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Biomedicines
Special Issues
Neonatal Disease: From Pathophysiology to Current and Emerging Therapeutic Approaches
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Neonatal Disease: From Pathophysiology to Current and Emerging Therapeutic Approaches

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cell Biology and Pathology".

Deadline for manuscript submissions: closed (31 October 2024) | Viewed by 10557

Special Issue Editor

Dr. Fumihiko Namba

E-Mail Website
Guest Editor
Department of Pediatrics, Saitama Medical Center, Saitama Medical University, Kawagoe 3508550, Japan
Interests: bronchopulmonary dysplasia; patent ductus arteriosus; preterm infants
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In light of the remarkable advancements in perinatal and neonatal care, we have witnessed a significant reduction in neonatal and infant mortality rates. Yet, challenges persist, as some infants grapple with neurological, respiratory, gastrointestinal, and other complications despite receiving standard treatments. While fetal therapy, cell therapy, therapeutic medical gases, and therapeutic monoclonal antibodies have emerged as promising avenues for addressing neonatal diseases, there remains a pressing need for a deeper comprehension of the underlying pathophysiology and the development of novel treatment modalities tailored to this intricate landscape.

We cordially invite distinguished researchers like yourself to contribute their original research and comprehensive review articles that delve into the recent breakthroughs in understanding the pathophysiology of neonatal diseases. Additionally, we are eager to receive submissions that shed light on innovative therapeutic approaches and their profound impact on the well-being of afflicted children. We also extend an invitation to researchers exploring the molecular mechanisms underpinning pharmacological interventions in neonatal care.

We earnestly seek original, high-quality contributions that have not been previously published elsewhere nor are currently under review by other esteemed journals or peer-reviewed conferences. Your expertise and insights will undoubtedly enrich the discourse surrounding neonatal healthcare and ultimately pave the way for improved outcomes in neonatal medicine.

We look forward to receiving your valuable contributions and fostering a platform for exchanging knowledge that will undoubtedly shape the future of neonatal care.

Dr. Fumihiko Namba
Guest Editor

Manuscript Submission Information

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Published Papers (7 papers)

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Research

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18 pages, 2655 KiB  
Article
Effects of Prostaglandin E1 and Balloon Atrial Septostomy on Cerebral Blood Flow and Oxygenation in Newborns Diagnosed with Transposition of the Great Arteries
by Manuela Cucerea, Maria-Livia Ognean, Alin-Constantin Pinzariu, Marta Simon, Laura Mihaela Suciu, Dana-Valentina Ghiga, Elena Moldovan and Mihaela Moscalu
Biomedicines 2024, 12(9), 2018; https://doi.org/10.3390/biomedicines12092018 - 4 Sep 2024
Viewed by 667
Abstract
Dextro-transposition of the great arteries (D-TGA) is a critical congenital heart defect that can impact neurodevelopment due to cerebral perfusion and oxygenation disorders followed by alterations in synaptogenesis, gyrification, sulcation, and the microstructure. Brain injuries can occur both pre-operatively and postoperatively, especially white [...] Read more.
Dextro-transposition of the great arteries (D-TGA) is a critical congenital heart defect that can impact neurodevelopment due to cerebral perfusion and oxygenation disorders followed by alterations in synaptogenesis, gyrification, sulcation, and the microstructure. Brain injuries can occur both pre-operatively and postoperatively, especially white matter injuries, neuronal loss, and stroke. Materials and Methods: In a retrospective study conducted at a tertiary center between 2016 and 2023, we investigated the early effects of Prostaglandin E1 (PGE1) administration and balloon atrial septostomy (BAS) on cerebral blood flow and oxygenation in inborn neonates with D-TGA. Cerebral Doppler Ultrasound in the anterior cerebral artery (ACA) was performed to assess the resistive index (RI), Peak Systolic Velocity (PSV), and End-Diastolic Velocity (EVD) before PGE1, before the BAS procedure, and 24 h after birth. Cerebral regional saturations of oxygen (crSO2) and cerebral fractional tissue oxygen extraction (cFTOE) were evaluated. D-TGA patients were divided into the PGE1 group and the PGE1 + BAS group. Age-matched healthy controls were used for comparison. Results: All 83 D-TGA newborns received PGE1 within two hours after delivery, of whom 46 (55.42%) underwent BAS. In addition, 77 newborns composed the control group. PGE1 administration increased crSO2 from 47% to 50% in the PGE1 group, but lower than in controls at 24 h of life, while cFTOE remained elevated. The RI increased 24 h after delivery (0.718 vs. 0.769; p = 0.000002) due to decreased EDV (10.71 vs. 8.74; p < 0.0001) following PGE1 treatment. The BAS procedure resulted in a significant increase in crSO2 from 42% to 51% at 24 h of life in the PGE1 + BAS group. Doppler parameters exhibited a similar trend as observed in the PGE1 group. Conclusions: PGE1 treatment and BAS are lifesaving interventions that may improve cerebral perfusion and oxygenation in newborns with D-TGA during the transition period, as reflected by increasing SpO2 and crSO2. Full article
(This article belongs to the Special Issue Neonatal Disease: From Pathophysiology to Current and Emerging Therapeutic Approaches)
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9 pages, 228 KiB  
Article
The Characteristics and Two-Year Neurodevelopmental Outcomes of Home Oxygen Therapy among Preterm Infants with Bronchopulmonary Dysplasia: A Retrospective Study in a Medical Center in Taiwan
by Han-Pi Chang, En-Pei Lee and Ming-Chou Chiang
Biomedicines 2024, 12(7), 1564; https://doi.org/10.3390/biomedicines12071564 - 15 Jul 2024
Viewed by 781
Abstract
Home oxygen therapy (HOT) is frequently used as a therapeutic strategy for children experiencing chronic oxygen dependency associated with bronchopulmonary dysplasia (BPD). Recent studies have highlighted substantial variations in the characteristics and outcomes of infants requiring oxygen, primarily due to the absence of [...] Read more.
Home oxygen therapy (HOT) is frequently used as a therapeutic strategy for children experiencing chronic oxygen dependency associated with bronchopulmonary dysplasia (BPD). Recent studies have highlighted substantial variations in the characteristics and outcomes of infants requiring oxygen, primarily due to the absence of a consensus on the management of HOT in infants with BPD. We conducted this retrospective study and reviewed the medical records of extremely and very preterm infants who were diagnosed with BPD in a tertiary center in northern Taiwan from January 2020 to September 2021. Their neurodevelopmental outcomes were evaluated at 18 to 24 months of corrected age. A total of 134 patients diagnosed with BPD were divided into a HOT group (n = 39) and a room air group (n = 95). The children in the HOT group had a higher incidence of hemodynamic significant patent ductus arteriosus (PDA) (p = 0.005) and PDA ligation (p = 0.004), high-frequency oscillatory ventilation (p < 0.001), nitrogen oxide inhalation (p < 0.001), pulmonary hypertension (p = 0.01), and longer invasive ventilation (p < 0.001), as well as longer hospitalization (p < 0.001). A multivariate logistic regression model demonstrated that prolonged invasive ventilation (OR = 1.032, 95% CI 0.984–1.020, p = 0.001) was correlated with oxygen dependency in children. Infants with BPD born at advanced gestational age (OR = 0.760, 95%CI 0.582–0.992, p = 0.044) had a decreasing risk of requiring HOT. The children in the HOT group had a higher incidence of emergency room visits (p < 0.001) and re-hospitalization (p = 0.007) within one year of corrected age. The neurodevelopmental outcomes revealed the HOT group had an increasing portion of moderate to severe cognitive delay (18.2% vs. 3.7%, p = 0.009) and moderate to severe language delay (24.2% vs. 6.1%, p = 0.006) at 18 to 24 months of corrected age. In conclusion, infants with BPD necessitating HOT required prolonged invasive ventilation during hospitalization and exhibited a greater prevalence of unfavorable neurodevelopmental outcomes at 18 to 24 months of corrected age as well. Full article
(This article belongs to the Special Issue Neonatal Disease: From Pathophysiology to Current and Emerging Therapeutic Approaches)
16 pages, 5483 KiB  
Article
Extracellular Nicotinamide Phosphoribosyltransferase Is a Therapeutic Target in Experimental Necrotizing Enterocolitis
by Melissa D. Halpern, Akash Gupta, Nahla Zaghloul, Senthilkumar Thulasingam, Christine M. Calton, Sara M. Camp, Joe G. N. Garcia and Mohamed Ahmed
Biomedicines 2024, 12(5), 970; https://doi.org/10.3390/biomedicines12050970 - 28 Apr 2024
Viewed by 1346
Abstract
Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency of prematurity. Postulated mechanisms leading to inflammatory necrosis of the ileum and colon include activation of the pathogen recognition receptor Toll-like receptor 4 (TLR4) and decreased levels of transforming growth factor beta (TGFβ). Extracellular [...] Read more.
Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency of prematurity. Postulated mechanisms leading to inflammatory necrosis of the ileum and colon include activation of the pathogen recognition receptor Toll-like receptor 4 (TLR4) and decreased levels of transforming growth factor beta (TGFβ). Extracellular nicotinamide phosphoribosyltransferase (eNAMPT), a novel damage-associated molecular pattern (DAMP), is a TLR4 ligand and plays a role in a number of inflammatory disease processes. To test the hypothesis that eNAMPT is involved in NEC, an eNAMPT-neutralizing monoclonal antibody, ALT-100, was used in a well-established animal model of NEC. Preterm Sprague–Dawley pups delivered prematurely from timed-pregnant dams were exposed to hypoxia/hypothermia and randomized to control—foster mother dam-fed rats, injected IP with saline (vehicle) 48 h after delivery; control + mAB—foster dam-fed rats, injected IP with 10 µg of ALT-100 at 48 h post-delivery; NEC—orally gavaged, formula-fed rats injected with saline; and NEC + mAb—formula-fed rats, injected IP with 10 µg of ALT-100 at 48 h. The distal ileum was processed 96 h after C-section delivery for histological, biochemical, molecular, and RNA sequencing studies. Saline-treated NEC pups exhibited markedly increased fecal blood and histologic ileal damage compared to controls (q < 0.0001), and findings significantly reduced in ALT-100 mAb-treated NEC pups (q < 0.01). Real-time PCR in ileal tissues revealed increased NAMPT in NEC pups compared to pups that received the ALT-100 mAb (p < 0.01). Elevated serum levels of tumor necrosis factor alpha (TNFα), interleukin 6 (IL-6), interleukin-8 (IL-8), and NAMPT were observed in NEC pups compared to NEC + mAb pups (p < 0.01). Finally, RNA-Seq confirmed dysregulated TGFβ and TLR4 signaling pathways in NEC pups that were attenuated by ALT-100 mAb treatment. These data strongly support the involvement of eNAMPT in NEC pathobiology and eNAMPT neutralization as a strategy to address the unmet need for NEC therapeutics. Full article
(This article belongs to the Special Issue Neonatal Disease: From Pathophysiology to Current and Emerging Therapeutic Approaches)
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13 pages, 470 KiB  
Article
The Outcomes of Preterm Infants with Neonatal Respiratory Distress Syndrome Treated by Minimally Invasive Surfactant Therapy and Non-Invasive Ventilation
by Tzyy-Rong Huang, Hsiu-Lin Chen, Shu-Ting Yang, Pin-Chun Su and Hao-Wei Chung
Biomedicines 2024, 12(4), 838; https://doi.org/10.3390/biomedicines12040838 - 10 Apr 2024
Cited by 1 | Viewed by 2479
Abstract
In recent years, the utilization of minimally invasive surfactant therapy (MIST) and Non-invasive ventilation (NIV) as the primary respiratory assistance has become increasingly prevalent among preterm infants with neonatal respiratory distress syndrome (RDS). This study aims to compare the outcomes between MIST administered [...] Read more.
In recent years, the utilization of minimally invasive surfactant therapy (MIST) and Non-invasive ventilation (NIV) as the primary respiratory assistance has become increasingly prevalent among preterm infants with neonatal respiratory distress syndrome (RDS). This study aims to compare the outcomes between MIST administered with nasal continuous positive airway pressure (NCPAP) versus nasal intermittent positive pressure ventilation (NIPPV), with the objective of exploring the respiratory therapeutic benefits of these two approaches. This retrospective study collected data from the neonatal intensive care unit of Kaohsiung Medical University Hospital spanning from January 2016 to June 2021. Infants were divided into two groups based on the type of NIV utilized. The NCPAP group comprised 32 infants, while the NIPPV group comprised 22 infants. Statistical analysis revealed significant differences: the NIPPV group had a smaller gestational age, lower birth weight, higher proportion of female infants, and earlier initiation of MIST. Additionally, the NIPPV group exhibited higher incidence rates of retinopathy of prematurity, longer respiratory support duration, prolonged hospitalization, and mortality. However, upon adjustment, these differences were not statistically significant. Analysis of venous blood gas and respiratory parameter changes indicated that both the NCPAP and NIPPV groups experienced improvements in oxygenation and ventilation following MIST. Full article
(This article belongs to the Special Issue Neonatal Disease: From Pathophysiology to Current and Emerging Therapeutic Approaches)
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12 pages, 2286 KiB  
Article
Genetic Ablation of Pyruvate Dehydrogenase Kinase Isoform 4 Gene Enhances Recovery from Hyperoxic Lung Injury: Insights into Antioxidant and Inflammatory Mechanisms
by Keisuke Watanabe, Akie Kato, Hiroyuki Adachi, Atsuko Noguchi, Hirokazu Arai, Masato Ito, Fumihiko Namba and Tsutomu Takahashi
Biomedicines 2024, 12(4), 746; https://doi.org/10.3390/biomedicines12040746 - 27 Mar 2024
Viewed by 1260
Abstract
Background: Pyruvate dehydrogenase kinase isoform 4 (PDK4) plays a pivotal role in the regulation of cellular proliferation and apoptosis. The objective of this study was to examine whether the genetic depletion of the PDK4 gene attenuates hyperoxia-induced lung injury in neonatal mice. Methods: [...] Read more.
Background: Pyruvate dehydrogenase kinase isoform 4 (PDK4) plays a pivotal role in the regulation of cellular proliferation and apoptosis. The objective of this study was to examine whether the genetic depletion of the PDK4 gene attenuates hyperoxia-induced lung injury in neonatal mice. Methods: Neonatal PDK4−/− mice and wild-type (WT) mice were exposed to oxygen concentrations of 21% (normoxia) and 95% (hyperoxia) for the first 4 days of life. Pulmonary histological assessments were performed, and the mRNA levels of lung PDK4, monocyte chemoattractant protein (MCP)-1 and interleukin (IL)-6 were assessed. The levels of inflammatory cytokines in lung tissue were quantified. Results: Following convalescence from neonatal hyperoxia, PDK4−/− mice exhibited improved lung alveolarization. Notably, PDK4−/− mice displayed significantly elevated MCP-1 protein levels in pulmonary tissues following 4 days of hyperoxic exposure, whereas WT mice showed increased IL-6 protein levels under similar conditions. Furthermore, neonatal PDK4−/− mice subjected to hyperoxia demonstrated markedly higher MCP-1 mRNA expression at 4 days of age compared to WT mice, while IL-6 mRNA expression remained unaffected in PDK4−/− mice. Conclusions: Newborn PDK4−/− mice exhibited notable recovery from hyperoxia-induced lung injury, suggesting the potential protective role of PDK4 depletion in mitigating lung damage. Full article
(This article belongs to the Special Issue Neonatal Disease: From Pathophysiology to Current and Emerging Therapeutic Approaches)
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Review

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13 pages, 2307 KiB  
Review
Tadalafil for Treatment of Fetal Growth Restriction: A Review of Experimental and Clinical Studies
by Shintaro Maki, Sho Takakura, Makoto Tsuji, Shoichi Magawa, Yuya Tamaishi, Masafumi Nii, Michiko Kaneda, Kenta Yoshida, Kuniaki Toriyabe, Eiji Kondo and Tomoaki Ikeda
Biomedicines 2024, 12(4), 804; https://doi.org/10.3390/biomedicines12040804 - 4 Apr 2024
Cited by 1 | Viewed by 1652
Abstract
Fetal growth restriction (FGR) is a major concern in perinatal care. Various medications have been proposed as potential treatments for this serious condition. Nonetheless, there is still no definitive treatment. We studied tadalafil, a phosphodiesterase-5 inhibitor, as a therapeutic agent for FGR in [...] Read more.
Fetal growth restriction (FGR) is a major concern in perinatal care. Various medications have been proposed as potential treatments for this serious condition. Nonetheless, there is still no definitive treatment. We studied tadalafil, a phosphodiesterase-5 inhibitor, as a therapeutic agent for FGR in clinical studies and animal experiments. In this review, we summarize our preclinical and clinical data on the use of tadalafil for FGR. Our studies in mouse models indicated that tadalafil improved FGR and hypertensive disorders of pregnancy. A phase II trial we conducted provided evidence supporting the efficacy of tadalafil in prolonging pregnancy (52.4 vs. 36.8 days; p = 0.03) and indicated a good safety profile for fetuses and neonates. Fetal, neonatal, and infant mortality was significantly lower in mothers receiving tadalafil treatment than that in controls (total number: 1 vs. 7, respectively; p = 0.03), and no severe adverse maternal events associated with tadalafil were observed. Although further studies are needed to establish the usefulness of tadalafil in FGR treatment, our research indicates that the use of tadalafil in FGR treatment may be a paradigm shift in perinatal care. Full article
(This article belongs to the Special Issue Neonatal Disease: From Pathophysiology to Current and Emerging Therapeutic Approaches)
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Other

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7 pages, 189 KiB  
Opinion
Phosphodiesterase Inhibitors in Fetal Growth Restriction: Do Not Forget to Consider Fetal Sex and Subcellular Compartmentation
by Anne-Christine Peyter, David Baud and Jean-François Tolsa
Biomedicines 2024, 12(10), 2329; https://doi.org/10.3390/biomedicines12102329 - 14 Oct 2024
Viewed by 628
Abstract
Fetal growth restriction (FGR) is a common complication of pregnancy, associated with major perinatal mortality and morbidity, and with an increased risk to develop cardiometabolic diseases later in life. There is currently no effective approach to prevent or treat FGR, despite numerous animal [...] Read more.
Fetal growth restriction (FGR) is a common complication of pregnancy, associated with major perinatal mortality and morbidity, and with an increased risk to develop cardiometabolic diseases later in life. There is currently no effective approach to prevent or treat FGR, despite numerous animal and human studies assessing substances likely to improve fetal growth. Phosphodiesterase (PDE) inhibitors appeared as promising drugs to improve FGR management. However, to date, studies have led to somewhat disappointing or controversial results. In this Opinion article, we would like to draw attention to the need to consider the biological sex and the relative reactivity of human umbilical vein and arteries when developing therapeutic interventions to improve human umbilical circulation using PDE inhibitors. Indeed, we suspect that fetal sex, vessel type and the presence of FGR may influence subcellular compartmentation, which could jeopardize beneficial effects of PDE inhibitors. Full article
(This article belongs to the Special Issue Neonatal Disease: From Pathophysiology to Current and Emerging Therapeutic Approaches)
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