathy of prematurity. It outlines the impact of prophylaxis and treatment of anemia of prematurity and offers suggestions on improving monitoring and management of the condition.

In the fetus and the neonate, altered macrophage function has been implicated not only in inflammatory disorders but also in developmental abnormalities marked by altered onset, interruption, or imbalance of key structural changes. The developmental role of macrophages were first noted nearly a century ago, at about the same time when these cells were being identified as central effectors in phagocytosis and elimination of microbes. Since that time, we have made considerable progress in understanding the diverse roles that these cells play in both physiology and disease. Here, we review the role of fetal and neonatal macrophages in immune surveillance, innate immunity, homeostasis, tissue remodeling, angiogenesis, and repair of damaged tissues. We also discuss the possibility of therapeutic manipulation of the relative abundance and activation status of macrophage subsets in various diseases. This article combines peer-reviewed evidence from our own studies with results of an extensive literature search in the databases PubMed, EMBASE, and Scopus. IMPACT: We have reviewed the structure, differentiation, and classification of macrophages in the neonatal period. Neonatal macrophages are derived from embryonic, hepatic, and bone marrow precursors. Macrophages play major roles in tissue homeostasis, innate immunity, inflammation, tissue repair, angiogenesis, and apoptosis of various cellular lineages in various infectious and inflammatory disorders. Macrophages and related inflammatory mediators could be important therapeutic targets in several neonatal diseases.

Abstract Integrins are heterodimeric transmembrane cell adhesion molecules made up of alpha (α) and beta (β) subunits arranged in numerous dimeric pairings. These complexes have varying affinities to extracellular ligands. Integrins regulate cellular growth, proliferation, migration, signaling, and cytokine activation and release and thereby play important roles in cell proliferation and migration, apoptosis, tissue repair, as well as in all processes critical to inflammation, infection, and angiogenesis. This review presents current evidence from human and animal studies on integrin structure and molecular signaling, with particular emphasis on signal transduction in infants. We have included evidence from our own laboratory studies and from an extensive literature search in databases PubMed, EMBASE, Scopus, and the electronic archives of abstracts presented at the annual meetings of the Pediatric Academic Societies. To avoid bias in identification of existing studies, key words were short-listed prior to the actual search both from anecdotal experience and from PubMed’s Medical Subject Heading (MeSH) thesaurus. Impact Integrins are a family of ubiquitous αβ heterodimeric receptors that interact with numerous ligands in physiology and disease. Integrins play a key role in cell proliferation, tissue repair, inflammation, infection, and angiogenesis. This review summarizes current evidence from human and animal studies on integrin structure and molecular signaling and promising role in diseases of inflammation, infection, and angiogenesis in infants. This review shows that integrin receptors and ligands are novel therapeutic targets of clinical interest and hold promise as novel therapeutic targets in the management of several neonatal diseases.