記述言語：英語   出版者・発行元：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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記述言語：英語   出版者・発行元：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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記述言語：英語   出版者・発行元：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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記述言語：英語  

記述言語：日本語   出版者・発行元：日本毒性学会  

<p>発達毒性を有する環境汚染物質の多くは、妊娠期曝露によって胎児への血流異常を引き起こす。胎児への血流異常は胎児発育不全（FGR）の主要因であり、FGRを誘発する環境汚染物質の毒性の共通性を理解するためには、胎児への血流低下そのものが児の発達に及ぼす影響について分析する必要がある。そこで本研究では、胎児への血流を制御可能な新規モデル動物の作製法確立を目的として行った。</p><p>妊娠17日目のラットの子宮動脈、卵巣動脈に、吸水により緩徐に膨張するアメロイドコンストリクター（AC）を装着することで各血管を狭窄し、モデル動物を作製した。内径0.40 mmまたは0.45 mmのACを装着して、子宮内血流量の経時的変化、仔の体重推移と行動変化、大脳皮質ならびに海馬における神経細胞数を評価した。血流測定の結果、AC装着による子宮内血流量の緩徐な低下が認められ、妊娠20日には内径0.40 mmのACにより60%、内径0.45 mmのACにより70%まで低下した。体重推移では、両方のAC装着群で、生後3日から22日まで偽手術群に対して慢性的な減少が認められた。行動試験の結果、生後8日における背地走性の低下、生後1ヵ月における協調運動能と運動学習能の低下、生後5ヵ月での認知機能と空間作業記憶の低下がAC装着群で認められた。さらに、生後2ヵ月のAC装着群で、大脳皮質および海馬において神経細胞数の減少が認められた。</p><p>本研究により、緩徐かつ持続的な胎児への血流不全を再現した新規モデルの作製に成功した。さらに、AC内径を変えることで、血流の段階的な制御が可能であることを示唆した。また、手術により作製されたFGR仔ラットの脳組織や脳機能の変化は、臨床上でヒトに認められるFGRに近い表現型を示していた。今後、本モデル動物を用い、血流不全そのものが発達に及ぼす影響について調査することで、血流不全を引き起こす様々な環境汚染物質の発達毒性の共通性を横断的に理解することに貢献する。</p>

DOI： 10.14869/toxpt.51.1.0_p-318

CiNii Research

記述言語：英語   出版者・発行元：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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記述言語：英語   出版者・発行元：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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記述言語：英語   出版者・発行元：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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記述言語：英語   出版者・発行元：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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出版者・発行元：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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記述言語：英語   出版者・発行元：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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記述言語：日本語   出版者・発行元：日本毒性学会  

<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

出版者・発行元：Journal of Cerebral Blood Flow and Metabolism  

DOI： 10.1177/0271678X20972656

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出版者・発行元：Frontiers in Cellular Neuroscience  

DOI： 10.3389/fncel.2020.00212

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出版者・発行元：Cytotherapy  

DOI： 10.1016/j.jcyt.2020.01.009

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出版者・発行元：Stem Cells and Development  

DOI： 10.1089/scd.2019.0221

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記述言語：日本語   出版者・発行元：日本毒性学会  

<p>【目的】重金属類やダイオキシン類に加え、残留性有機汚染物質やPM2.5を含む大気汚染物質など、生殖発生毒性を有する環境汚染物質は多数存在する。これらの物質の多くは、共通して胎児への血流不全を引き起こし、脳発達異常のリスク因子であることが報告されている。そこで本研究では、生殖発生毒性の横断的な理解を進めるべく、胎児への血流を抑制可能な新規動物モデルの確立を目的として行った。</p><p>【方法】吸水により膨張する血管狭窄器具（内径0.40または0.45 mm）を妊娠17日のSDラットの子宮動脈、卵巣動脈に装着した。その後、子宮内血流量の経時的変化、仔の体重推移、行動変化、組織学的変化を評価した。</p><p>【結果】子宮内血流量は、器具装着後に時間経過とともに緩徐に低下した。妊娠20日には、内径0.40 mm器具によって60%まで、内径0.45 mm器具によって70%まで低下した。仔の体重推移では、いずれの装着によっても、生後3日から22日まで、偽手術群に対して有意な体重の低下が認められた。特に、低体重個体（-1.5SD値以下）の割合が偽手術群では9%であったのに対し、0.40 mmで51%、0.45 mmでは42%であった。行動試験の結果、8～11日齢における背地走性の低下、1カ月齢における協調運動能と運動学習能の低下が、いずれの装着群においても認められた。加えて、0.40 mm群においては認知機能と空間作業記憶能の低下も認められた。行動試験で変化の認められた機能を司る大脳皮質及び海馬の組織学的解析を行った結果、神経新生の有意な減少が確認された。</p><p>【結論】本研究により、胎児への血流を緩徐かつ持続的に抑制可能な新規モデルの作製に成功した。さらに、使用する器具の内径を変えることで、血流抑制の段階的な調整が可能であることを示した。本研究で確立したモデルは、胎児への血流不全に伴う病理病態、ならびにその病態が生じる機序の解明に繋がり、生殖発生毒性のさらなる理解や新規物質の生殖発生毒の予測に貢献することが期待される。</p>

DOI： 10.14869/toxpt.47.1.0_p-178

CiNii Research

出版者・発行元：Pediatrics International  

DOI： 10.1111/ped.13966

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記述言語：英語   出版者・発行元：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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出版者・発行元：Frontiers in Neurology  

DOI： 10.3389/fneur.2018.00987

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