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Article ; Online: Introduction.

Chaaban, Hala / Hunter, Catherine

2022 Volume 47, Issue 1, Page(s) 151697

Language	English
Publishing date	2022-12-20
Publishing country	United States
Document type	Editorial
ZDB-ID	752403-1
ISSN	1558-075X ; 0146-0005
ISSN (online)	1558-075X
ISSN	0146-0005
DOI	10.1016/j.semperi.2022.151697
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Article: The role of neutrophil extracellular traps in necrotizing enterocolitis.

Klinke, Michaela / Chaaban, Hala / Boettcher, Michael

Frontiers in pediatrics

2023 Volume 11, Page(s) 1121193

Abstract: Necrotizing enterocolitis (NEC) continues to be one of the most common causes of mortality and morbidity in preterm infants. Although not fully elucidated, studies suggest that prematurity, formula feeding, imbalanced vascular supply, and altered ... ...

Abstract	Necrotizing enterocolitis (NEC) continues to be one of the most common causes of mortality and morbidity in preterm infants. Although not fully elucidated, studies suggest that prematurity, formula feeding, imbalanced vascular supply, and altered bacterial colonization play major roles in the pathogenesis of NEC. NEC is characterized by increased cytokine release and leukocyte infiltration. Recent data from preterm infants and animal models of NEC suggest that neutrophil extracellular traps (NETs) are released in intestinal tissue. The contribution of NETs in the pathogenesis and/or prevention/treatment of this disease continues to be controversial. Here, we review the available data on NETs release in NEC in human patients and in different NEC models, highlighting their potential contribution to pathology and resolution of inflammation. Here, we review the available data on NETs release in NEC in human patients and the different NEC models, highlighting their potential contribution to pathology or resolution of inflammation.
Language	English
Publishing date	2023-03-15
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2711999-3
ISSN	2296-2360
ISSN	2296-2360
DOI	10.3389/fped.2023.1121193
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Article: The Nonbacterial Microbiome: Fungal and Viral Contributions to the Preterm Infant Gut in Health and Disease.

Wilson, Adam / Bogie, Brett / Chaaban, Hala / Burge, Kathryn

Microorganisms

2023 Volume 11, Issue 4

Abstract: The intestinal microbiome is frequently implicated in necrotizing enterocolitis (NEC) pathogenesis. While no particular organism has been associated with NEC development, a general reduction in bacterial diversity and increase in pathobiont abundance has ...

Abstract	The intestinal microbiome is frequently implicated in necrotizing enterocolitis (NEC) pathogenesis. While no particular organism has been associated with NEC development, a general reduction in bacterial diversity and increase in pathobiont abundance has been noted preceding disease onset. However, nearly all evaluations of the preterm infant microbiome focus exclusively on the bacterial constituents, completely ignoring any fungi, protozoa, archaea, and viruses present. The abundance, diversity, and function of these nonbacterial microbes within the preterm intestinal ecosystem are largely unknown. Here, we review findings on the role of fungi and viruses, including bacteriophages, in preterm intestinal development and neonatal intestinal inflammation, with potential roles in NEC pathogenesis yet to be determined. In addition, we highlight the importance of host and environmental influences, interkingdom interactions, and the role of human milk in shaping fungal and viral abundance, diversity, and function within the preterm intestinal ecosystem.
Language	English
Publishing date	2023-03-31
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2720891-6
ISSN	2076-2607
ISSN	2076-2607
DOI	10.3390/microorganisms11040909
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Article ; Online: In Vitro Apical-Out Enteroid Model of Necrotizing Enterocolitis.

Burge, Kathryn / Wilson, Adam / Chaaban, Hala

Journal of visualized experiments : JoVE

2022 , Issue 184

Abstract: Necrotizing enterocolitis (NEC) is a devastating disease affecting preterm infants, characterized by intestinal inflammation and necrosis. Enteroids have recently emerged as a promising system to model gastrointestinal pathologies. However, currently ... ...

Abstract	Necrotizing enterocolitis (NEC) is a devastating disease affecting preterm infants, characterized by intestinal inflammation and necrosis. Enteroids have recently emerged as a promising system to model gastrointestinal pathologies. However, currently utilized methods for enteroid manipulation either lack access to the apical surface of the epithelium (three-dimensional [3D]) or are time-consuming and resource-intensive (two-dimensional [2D] monolayers). These methods often require additional steps, such as microinjection, for the model to become physiologically translatable. Here, we describe a physiologically relevant and inexpensive protocol for studying NEC in vitro by reversing enteroid polarity, resulting in the apical surface facing outward (apical-out). An immunofluorescent staining protocol to examine enteroid barrier integrity and junctional protein expression following exposure to tumor necrosis factor-alpha (TNF-α) or lipopolysaccharide (LPS) under normoxic or hypoxic conditions is also provided. The viability of 3D apical-out enteroids exposed to normoxic or hypoxic LPS or TNF-α for 24 h is also evaluated. Enteroids exposed to either LPS or TNF-α, in combination with hypoxia, exhibited disruption of epithelial architecture, a loss of adherens junction protein expression, and a reduction in cell viability. This protocol describes a new apical-out NEC-in-a-dish model which presents a physiologically relevant and cost-effective platform to identify potential epithelial targets for NEC therapies and study the preterm intestinal response to therapeutics.
MeSH term(s)	Animals ; Disease Models, Animal ; Enterocolitis, Necrotizing/pathology ; Humans ; Infant, Newborn ; Infant, Newborn, Diseases ; Infant, Premature ; Intestinal Mucosa/metabolism ; Intestines/pathology ; Lipopolysaccharides/metabolism ; Tumor Necrosis Factor-alpha/metabolism
Chemical Substances	Lipopolysaccharides ; Tumor Necrosis Factor-alpha
Language	English
Publishing date	2022-06-08
Publishing country	United States
Document type	Journal Article ; Video-Audio Media ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2259946-0
ISSN	1940-087X ; 1940-087X
ISSN (online)	1940-087X
ISSN	1940-087X
DOI	10.3791/64003
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Article ; Online: Effect of Hyaluronic Acid 35 kDa on an In Vitro Model of Preterm Small Intestinal Injury and Healing using Enteroid-derived Monolayers.

Wilson, Adam / Burge, Kathryn / Eckert, Jeffrey / Chaaban, Hala

Journal of visualized experiments : JoVE

2022 , Issue 185

Abstract: In vitro scratch wound assays are commonly used to investigate the mechanisms and characteristics of epithelial healing in a variety of tissue types. Here, we describe a protocol to generate a two-dimensional (2D) monolayer from three-dimensional (3D) ... ...

Abstract	In vitro scratch wound assays are commonly used to investigate the mechanisms and characteristics of epithelial healing in a variety of tissue types. Here, we describe a protocol to generate a two-dimensional (2D) monolayer from three-dimensional (3D) non-human primate enteroids derived from intestinal crypts of the terminal ileum. These enteroid-derived monolayers were then utilized in an in vitro scratch wound assay to test the ability of hyaluronan 35 kDa (HA35), a human milk HA mimic, to promote cell migration and proliferation along the epithelial wound edge. After the monolayers were grown to confluency, they were manually scratched and treated with HA35 (50 µg/mL, 100 µg/mL, 200 µg/mL) or control (PBS). Cell migration and proliferation into the gap were imaged using a transmitted-light microscope equipped for live-cell imaging. Wound closure was quantified as percent wound healing using the Wound Healing Size Plugin in ImageJ. The scratch area and rate of cell migration and the percentage of wound closure were measured over 24 h. HA35 in vitro accelerates wound healing in small intestinal enteroid monolayers, likely through a combination of cell proliferation at the wound edge and migration to the wound area. These methods can potentially be used as a model to explore intestinal regeneration in the preterm human small intestine.
MeSH term(s)	Animals ; Cell Movement ; Cell Proliferation ; Hyaluronic Acid/pharmacology ; Intestine, Small ; Wound Healing
Chemical Substances	Hyaluronic Acid (9004-61-9)
Language	English
Publishing date	2022-07-28
Publishing country	United States
Document type	Journal Article ; Video-Audio Media ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2259946-0
ISSN	1940-087X ; 1940-087X
ISSN (online)	1940-087X
ISSN	1940-087X
DOI	10.3791/63758
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Article ; Online: Biomarkers of Necrotizing Enterocolitis: The Search Continues.

Gunasekaran, Aarthi / Devette, Christa / Levin, Samuel / Chaaban, Hala

Clinics in perinatology

2022 Volume 49, Issue 1, Page(s) 181–194

Abstract: Necrotizing enterocolitis (NEC) is the most common gastrointestinal (GI) emergency in the neonatal intensive care unit. Despite advances in medical care, mortality and morbidity from NEC have not changed. This is likely due to the lack of a clear ... ...

Abstract	Necrotizing enterocolitis (NEC) is the most common gastrointestinal (GI) emergency in the neonatal intensive care unit. Despite advances in medical care, mortality and morbidity from NEC have not changed. This is likely due to the lack of a clear understanding of this multifactorial disease, and reliable biomarkers for accurate diagnosis of NEC. Currently, the diagnosis of NEC is made by a combination of nonspecific clinical signs, symptoms, and radiological findings. Though biomarkers have been studied extensively, none offer an acceptable sensitivity or specificity to be used. This review will focus on the available literature on biomarkers for preterm NEC, acknowledging the limitations in studies including the variability of inclusion criteria, and most importantly, the lack of gold standard case definition for NEC.
MeSH term(s)	Biomarkers ; Enterocolitis, Necrotizing/diagnosis ; Female ; Fetal Diseases ; Humans ; Infant, Newborn ; Infant, Newborn, Diseases ; Infant, Premature
Chemical Substances	Biomarkers
Language	English
Publishing date	2022-01-21
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	193116-7
ISSN	1557-9840 ; 0095-5108
ISSN (online)	1557-9840
ISSN	0095-5108
DOI	10.1016/j.clp.2021.11.011
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Article: State-of-the-art review and update of

Bautista, Geoanna M / Cera, Anjali J / Chaaban, Hala / McElroy, Steven J

Frontiers in pediatrics

2023 Volume 11, Page(s) 1161342

Abstract: NEC remains one of the most common causes of mortality and morbidity in preterm infants. Animal models of necrotizing enterocolitis (NEC) have been crucial in improving our understanding of this devastating disease and identifying biochemical pathways ... ...

Abstract	NEC remains one of the most common causes of mortality and morbidity in preterm infants. Animal models of necrotizing enterocolitis (NEC) have been crucial in improving our understanding of this devastating disease and identifying biochemical pathways with therapeutic potential. The pathogenesis of NEC remains incompletely understood, with no specific entity that unifies all infants that develop NEC. Therefore, investigators rely on animal models to manipulate variables and provide a means to test interventions, making them valuable tools to enhance our understanding and prevent and treat NEC. The advancements in molecular analytic tools, genetic manipulation, and imaging modalities and the emergence of scientific collaborations have given rise to unique perspectives and disease correlates, creating novel pathways of investigation. A critical review and understanding of the current phenotypic considerations of the highly relevant animal models of NEC are crucial to developing novel therapeutic and preventative strategies for NEC.
Language	English
Publishing date	2023-04-04
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2711999-3
ISSN	2296-2360
ISSN	2296-2360
DOI	10.3389/fped.2023.1161342
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Article: Melatonin Use in Infants Admitted to Intensive Care Units.

Bradford, Caitlyn / Miller, Jamie L / Harkin, Maura / Chaaban, Hala / Neely, Stephen B / Johnson, Peter N

The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG

2023 Volume 28, Issue 7, Page(s) 635–642

Abstract: Objectives: Sleep deprivation is a risk factor for delirium development, which is a frequent complication of intensive care unit admission. Melatonin has been used for both delirium prevention and treatment. Melatonin safety, efficacy, and dosing ... ...

Abstract	Objectives: Sleep deprivation is a risk factor for delirium development, which is a frequent complication of intensive care unit admission. Melatonin has been used for both delirium prevention and treatment. Melatonin safety, efficacy, and dosing information in neonates and infants is lacking. The purpose of this study was to describe melatonin use in infants regarding indication, dosing, efficacy, and safety. Methods: This descriptive, retrospective study included infants <12 months of age admitted to an intensive care unit receiving melatonin. Data collection included demographics, melatonin regimen, sedative and analgesic agents, antipsychotics, and delirium-causing medications. The primary objective was to identify the melatonin indication and median dose. The secondary objectives included change in delirium, pain, and sedation scores; change in dosing of analgesic and sedative agents; and adverse event identification. Wilcoxon signed rank tests and linear mixed models were employed with significance defined at p < 0.05. Results: Fifty-five patients were included, with a median age of 5.5 months (IQR, 3.9-8.2). Most (n = 29; 52.7%) received melatonin for sleep promotion. The median body weight-based dose was 0.31 mg/kg/dose (IQR, 0.20-0.45). There was a statistical reduction in cumulative morphine equivalent dosing 72 hours after melatonin administration versus before, 17.1 versus 21.4 mg/kg (p = 0.049). No adverse events were noted. Conclusions: Most patients (n = 29; 52.7%) received melatonin for sleep promotion at a median dose was 0.31 mg/kg/dose. Initiation of melatonin was associated with a reduction of opioid exposure; however, there was no reduction in pain/sedation scores.
Language	English
Publishing date	2023-11-23
Publishing country	United States
Document type	Journal Article
ZDB-ID	3028543-4
ISSN	1551-6776
ISSN	1551-6776
DOI	10.5863/1551-6776-28.7.635
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Article ; Online: Impact of neonatal nutrition on necrotizing enterocolitis.

Monzon, Noahlana / Kasahara, Emma M / Gunasekaran, Aarthi / Burge, Kathryn Y / Chaaban, Hala

Seminars in pediatric surgery

2023 Volume 32, Issue 3, Page(s) 151305

Abstract: Necrotizing enterocolitis (NEC) is the leading cause of morbidity and mortality in preterm infants. NEC is multifactorial and the result of a complex interaction of feeding, dysbiosis, and exaggerated inflammatory response. Feeding practices in the ... ...

Abstract	Necrotizing enterocolitis (NEC) is the leading cause of morbidity and mortality in preterm infants. NEC is multifactorial and the result of a complex interaction of feeding, dysbiosis, and exaggerated inflammatory response. Feeding practices in the neonatal intensive care units (NICUs) can vary among institutions and have significant impact on the vulnerable gastointestinal tract of preterm infants. . These practices encompass factors such as the type of feeding and fortification, duration of feeding, and rate of advancement, among others. The purpose of this article is to review the data on some of the most common feeding practices in the NICU and their impact on the development of NEC in preterm infants. Data on the human milk bioactive component glycosaminoglycans, specifically hyaluronan, will also be discussed in the context of postnatal intestinal development and NEC prevention.
MeSH term(s)	Infant ; Infant, Newborn ; Humans ; Infant, Premature ; Enterocolitis, Necrotizing/etiology ; Enterocolitis, Necrotizing/prevention & control ; Milk, Human ; Intensive Care Units, Neonatal ; Infant, Newborn, Diseases
Language	English
Publishing date	2023-05-23
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1133381-9
ISSN	1532-9453 ; 1055-8586
ISSN (online)	1532-9453
ISSN	1055-8586
DOI	10.1016/j.sempedsurg.2023.151305
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Article ; Online: Lipid Composition, Digestion, and Absorption Differences among Neonatal Feeding Strategies: Potential Implications for Intestinal Inflammation in Preterm Infants.

Burge, Kathryn / Vieira, Frederico / Eckert, Jeffrey / Chaaban, Hala

Nutrients

2021 Volume 13, Issue 2

Abstract: Necrotizing enterocolitis (NEC) is a significant cause of morbidity and mortality in the neonatal population. Formula feeding is among the many risk factors for developing the condition, a practice often required in the cohort most often afflicted with ... ...

Abstract	Necrotizing enterocolitis (NEC) is a significant cause of morbidity and mortality in the neonatal population. Formula feeding is among the many risk factors for developing the condition, a practice often required in the cohort most often afflicted with NEC, preterm infants. While the virtues of many bioactive components of breast milk have been extolled, the ability to digest and assimilate the nutritional components of breast milk is often overlooked. The structure of formula differs from that of breast milk, both in lipid composition and chemical configuration. In addition, formula lacks a critical digestive enzyme produced by the mammary gland, bile salt-stimulated lipase (BSSL). The gastrointestinal system of premature infants is often incapable of secreting sufficient pancreatic enzymes for fat digestion, and pasteurization of donor milk (DM) has been shown to inactivate BSSL, among other important compounds. Incompletely digested lipids may oxidize and accumulate in the distal gut. These lipid fragments are thought to induce intestinal inflammation in the neonate, potentially hastening the development of diseases such as NEC. In this review, differences in breast milk, pasteurized DM, and formula lipids are highlighted, with a focus on the ability of those lipids to be digested and subsequently absorbed by neonates, especially those born prematurely and at risk for NEC.
MeSH term(s)	Digestion/physiology ; Enterocolitis, Necrotizing/etiology ; Female ; Gastrointestinal Absorption/physiology ; Humans ; Infant Formula/chemistry ; Infant Nutritional Physiological Phenomena ; Infant, Newborn ; Infant, Premature ; Infant, Premature, Diseases/etiology ; Lipid Metabolism/physiology ; Lipids/analysis ; Male ; Milk, Human/chemistry ; Sterol Esterase/metabolism
Chemical Substances	Lipids ; bile salt-stimulated lipase (EC 3.1.1.-) ; Sterol Esterase (EC 3.1.1.13)
Language	English
Publishing date	2021-02-08
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2518386-2
ISSN	2072-6643 ; 2072-6643
ISSN (online)	2072-6643
ISSN	2072-6643
DOI	10.3390/nu13020550
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