Language：English   Publisher：Iscience  

Fetal growth restriction (FGR), driven by intrauterine hypoperfusion, delays brain development and heightens the risk of neurodevelopmental disorders. Nonetheless, current diagnostic strategies rarely capture the subtle neuropathology that emerges in mild FGR. To overcome this limitation, we employed an innovative rodent model that replicates mild FGR through gradual and chronic intrauterine hypoperfusion, mirroring clinical conditions overlooked by conventional severe or acute FGR models. Global proteomics of cerebrospinal fluid identified Alpha-2-Macroglobulin, Neuroserpin, CD200, and Polyubiquitin-B as biomarkers correlated with birth weight and persisting postnatally. Their expression reflected changes in brain tissue and serum, was associated with behavioral deficits, and partially recovered under mesenchymal stem/stromal cell treatment—indicating potential for therapeutic monitoring. Notably, brain-specific Neuroserpin, emerged as a robust indicator of FGR-related neurodevelopmental impairment. This study is the first to propose low-invasive serum biomarkers for the early postnatal detection of mild FGR-induced brain abnormalities, enabling neonatal screening, targeted interventions, and improved long-term outcomes.

DOI： 10.1016/j.isci.2025.113237

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Language：English   Publisher：Brain and Development  

Objective: To clarify the difference in clinical-radiological features between neonatal-onset arterial ischemic stroke (AIS) and presumed neonatal AIS with a normal neonatal neurological history. Methods: Twenty-one neonatal AIS patients and seven with presumed neonatal AIS were identified in Aichi Prefecture, Japan, between 2010 and 2014. MRI and clinical characteristics were determined. Results: Nine patients (43 %) with neonatal AIS and only one patient (13 %) with presumed neonatal AIS underwent emergency cesarean sections (ECS). Pyramidal tract involvement was more common in patients with presumed neonatal AIS (71 %) than in those with neonatal AIS (24 %). The most common sequela, hemiplegia, was present in 33 % of patients with neonatal AIS and 71 % with presumed neonatal AIS. Conclusions: The small number of ECS in presumed neonatal AIS suggests different causal factors from those of neonatal AIS. Given the different distributions of lesions and sequelae, there can be undiagnosed patients with presumed neonatal AIS and no sequelae.

DOI： 10.1016/j.braindev.2025.104343

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Language：English   Publisher：Stem Cells Translational Medicine  

Hypoxic–ischemic encephalopathy (HIE), associated with high mortality and neurological sequelae, lacks established treatment except therapeutic hypothermia. Clinical-grade multilineage-differentiating stress-enduring (Muse) cells (CL2020) demonstrated safety and efficacy in nonclinical HIE rat models, thereby leading to an investigator-initiated clinical trial to evaluate CL2020 safety and tolerability in neonatal HIE as a single-center open-label dose-escalation study with 9 neonates with moderate-to-severe HIE who received therapeutic hypothermia. Each patient received a single intravenous injection of CL2020 cells between 5 and 14 days of age. The low-dose (3 patients) and high-dose (6 patients) groups received 1.5 × 10⁶ and 1.5 × 10⁷ cells/dose, respectively. The occurrence of any adverse event within 12 weeks following CL2020 administration was the primary endpoint of this trial. No significant changes in physiological signs including heart rate, blood pressure, and oxygen saturation were observed during or after administration. The only adverse event that may be related to cell administration was a mild γ-glutamyltransferase level elevation in one neonate, which spontaneously resolved without any treatment. All patients enrolled in the trial survived, and normal developmental quotients (≥ 85) in all 3 domains of the Kyoto Scale of Psychological Development 2001 were observed in 67% of the patients in this trial. CL2020 administration was demonstrated to be safe and tolerable for neonates with HIE. Considering the small number of patients, a randomized controlled confirmatory study is warranted to verify these preliminary findings and evaluate the efficacy of this therapy.

DOI： 10.1093/stcltm/szae071

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Language：English  

Language：Japanese   Publisher：The Japanese Society of Toxicology  

<p>Various environmental pollutants with developmental toxicity cause abnormalities in fetal blood flow when exposed during pregnancy. Abnormalities in fetal blood flow are a major cause of Fetal Growth Restriction (FGR), and to understand the commonalities in the toxicity of environmental pollutants inducing FGR, it is necessary to analyze the impact of reduced fetal blood flow on child development itself. Therefore, the present study aimed to establish a new animal model that could regulate blood flow to the fetus. </p><p>The model animals were prepared by constricting the uterine and ovarian artery of pregnant rats on gestational day 17 with ameloid constrictors (AC), which expand slowly by absorbing water. The AC installation decreased intrauterine blood flow gradually. 0.40 mm AC and 0.45 mm AC decrease to 60% and 70% by gestational day 20. As for body weight, both AC groups showed a chronic decrease compared to the sham operation group. Behavioral tests revealed a decrease in negative geotaxis at day 8, a decrease in coordination and motor learning abilities at 1 month, and a decrease in cognitive function and spatial working memory at 5 months in AC groups. Moreover, a reduction in neurons in the cerebral cortex and hippocampus was observed in AC groups at 2 months. This study provided a novel model mimicking a slow and continuous decrease in fetal blood flow. It also demonstrated that varying the inner diameter of the AC allows for gradual blood flow suppression. This model will contribute to a cross-sectional understanding of the commonalities in developmental toxicity of various pollutants causing blood flow insufficiency.</p>

DOI： 10.14869/toxpt.51.1.0_p-318

CiNii Research

Language：English   Publisher：Scientific Reports  

Multilineage-differentiating stress-enduring (Muse) cells are endogenous reparative pluripotent stem cells present in the bone marrow, peripheral blood, and organ connective tissues. We assessed the homing and therapeutic effects of systemically administered nafimestrocel, a clinical-grade human Muse cell-based product, without immunosuppressants in a neonatal hypoxic–ischemic (HI) rat model. HI injury was induced on postnatal day 7 (P7) and was confirmed by T2-weighted magnetic resonance imaging on P10. HI rats received a single dose nafimestrocel (1 × 10⁶ cells/body) or Hank’s balanced salt solution (vehicle group) intravenously at either three days (on P10; M3 group) or seven days (on P14; M7 group) after HI insult. Radioisotope experiment demonstrated the homing of chromium-51-labeled nafimestrocel to the both cerebral hemispheres. The cylinder test (M3 and M7 groups) and open-field test (M7 group) showed significant amelioration of paralysis and hyperactivity at five weeks of age compared with those in the vehicle group. Nafimestrocel did not cause adverse events such as death or pathological changes in the lung at ten weeks in the both groups. Nafimestrocel attenuated the production of tumor necrosis factor-α and inducible nitric oxide synthase from activated cultured microglia in vitro. These results demonstrate the potential therapeutic benefits and safety of nafimestrocel.

DOI： 10.1038/s41598-023-41026-3

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Language：English   Publisher：Frontiers in Pediatrics  

Introduction: To investigate the mechanism underlying the increased risk of subsequent neurodevelopmental disorders in children born to mothers with preeclampsia, we evaluated the neurodevelopment of offspring of a preeclampsia rat model induced by the administration of N-nitro-L-arginine methyl ester (L-NAME) and identified unique protein signatures in the offspring cerebrospinal fluid. Methods: Pregnant rats received an intraperitoneal injection of L-NAME (250 mg/kg/day) during gestational days 15–20 to establish a preeclampsia model. Behavioral experiments (negative geotaxis, open-field, rotarod treadmill, and active avoidance tests), immunohistochemistry [anti-neuronal nuclei (NeuN) staining in the hippocampal dentate gyrus and cerebral cortex on postnatal day 70], and proteome analysis of the cerebrospinal fluid on postnatal day 5 were performed on male offspring. Results: Offspring of the preeclampsia dam exhibited increased growth restriction at birth (52.5%), but showed postnatal catch-up growth on postnatal day 14. Several behavioral abnormalities including motor development and vestibular function (negative geotaxis test: p < 0.01) in the neonatal period; motor coordination and learning skills (rotarod treadmill test: p = 0.01); and memory skills (active avoidance test: p < 0.01) in the juvenile period were observed. NeuN-positive cells in preeclampsia rats were significantly reduced in both the hippocampal dentate gyrus and cerebral cortex (p < 0.01, p < 0.01, respectively). Among the 1270 proteins in the cerebrospinal fluid identified using liquid chromatography-tandem mass spectrometry, 32 were differentially expressed. Principal component analysis showed that most cerebrospinal fluid samples achieved clear separation between preeclampsia and control rats. Pathway analysis revealed that differentially expressed proteins were associated with endoplasmic reticulum translocation, Rab proteins, and ribosomal proteins, which are involved in various nervous system disorders including autism spectrum disorders, schizophrenia, and Alzheimer's disease. Conclusion: The offspring of the L-NAME-induced preeclampsia model rats exhibited key features of neurodevelopmental abnormalities on behavioral and pathological examinations similar to humans. We found altered cerebrospinal fluid protein profiling in this preeclampsia rat, and the unique protein signatures related to endoplasmic reticulum translocation, Rab proteins, and ribosomal proteins may be associated with subsequent adverse neurodevelopment in the offspring.

DOI： 10.3389/fped.2023.1168173

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Language：English   Publisher：Scientific Reports  

Neonatal necrotizing enterocolitis (NEC) is a serious disease of premature infants that necessitates intensive care and frequently results in life-threatening complications and high mortality. Dedifferentiated fat cells (DFATs) are mesenchymal stem cell-like cells derived from mature adipocytes. DFATs were intraperitoneally administrated to a rat NEC model, and the treatment effect and its mechanism were evaluated. The NEC model was created using rat pups hand fed with artificial milk, exposed to asphyxia and cold stress, and given oral lipopolysaccharides after cesarean section. The pups were sacrificed 96 h after birth for macroscopic histological examination and proteomics analysis. DFATs administration significantly improved the survival rate from 25.0 (vehicle group) to 60.6% (DFAT group) and revealed a significant reduction in macroscopical, histological, and apoptosis evaluation compared with the vehicle group. Additionally, the expression of C–C motif ligand 2 was significantly decreased, and that of interleukin-6 decreased in the DFAT group. DFAT administration ameliorated 93 proteins mainly related to proteins of fatty acid metabolism of the 436 proteins up-/down-regulated by NEC. DFATs improved mortality and restored damaged intestinal tissues in NEC, possibly by improving the abnormal expression of fatty acid-related proteins and reducing inflammation.

DOI： 10.1038/s41598-023-34156-1

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Language：English   Publisher：Scientific Reports  

Fetal growth restriction (FGR), followed by postnatal early catch-up growth, is associated with an increased risk of metabolic dysfunction, including type 2 diabetes in humans. This study aims to determine the effects of FGR and early catch-up growth after birth on the pathogenesis of type 2 diabetes, with particular attention to glucose tolerance, pancreatic islet morphology, and fibrosis, and to elucidate its mechanism using proteomics analysis. The FGR rat model was made by inducing mild intrauterine hypoperfusion using ameroid constrictors (ACs). On day 17 of pregnancy, ACs were affixed to the uterine and ovarian arteries bilaterally, causing a 20.9% reduction in birth weight compared to sham pups. On postnatal day 4 (P4), the pups were assigned to either the good nutrition (GN) groups with 5 pups per dam to ensure postnatal catch-up growth or poor nutrition groups with 15 pups per dam to maintain lower body weight. After weaning, all pups were fed regular chow food ad libitum (P21). Rats in both FGR groups developed glucose intolerance; however, male rats in the FGR good nutrition (FGR-GN) group also developed hypertriglyceridemia and dysmorphic pancreatic islets with fibrosis. A comprehensive and functional analysis of proteins expressed in the pancreas showed that FGR, followed by early catch-up growth, severely aggravated cell adhesion-related protein expression in male offspring. Thus, FGR and early catch-up growth caused pancreatic islet morphological abnormalities and fibrosis associated with the disturbance of cell adhesion-related protein expressions. These changes likely induce glucose intolerance and dyslipidemia in male rats.

DOI： 10.1038/s41598-023-28584-2

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Publisher：Open Forum Infectious Diseases  

Background: Mitigation measures implemented during the coronavirus disease 2019 (COVID-19) pandemic remarkably reduced the incidence of infectious diseases among children. However, a re-emergence of respiratory syncytial virus (RSV) infection was observed in 2021 in Japan. We compared the clinical characteristics of hospitalized patients with RSV infection before and during COVID-19. Methods: We retrospectively enrolled children aged <6 years who were hospitalized with RSV infection in 18 hospitals and compared their clinical characteristics before (January 2019 to April 2020, 1675 patients) and during COVID-19 (September 2020 to December 2021, 1297 patients). Results: The mean age of patients with RSV infection was significantly higher during COVID-19 than before (17.4 vs 13.7 months, P <. 001). Compared with before COVID-19, a 2.6-fold increase in RSV cases in the 2-5 years age group was observed from sentinel surveillance during COVID-19, whereas a 1.2-fold increase was noted in the same age group among hospitalized patients. On average for all patients, consolidation shadows obtained on radiography were less frequently observed (26.1 vs 29.6%, P =. 04), and reduced respiratory assistance (42.2% vs 48.7%, P <. 001) and hospitalization stay (5.7 vs 6.0 days, P <. 001) was required in patients with RSV infection during COVID-19. Conclusions: Coronavirus disease 2019 and social activity restriction caused epidemiological changes in pediatric RSV infections, and a majority of patients with RSV infection aged ≥2 years did not develop severe symptoms requiring hospitalization. The RSV symptoms during the COVID-19 outbreak were equivalent to or milder than in the previous seasons.

DOI： 10.1093/ofid/ofac562

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Language：English   Publisher：BMJ Open  

Introduction Neonatal hypoxic-ischaemic encephalopathy (HIE) is an important illness associated with death or cerebral palsy. This study aims to assess the safety and tolerability of the allogenic human multilineage-differentiating stress-enduring cell (Muse cell)-based product (CL2020) cells in newborns with HIE. This is the first clinical trial of CL2020 cells in neonates. Methods and analysis This is a single-centre, open-label, dose-escalation study enrolling up to 12 patients. Neonates with HIE who receive a course of therapeutic hypothermia therapy, which cools to a body temperature of 33°C-34°C for 72 hours, will be included in this study. A single intravenous injection of CL2020 cells will be administered between 5 and 14 days of age. Subjects in the low-dose and high-dose cohorts will receive 1.5 and 15 million cells per dose, respectively. The primary outcome is the occurrence of any adverse events within 12 weeks after administration. The main secondary outcome is the Bayley Scales of Infant and Toddler Development Third Edition score and the developmental quotient per the Kyoto Scale of Psychological Development 2001 at 78 weeks. Ethics and dissemination This study will be conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. The Nagoya University Hospital Institutional Review Board (No. 312005) approved this study on 13 November 2019. The results of this study will be published in peer-reviewed journal and reported in international conferences. Trial registration numbers NCT04261335, jRCT2043190112.

DOI： 10.1136/bmjopen-2021-057073

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Language：Japanese   Publisher：The Japanese Society of Toxicology  

<p>Fetal growth restriction (FGR), which is mainly induced by intrauterine hypoperfusion, is one of the serious problems in perinatal medicine. Although FGR children show low birth bodyweight, many of them recover to normal weight as they grow up under abundant nutritional environment. However, recent clinical findings suggest that the incidence of type II diabetes may be increased in FGR children who have rapidly regained weight. Hence, the present study aimed to investigate effects of FGR and rapid catch-up growth after birth on glucose tolerance and pancreatic islet morphology and to clarify its mechanisms. To prepare the FGR rat model, mild intrauterine hypoperfusion was induced using vascular stenosis device. The device was affixed to the uterine and ovarian arteries on gestational day 17, resulting in a 20.9% reduction in birth weight. On postnatal day 4, the pups were assigned to either abundant nutrition (AN) or poor nutrition (PN) group. After weaning, all pups were fed regular chow food. Rats in both FGR groups developed glucose intolerance, but it was most prominent in male rats in the FGR GN group, which was also observed pancreatic fibrosis. A comprehensive and functional analysis of proteins expressed in the pancreas revealed that FGR, followed by rapid catch-up growth, significantly exacerbated the expression of cell adhesion-related proteins in the male offspring. Therefore, FGR and early catch-up growth are likely to induce glucose intolerance with islet morphological abnormalities related to disrupted expression of cell adhesion-related proteins.</p>

DOI： 10.14869/toxpt.49.1.0_p-251

CiNii Research

Publisher：Journal of Cerebral Blood Flow and Metabolism  

DOI： 10.1177/0271678X20972656

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Publisher：Frontiers in Cellular Neuroscience  

DOI： 10.3389/fncel.2020.00212

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Publisher：Cytotherapy  

DOI： 10.1016/j.jcyt.2020.01.009

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Publisher：Stem Cells and Development  

DOI： 10.1089/scd.2019.0221

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Language：Japanese   Publisher：The Japanese Society of Toxicology  

<p>Various environmental pollutants possessing the developmental and reproductive toxicity cause fetal growth restriction (FGR) associated with intrauterine hypo-perfusion. To understand pathology of FGR, we established a novel intrauterine hypo-perfusion model, of which blood flow in uterus are gradually and continuously suppressed, in the present study. The novel animal model displayed a low birth weight and dysfunction of central nervous system that are typical manifestations in FGR. The study will contribute to promotion the reproductive and developmental toxicology research.</p>

DOI： 10.14869/toxpt.47.1.0_p-178

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Publisher：Pediatrics International  

DOI： 10.1111/ped.13966

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Language：English   Publisher：Brain and Development  

Hypophosphatasia (HPP) is a rare disorder caused by low serum tissue non-specific alkaline phosphatase (ALP) activity due to hypomorphic mutations in the ALPL gene. HPP is characterized by defective bone mineralization. It frequently accompanies pyridoxine-responsive seizures. Because alkaline phosphatase change pyridoxal 5′ phosphate (PLP) into pyridoxal (PL), which can cross the blood brain barrier and regulates inhibitory neurotransmitter gamma-aminobutyric acid. The female patient was born at a gestational age of 37 weeks 2 days. She presented severe respiratory disorder due to extreme thoracic hypoplasia. With the extremely low serum ALP value (14 IU/L), she was clinically diagnosed as HPP. The diagnosis was confirmed with genetic testing. On day1, the subclinical seizures were detected by aEEG. Together with enzyme replacement therapy by asfotase alfa, pyridoxine hydrochloride was administered, then the seizures were rapidly controlled. While confirming that there was no seizure by aEEG monitoring, pyridoxine hydrochloride was gradually discontinued after 1 month. Before administration of pyridoxine hydrochloride, PL was extremely low (4.7 nM) and PLP was increased (1083 nM). After the withdrawal, PL was increased to 84.9 nM only by enzyme replacement. Monitoring with aEEG enabled early intervention for pyridoxine responsive seizures. Confirming increased serum PL concentration is a prudent step in determining when to reduce or discontinue pyridoxine hydrochloride during enzyme replacement therapy.

DOI： 10.1016/j.braindev.2019.03.015

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Publisher：Frontiers in Neurology  

DOI： 10.3389/fneur.2018.00987

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