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Sökning: WFRF:(Zhu Xiaoyang)

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1.
  • Duan, Jiajia, et al. (författare)
  • Histological chorioamnionitis and pathological stages on very preterm infant outcomes
  • 2024
  • Ingår i: HISTOPATHOLOGY. - 0309-0167 .- 1365-2559.
  • Tidskriftsartikel (refereegranskat)abstract
    • Aims: Histological chorioamnionitis (HCA) is a condition linked to preterm birth and neonatal infection and its relationship with various pathological stages in extremely preterm neonates, and with their associated short- and long-term consequences, remains a subject of research. This study investigated the connection between different pathological stages of HCA and both short-term complications and long-term outcomes in preterm infants born at or before 32 weeks of gestational age. Methods: Preterm infants born at <= 32 weeks of gestation who underwent placental pathology evaluation and were followed-up at 18-24 months of corrected age were included. Neonates were classified based on their exposure to HCA and were further subdivided into different groups according to maternal inflammatory responses (MIR) and fetal inflammatory responses (FIR) stages. We compared short-term complications during their hospital stay between the HCA-exposed and -unexposed groups and examined the influence of HCA stages on long-term outcomes. Results: The HCA group exhibited distinct characteristics such as higher rates of premature rupture of membranes > 18 h, reduced amniotic fluid, early-onset sepsis, bronchopulmonary dysplasia and intraventricular haemorrhage (IVH) grades III-IV (P < 0.05). The moderate-severe HCA group displayed lower gestational age, lower birth weight and higher incidence of IVH (grades III-IV) and preterm sepsis compared with the mild HCA group (P < 0.05). After adjusting for confounders, the MIR stages 2-3 group showed associations with cognitive impairment and cerebral palsy (P < 0.05), and the FIR stages 2-3 group also showed poor long-term outcomes and cognitive impairment (P < 0.05). Conclusions: Moderate-severe HCA was associated with increased early-onset sepsis, severe IVH and poor long-term outcomes, including cognitive impairment and cerebral palsy. Vigilant prevention strategies are warranted for severe HCA cases in order to mitigate poorer clinical outcomes.
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2.
  • Xu, Jianhua, et al. (författare)
  • A Variant of the Autophagy-Related 5 Gene is Associated with Child Cerebral Palsy
  • 2017
  • Ingår i: Frontiers in Cellular Neuroscience. - : Frontiers Media SA. - 1662-5102. ; 18
  • Tidskriftsartikel (refereegranskat)abstract
    • Cerebral palsy (CP) is a major cause of childhood disability in developed and developing countries, but the pathogenic mechanisms of CP development remain largely unknown. Autophagy is a highly conserved cellular self-digestion of damaged organelles and dysfunctional macromolecules. Growing evidence suggests that autophagy-related gene 5 (ATG5)-dependent autophagy is involved in neural development, neuronal differentiation, and neurological degenerative diseases. The aim of this study was to analyze ATG5 protein expression and gene polymorphisms in Chinese patients with CP and to evaluate the importance of ATG5 in the development of CP. Five polymorphisms from different regions of the ATG5 gene (rs510432, rs3804338, rs573775, rs2299863, and rs6568431) were analyzed in 715 CP patients and 658 controls using MassARRAY. Of these, 58 patients and 56 controls were selected for measurement of plasma ATG5 level using ELISA. The relevance of disease-associated SNPs was evaluated using the SHEsis program. We identified a significant association between rs6568431 and CP (OR = 1.388, 95% CI = 1.173∼1.643, Pallele = 0.0005, Pgenotype = 0.0015). Subgroup analysis showed a highly significant association of rs6568431 with spastic CP (n = 468, OR = 1.511, 95% CI = 1.251∼1.824, Pallele = 8.50e−005, Pgenotype = 1.57e−004) and spastic quadriplegia (OR = 1.927, 95% CI = 1.533∼2.421, Pallele = 7.35e−008, Pgenotype = 3.24e−009). Furthermore, mean plasma ATG5 levels were lower in CP patients than in controls, and individuals carrying the AA genotype of rs6568431 that was positively associated with CP had lower plasma ATG5 levels (P < 0.05). This study demonstrated an association of an ATG5 gene variant and low level of ATG5 protein with CP, and stronger associations with severe clinical manifestations were identified. Our results provide novel evidence for a role of ATG5 in CP and shed light on the molecular mechanisms underlying this neurodevelopmental disorder.
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3.
  • Bi, D., et al. (författare)
  • The association between sex-related interleukin-6 gene polymorphisms and the risk for cerebral palsy
  • 2014
  • Ingår i: Journal of Neuroinflammation. - : Springer Science and Business Media LLC. - 1742-2094. ; 11
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The relationship between genetic factors and the development of cerebral palsy (CP) has recently attracted much attention. Polymorphisms in the genes encoding proinflammatory cytokines have been shown to be associated with susceptibility to perinatal brain injury and development of CP. Interleukin-6 (IL-6) is a proinflammatory cytokine that plays a pivotal role in neonatal brain injury, but conflicting results have been reported regarding the association between IL-6 single nucleotide polymorphisms (SNPs) and CP. The purpose of this study was to analyze IL-6 gene polymorphisms and protein expression and to explore the role of IL-6 in the Chinese CP population. Methods: A total of 753 healthy controls and 713 CP patients were studied to detect the presence of five SNPs (rs1800796, rs2069837, rs2066992, rs2069840, and rs10242595) in the IL-6 locus. Of these, 77 healthy controls and 87 CP patients were selected for measurement of plasma IL-6 by Luminex assay. The SHEsis program was used to analyze the genotyping data. For all comparisons; multiple testing on each individual SNP was corrected by the SNPSpD program. Results: There were no differences in allele or genotype frequencies between the overall CP patients and controls among the five genetic polymorphisms. However, subgroup analysis found significant sex-related differences in allele and genotype frequencies. Differences were found between spastic CP and controls in males for rs2069837; between CP with periventricular leukomalacia and controls in males for rs1800796 and rs2066992; and between term CP and controls in males for rs2069837. Plasma IL-6 levels were higher in CP patients than in the controls, and this difference was more robust in full-term male spastic CP patients. Furthermore, the genotype has an effect on IL-6 synthesis. Conclusions: The influence of IL-6 gene polymorphisms on IL-6 synthesis and the susceptibility to CP is related to sex and gestational age.
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4.
  • Jin, S. C., et al. (författare)
  • Mutations disrupting neuritogenesis genes confer risk for cerebral palsy
  • 2020
  • Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 52:10
  • Tidskriftsartikel (refereegranskat)abstract
    • Whole-exome sequencing of 250 parent-offspring trios identifies an enrichment of rare damaging de novo mutations in individuals with cerebral palsy and implicates genetically mediated dysregulation of early neuronal connectivity in the etiology of this disorder. In addition to commonly associated environmental factors, genomic factors may cause cerebral palsy. We performed whole-exome sequencing of 250 parent-offspring trios, and observed enrichment of damaging de novo mutations in cerebral palsy cases. Eight genes had multiple damaging de novo mutations; of these, two (TUBA1AandCTNNB1) met genome-wide significance. We identified two novel monogenic etiologies,FBXO31andRHOB, and showed that theRHOBmutation enhances active-state Rho effector binding while theFBXO31mutation diminishes cyclin D levels. Candidate cerebral palsy risk genes overlapped with neurodevelopmental disorder genes. Network analyses identified enrichment of Rho GTPase, extracellular matrix, focal adhesion and cytoskeleton pathways. Cerebral palsy risk genes in enriched pathways were shown to regulate neuromotor function in aDrosophilareverse genetics screen. We estimate that 14% of cases could be attributed to an excess of damaging de novo or recessive variants. These findings provide evidence for genetically mediated dysregulation of early neuronal connectivity in cerebral palsy.
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5.
  • Qiao, Y. M., et al. (författare)
  • An association study of IL2RA polymorphisms with cerebral palsy in a Chinese population
  • 2022
  • Ingår i: Bmc Medical Genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 15:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Cerebral palsy (CP), the most common physical disability of childhood, is a nonprogressive movement disorder syndrome. Eighty percent of cases are considered idiopathic without a clear cause. Evidence has shown that cytokine abnormalities are widely thought to contribute to CP. Methods An association between 6 SNPs (rs12244380, rs2025345, rs12722561, rs4749926, rs2104286 and rs706778) in IL2RA (interleukin 2 receptor subunit alpha) and CP was investigated using a case-control method based on 782 CP cases and 778 controls. The allele, genotype and haplotype frequencies of SNPs were assessed using the SHEsis program. Subgroup analyses based on complications and clinical subtypes were also conducted. Results Globally, no differences in genotype or allele frequencies for any SNPs remained significant after Bonferroni correction between patients and controls, except rs706778, which deviated from Hardy-Weinberg equilibrium and was excluded from further analyses. However, subgroup analysis revealed a significant association of rs2025345 with spastic tetraplegia (P genotype = 0.048 after correction) and rs12722561 with CP accompanied by global developmental delay (P allele = 0.045 after correction), even after Bonferroni correction. Conclusions These findings indicated that genetic variations in IL2RA are significantly associated with CP susceptibility in the Chinese Han population, suggesting that IL2RA is likely involved in the pathogenesis of CP. Further investigation with a larger sample size in a multiethnic population is needed to confirm the association.
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6.
  • Shao, Linus Ruijin, 1964, et al. (författare)
  • Nuclear progesterone receptor A and B isoforms in mouse fallopian tube and uterus: implications for expression, regulation, and cellular function
  • 2006
  • Ingår i: American journal of physiology. - : American Physiological Society. - 0193-1849. ; 291:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Progesterone and its interaction with nuclear progesterone receptors (PR) PR-A and PR-B play a critical role in the regulation of female reproductive function in all mammals. However, our knowledge of the regulation and possible cellular function of PR protein isoforms in the fallopian tube and uterus in vivo is still very limited. In the present study, we revealed that equine chorionic gonadotropin (eCG) treatment resulted in a time-dependent increase in expression of both isoforms, reaching a maximal level at 48 h in the fallopian tube. Regulation of PR-A protein expression paralleled that of PR-B protein expression. However, in the uterus PR-B protein levels increased and peaked earlier than PR-A protein levels after eCG treatment. With prolonged exposure to eCG, PR-B protein levels decreased, whereas PR-A protein levels continued to increase. Furthermore, subsequent treatment with human (h)CG decreased the levels of PR protein isoforms in both tissues in parallel with increased endogenous serum progesterone levels. To further elucidate whether progesterone regulates PR protein isoforms, we demonstrated that a time-dependent treatment with progesterone (P(4)) decreased the expression of PR protein isoforms in both tissues, whereas decreases in p27, cyclin D(2), and proliferating cell nuclear antigen protein levels were observed only in the uterus. To define the potential PR-mediated effects on apoptosis, we demonstrated that the PR antagonist treatment increased the levels of PR protein isoforms, induced mitochondrial-associated apoptosis, and decreased in epidermal growth factor (EGF) and EGF receptor protein expression in both tissues. Interestingly, immunohistochemistry indicated that the induction of apoptosis by PR antagonists was predominant in the epithelium, whereas increase in PR protein expression was observed in stromal cells of both tissues. Taken together, these observations suggest that 1) the tissue-specific and hormonal regulation of PR isoform expression in mouse fallopian tube and uterus, where they are potentially involved in regulation of mitochondrial-mediated apoptosis depending on the cellular compartment; and 2) a possible interaction between functional PR protein and growth factor signaling may have a coordinated role for regulating apoptotic process in both tissues in vivo.
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7.
  • Wang, Yangong, et al. (författare)
  • Exome sequencing reveals genetic heterogeneity and clinically actionable findings in children with cerebral palsy
  • 2024
  • Ingår i: NATURE MEDICINE. - 1078-8956 .- 1546-170X. ; 30, s. 1395-1405
  • Tidskriftsartikel (refereegranskat)abstract
    • Cerebral palsy (CP) is the most common motor disability in children. To ascertain the role of major genetic variants in the etiology of CP, we conducted exome sequencing on a large-scale cohort with clinical manifestations of CP. The study cohort comprised 505 girls and 1,073 boys. Utilizing the current gold standard in genetic diagnostics, 387 of these 1,578 children (24.5%) received genetic diagnoses. We identified 412 pathogenic and likely pathogenic (P/LP) variants across 219 genes associated with neurodevelopmental disorders, and 59 P/LP copy number variants. The genetic diagnostic rate of children with CP labeled at birth with perinatal asphyxia was higher than the rate in children without asphyxia (P = 0.0033). Also, 33 children with CP manifestations (8.5%, 33 of 387) had findings that were clinically actionable. These results highlight the need for early genetic testing in children with CP, especially those with risk factors like perinatal asphyxia, to enable evidence-based medical decision-making. Using exome sequencing data from one of the largest cohorts of children with cerebral palsy, the genetic diagnostic rates of single-nucleotide and copy number variants were assessed and a sizeable fraction found to be clinically actionable.
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8.
  • Wang, Yangong, et al. (författare)
  • TEP1 is a risk gene for sporadic cerebral palsy
  • 2021
  • Ingår i: Journal of genetics and genomics. - : Elsevier BV. - 1673-8527. ; 48:12, s. 1134-1138
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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9.
  • Xia, L., et al. (författare)
  • Combined analysis of interleukin-10 gene polymorphisms and protein expression in children with cerebral palsy
  • 2018
  • Ingår i: Frontiers in Neurology. - : Frontiers Media SA. - 1664-2295. ; 9:MAR
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Interleukin-10 (IL-10) is an important anti-inflammatory and immunosuppressive cytokine, and it has indispensable functions in both the onset and development of inflammatory disorders. The association between persistent inflammation and the development of cerebral palsy (CP) has attracted much attention. Objective: The purpose of this study was to investigate whether IL-10 gene polymorphisms and plasma protein expression are associated with CP and to analyze the role of IL-10 in CP. Methods: A total of 282 CP patients and 197 healthy controls were genotyped for IL-10 polymorphisms (rs1554286, rs1518111, rs3024490, rs1800871, and rs1800896). Among them, 95 CP patients and 93 healthy controls were selected for plasma IL-10 measurement. Results: The differences in the rs3024490 (p = 0.033) and rs1800871 (p = 0.033) allele frequencies of IL-10 were determined between CP patients and controls. The frequencies of allele and genotype between CP patients with spastic tetraplegia and normal controls of IL-10 polymorphisms showed significant differences for rs1554286, rs151811, rs3024490, rs1800871, and rs1800896 (pallele = 0.015, 0.009, 0.006, 0.003, and 0.006, pgenotype = 0.039, 0.018, 0.027, 0.012, and 0.03, respectively). The plasma IL-10 protein level in CP patients was higher than normal controls (9.13 ± 0.77 vs. 6.73 ± 0.63 pg/ml, p = 0.017). IL-10 polymorphisms and protein association analysis showed that the TT genotype had higher plasma IL-10 protein levels compared to the GG + GT genotype at rs3024490 (11.14 ± 7.27 vs. 7.44 ± 6.95 pg/ml, p = 0.045, respectively) in CP cases. Conclusion: These findings provide an important contribution toward explaining the pleiotropic role of IL-10 in the complex etiology of CP. © 2018 Xia, Chen, Bi, Song, Zhang, Wang, Zhu, Shang, Xu, Wang, Xing and Zhu.
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10.
  • Yu, T., et al. (författare)
  • Association of NOS1 gene polymorphisms with cerebral palsy in a Han Chinese population: a case-control study
  • 2018
  • Ingår i: Bmc Medical Genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 11:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Cerebral palsy (CP) is the leading cause of motor disability in children; however, its pathogenesis is unknown in most cases. Growing evidence suggests that Nitric oxide synthase 1 (NOS1) is involved in neural development and neurologic diseases. The purpose of this study was to determine whether genetic variants of NOS1 contribute to CP susceptibility in a Han Chinese population. Methods: A case-control study involving 652 CP patients and 636 healthy controls was conducted. Six SNPs in the NOS1 gene (rs3782219, rs6490121, rs2293054, rs10774909, rs3741475, and rs2682826) were selected, and the MassARRAY typing technique was applied for genotyping. Data analysis was conducted using SHEsis online software, and multiple test corrections were performed using SNPSpD online software. Results: There were no significant differences in genotype and allele frequencies between patients and controls for the SNPs except rs6490121, which deviated from Hardy-Weinberg equilibrium and was excluded from further analyses. Subgroup analysis revealed differences in genotype frequencies between the CP with neonatal encephalopathy group (CP + NE) and control group for rs10774909, rs3741475, and rs2682826 (after SNPSpD correction, p = 0.004, 0.012, and 0. 002, respectively). The T allele of NOS1 SNP rs3782219 was negatively associated with spastic quadriplegia (OR = 0.742, 95% CI = 0.600-0.918, after SNPSpD correction, p = 0.023). There were no differences in allele or genotype frequencies between CP subgroups and controls for the other genetic polymorphisms. Conclusions: NOS1 is associated with CP + NE and spastic quadriplegia, suggesting that NOS1 is likely involved in the pathogenesis of CP and that it is a potential therapeutic target for treatment of cerebral injury.
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11.
  • Yuan, Junying, et al. (författare)
  • Cerebral Palsy Heterogeneity: Clinical Characteristics and Diagnostic Significance from a Large-Sample Analysis
  • 2024
  • Ingår i: NEUROEPIDEMIOLOGY. - 0251-5350 .- 1423-0208.
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: Cerebral palsy (CP) is a nonprogressive movement disorder resulting from a prenatal or perinatal brain injury that benefits from early diagnosis and intervention. The timing of early CP diagnosis remains controversial, necessitating analysis of clinical features in a substantial cohort. Methods: We retrospectively reviewed medical records from a university hospital, focusing on children aged >= 24 months or followed up for >= 24 months and adhering to the International Classification of Diseases-10 for diagnosis and subtyping. Results: Among the 2012 confirmed CP cases, 68.84% were male and 51.44% had spastic diplegia. Based on the Gross Motor Function Classification System (GMFCS), 62.38% were in levels I and II and 19.88% were in levels IV and V. Hemiplegic and diplegic subtypes predominantly fell into levels I and II, while quadriplegic and mixed types were mainly levels IV and V. White matter injuries appeared in 46.58% of cranial MRI findings, while maldevelopment was rare (7.05%). Intellectual disability co-occurred in 43.44% of the CP cases, with hemiplegia having the lowest co-occurrence (20.28%, 58/286) and mixed types having the highest co-occurrence (73.85%, 48/65). Additionally, 51.67% (697/1,349) of the children with CP aged >= 48 months had comorbidities. Conclusions: This study underscores white matter injury as the primary CP pathology and identifies intellectual disability as a common comorbidity. Although CP can be identified in infants under 1 year old, precision in diagnosis improves with development. These insights inform early detection and tailored interventions, emphasizing their crucial role in CP management.
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12.
  • Yuan, J., et al. (författare)
  • Lithium treatment is safe in children with intellectual disability
  • 2018
  • Ingår i: Frontiers in Molecular Neuroscience. - : Frontiers Media SA. - 1662-5099. ; 11
  • Tidskriftsartikel (refereegranskat)abstract
    • Lithium is a widely used and effective treatment for individuals with psycho-neurological disorders, and it exhibits protective and regenerative properties in multiple brain injury animal models, but the clinical experience in young children is limited due to potential toxicity. As an interim analysis, this paper reports the safety/tolerability profiles of low-dose lithium treatment in children with intellectual disability (ID) and its possible beneficial effects. In a randomized, single-center clinical trial, 124 children with ID were given either oral lithium carbonate 6 mg/kg twice per day or the same dose of calcium carbonate as a placebo (n = 62/group) for 3 months. The safety of low-dose lithium treatment in children, and all the adverse events were monitored. The effects of low-dose lithium on cognition was evaluated by intelligence quotient (IQ), adaptive capacity was assessed by the Infant-Junior Middle School Students Social-Life Abilities Scale (IJMSSSLAS), and overall performance was evaluated according to the Clinical Global Impression-Improvement (CGI-I) scale. After 3 months of lithium treatment, 13/61 children (21.3%) presented with mild side effects, including 4 (6.6%) with gastrointestinal symptoms, 4 (6.6%) with neurological symptoms, 2 (3.3%) with polyuria, and 3 (4.9%) with other symptoms—one with hyperhidrosis, one with alopecia, and one with drooling. Four children in the lithium group had elevated blood thyroid stimulating hormone, which normalized spontaneously after lithium discontinuation. Both IQ and IJMSSSAS scores increased following 3 months of lithium treatment (F = 11.03, p = 0.002 and F = 7.80, p = 0.007, respectively), but such increases were not seen in the placebo group. CGI-I scores in the lithium group were 1.25 points lower (better) than in the placebo group (F = 82.66, p < 0.001) after 3 months of treatment. In summary, lithium treatment for 3 months had only mild and reversible side effects and had positive effects on cognition and overall performance in children with ID. © 2018 Yuan, Song, Zhu, Sun, Xia, Zhang, Gao, Agam, Wang, Blomgren and Zhu.
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13.
  • Zhang, X. L., et al. (författare)
  • Germinal matrix hemorrhage induces immune responses, brain injury, and motor impairment in neonatal rats
  • 2023
  • Ingår i: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 0271-678X .- 1559-7016. ; 43:2_suppl, s. 49-65
  • Tidskriftsartikel (refereegranskat)abstract
    • Germinal matrix hemorrhage (GMH) is a major complication of prematurity that causes secondary brain injury and is associated with long-term neurological disabilities. This study used a postnatal day 5 rat model of GMH to explore immune response, brain injury, and neurobehavioral changes after hemorrhagic injury. The results showed that CD45(high)/CD11b(+) immune cells increased in the brain after GMH and were accompanied by increased macrophage-related chemokine/cytokines and inflammatory mediators. Hematoma formed as early as 2 h after injection of collagenase VII and white matter injury appeared not only in the external capsule and hippocampus, but also in the thalamus. In addition, GMH caused abnormal motor function as revealed by gait analysis, and locomotor hyperactivity in the elevated plus maze, though no other obvious anxiety or recognition/memory function changes were noted when examined by the open field test and novel object recognition test. The animal model used here partially reproduces the GMH-induced brain injury and motor dysfunction seen in human neonates and therefore can be used as a valid tool in experimental studies for the development of effective therapeutic strategies for GMH-induced brain injury.
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14.
  • Albertsson, Anna-Maj, et al. (författare)
  • The immune response after hypoxia-ischemia in a mouse model of preterm brain injury.
  • 2014
  • Ingår i: Journal of neuroinflammation. - : Springer Science and Business Media LLC. - 1742-2094. ; 11:1
  • Tidskriftsartikel (refereegranskat)abstract
    • BackgroundPreterm brain injury consists primarily of periventricular leukomalacia accompanied by elements of gray-matter injury, and these injuries are associated with cerebral palsy and cognitive impairments. Inflammation is believed to be an important contributing factor to these injuries. The aim of this study was to examine the immune response in a postnatal day (PND) 5 mouse model of preterm brain injury induced by hypoxia-ischemia (HI) that is characterized by focal white and gray-matter injury.MethodsC57Bl/6 mice at PND 5 were subjected to unilateral HI induced by left carotid artery ligation and subsequent exposure to 10% O2 for 50 minutes, 70 minutes, or 80 minutes. At seven days post-HI, the white/gray-matter injury was examined. The immune responses in the brain after HI were examined at different time points after HI using RT-PCR and immunohistochemical staining.ResultsHI for 70 minutes in PND 5 mice induced local white-matter injury with focal cortical injury and hippocampal atrophy, features that are similar to those seen in preterm brain injury in human infants. HI for 50 minutes resulted in a small percentage of animals being injured, and HI for 80 minutes produced extensive infarction in multiple brain areas. Various immune responses, including changes in transcription factors and cytokines that are associated with a T-helper (Th)1/Th17-type response, an increased number of CD4+ T-cells, and elevated levels of triggering receptor expressed on myeloid cells 2 (TREM-2) and its adaptor protein DNAX activation protein of 12 kDa (DAP12) were observed using the HI 70 minute preterm brain injury model.ConclusionsWe have established a reproducible model of HI in PND 5 mice that produces consistent local white/gray-matter brain damage that is relevant to preterm brain injury in human infants. This model provides a useful tool for studying preterm brain injury. Both innate and adaptive immune responses are observed after HI, and these show a strong pro-inflammatory Th1/Th17-type bias. Such findings provide a critical foundation for future studies on the mechanism of preterm brain injury and suggest that blocking the Th1/Th17-type immune response might provide neuroprotection after preterm brain injury.
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15.
  • Albertsson, Anna-Maj, et al. (författare)
  • γδ T cells contribute to injury in the developing brain.
  • 2018
  • Ingår i: The American journal of pathology. - : Elsevier BV. - 1525-2191 .- 0002-9440. ; 188:3, s. 757-767
  • Tidskriftsartikel (refereegranskat)abstract
    • Brain injury in premature infants, especially periventricular leukomalacia, is an important cause of neurological disabilities. Inflammation contributes to the development of perinatal brain injury, but the essential mediators leading to brain injury in early life remain largely unknown. Neonates have reduced capacity for mounting conventional αβT-cell responses. However γδT-cells are already functionally competent during early development and are important in early life immunity. We investigated the potential contribution of γδT-cells to preterm brain injury by using postmortem brains from human preterm infants with periventricular leukomalacia and two animal models of preterm brain injury-the hypoxic-ischemic mouse model and a fetal sheep asphyxia model. Large numbers of γδT-cells were observed in the brains of mice, sheep, and postmortem preterm infants after injury, and depletion of γδT-cells provided protection in the mouse model. The common γδT-cell associated cytokines interferon-γ and interleukin (IL)-17A were not detectable in the brain. Although there were increased mRNA levels of Il17f and Il22 in the mouse brains after injury, neither IL-17F nor IL-22 cytokines contributed to preterm brain injury. These findings highlight unique features of injury in the developing brain where, unlike injury in the mature brain, γδT-cells function as important initiators of injury independently of common γδT-cell associated cytokines. This new finding will help to identify therapeutic targets for preventing or treating preterm infants with brain injury.
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16.
  • Ali, Abukar, 1988, et al. (författare)
  • Antibiotic-killed Staphylococcus aureus induces destructive arthritis in mice.
  • 2015
  • Ingår i: Arthritis & rheumatology (Hoboken, N.J.). - : Wiley. - 2326-5205 .- 2326-5191. ; 67:1, s. 107-116
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: Permanent reduction in joint function is a severe post-infectious complication in patients with Staphylococcus aureus septic arthritis. This reduction in joint function might be caused by persistent joint inflammation after the adequate eradication of bacteria by antibiotics. Methods: We studied whether antibiotic-killed S. aureus induced joint inflammation in mice and elucidated the molecular and cellular mechanism of this type of arthritis. Results: The intraarticular injection of antibiotic-killed S. aureus induced mild to moderate synovitis and bone erosions that lasted for a minimum of 14 days. The frequency and severity of synovitis were significantly reduced in tumor necrosis factor receptor 1 (TNFR1), receptor for Advanced Glycation End Products (RAGE), and toll like receptor 2 (TLR2) knockout mice compared with wild-type animals. The combined depletion of monocytes and neutrophils resulted in a significantly lower frequency of synovitis. Among bacterial factors, insoluble cell debris played a more important role than bacterial DNA or soluble components in inducing joint inflammation. Importantly, anti-TNF therapy abrogated the joint inflammation induced by antibiotic-killed S. aureus. Conclusion: Antibiotic-killed S. aureus induced and maintained the joint inflammation that is mediated through TLR2, TNFR1, and RAGE receptor. The cross-talk between neutrophils and monocytes is responsible for this type of arthritis. Anti-TNF therapy might be used as a novel therapeutic strategy, in combination with antibiotics, to treat staphylococcal septic arthritis. © 2014 American College of Rheumatology.
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17.
  • Cheng, Ye, et al. (författare)
  • Genetic variants in the HLA region contribute to the risk of cerebral palsy
  • 2024
  • Ingår i: BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE. - 0925-4439 .- 1879-260X. ; 1870:3
  • Tidskriftsartikel (refereegranskat)abstract
    • Cerebral palsy (CP) is the most common physical disability in childhood, and genetic factors play an important role in its pathogenesis. However, the genetic contributions remain incompletely elucidated. Here, we conducted a two-stage association study between 1090 CP cases and 1100 healthy controls after whole exome sequencing. The human leukocyte antigen (HLA) allelic predispositions were further analyzed in overall CP and subgroups using multivariate logistic regression. We found a strong signal in the HLA region on chromosome 6, where rs3131787 harbored the most significant association with CP (P = 2.05 x 10-14, OR = 2.22). In comparison to controls, the carrier frequencies of HLA-B*13:02 were significantly higher in children with CP (9.82 % in control vs 19.27 % in CP, P = 1.03 x 10-4, OR = 2.17). Furthermore, the effect of HLA-B*13:02 on increasing the risk of CP mainly existed in cryptogenic CP without exposure to premature birth, low birth weight, birth asphyxia, or periventricular leukomalacia. This study indicated a strong association of HLA variants with CP, which implied that immune dysregulation resulting from immunogenetic variants might underlie the pathogenesis of CP. Our findings provide genetic evidence that an immunomodulator may serve as a promising therapeutic intervention for patients with CP by reinstating the neuroinflammation hemostasis.
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18.
  • Ding, X., et al. (författare)
  • Gut microbiota changes in patients with autism spectrum disorders
  • 2020
  • Ingår i: Journal of Psychiatric Research. - : Elsevier BV. - 0022-3956 .- 1879-1379. ; 129, s. 149-159
  • Tidskriftsartikel (refereegranskat)abstract
    • Autism spectrum disorder (ASD) has a high incidence of intestinal comorbidity, indicating a strong association with gut microbiota. The purpose of this study was to characterize gut microbiota profiles in children with ASD. Seventy-seven children with ASD [33 with mild ASD and 44 with severe ASD according to the Childhood Autism Rating Scale score] and 50 age-matched healthy children were enrolled. Compared with children in the healthy control (HC) group, those in the ASD group showed higher biomass, richness, and biodiversity of gut microbiota, and an altered microbial community structure. At the genus level, there was a significant increase in the relative abundance of unidentified Lachnospiraceae, Clostridiales, Erysipelotrichaceae, Dorea, Collinsella, and Lachnoclostridium, whereas Bacteroides, Faecalibacterium, Parasutterella, and Paraprevotella were significantly lower in the ASD group than in the control group. The presence of unidentified Erysipelotrichaceae, Faecalibacterium, and Lachnospiraceae was positively correlated with ASD severity. Notably, three microbial markers (Faecalitalea, Caproiciproducens and Collinsella) were identified in a random forest model with an area under the curve (AUC) of 0.94 for differentiation between HCs and ASD patients. Furthermore, the validation model was consistent with the discovery set (AUC = 0.98, 95% CI: 97.9%-100%). The training and testing sets were more effective when the number of bacteria was increased. In addition, the functional properties (such as galactose metabolism, glycosyltransferase activity, and glutathione metabolism) displayed significant differences between the ASD and HC groups. The current study provides evidence for the relationship between gut microbiota and ASD, with the findings suggesting that gut microbiota could contribute to symptomology. Thus, modulation of gut microbiota may be a new therapeutic strategy for ASD.
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19.
  • Du, Xiaonan, et al. (författare)
  • Systemic stimulation of TLR2 impairs neonatal mouse brain development.
  • 2011
  • Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 6:5
  • Tidskriftsartikel (refereegranskat)abstract
    • Inflammation is associated with perinatal brain injury but the underlying mechanisms are not completely characterized. Stimulation of Toll-like receptors (TLRs) through specific agonists induces inflammatory responses that trigger both innate and adaptive immune responses. The impact of engagement of TLR2 signaling pathways on the neonatal brain is still unclear. The aim of this study was to investigate the potential effect of a TLR2 agonist on neonatal brain development.
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20.
  • Han, Wei, et al. (författare)
  • Delayed, Long-Term Administration of the Caspase Inhibitor Q-VD-OPh Reduced Brain Injury Induced by Neonatal Hypoxia-Ischemia.
  • 2014
  • Ingår i: Developmental neuroscience. - : S. Karger AG. - 1421-9859 .- 0378-5866. ; 36:1, s. 64-72
  • Tidskriftsartikel (refereegranskat)abstract
    • Apoptosis contributes greatly to the morphological and biochemical features of cell death after neonatal cerebral hypoxia-ischemia (HI), making this mode of cell death a promising therapeutic target. We previously showed that 10 mg/kg of the caspase inhibitor Q-VD-OPh at the onset of and immediately after HI on postnatal day 9 reduced brain infarct volume. In this study, delayed administration of Q-VD-OPh, 12 and 36 h after HI, decreased HI-induced caspase-3 activity (DEVD cleavage) by 23% and diminished the levels of the proinflammatory chemokines CCL2 (MCP-1) and CCL3 (MIP-1α) by 29.3 and 29.1%, respectively, but not the levels of the anti-inflammatory cytokines IL-4 and IL-10. Long-term administration of Q-VD-OPh initiated at 12 h after HI, and continued at 24-hour intervals for 2 weeks, reduced total brain tissue loss by 31.3% from 41.5 ± 3.1 mm(3) in the vehicle group to 28.5 ± 3.0 mm(3) in the Q-VD-OPh group when evaluated 16 weeks after HI (p = 0.004). Q-VD-OPh treatment also ameliorated the loss of sensorimotor function, as evaluated by a cylinder rearing test (Q-VD-OPh: 30.8 ± 4.3% vs. vehicle: 59.7 ± 6.3% in nonimpaired forepaw preference) 3 weeks after HI, and reduced HI-induced hyperactivity, as measured in an open field test (Q-VD-OPh: 4,062 ± 198 cm vs. vehicle: 4,792 ± 205 cm in distance moved) 7 weeks after the insult. However, the functional protection was no longer observed when analyzed again at later time points. The mechanisms underlying the discrepancy between sustained morphological protection and transient functional protection remain to be elucidated. © 2014 S. Karger AG, Basel.
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21.
  • Han, W, et al. (författare)
  • Trends in live births in the past 20 years in Zhengzhou, China
  • 2011
  • Ingår i: ACTA OBSTETRICIA ET GYNECOLOGICA SCANDINAVICA. - 0001-6349. ; 90:4, s. 332-337
  • Tidskriftsartikel (refereegranskat)abstract
    • Abstract: Objective. To evaluate changing trends in neonatal births and deaths in a provincial women's and children's hospital over the past 20 years. Design: Retrospective longitudinal study. Setting. Henan Provincial Women's and Children's Hospital, China. Population. Live births in Henan Provincial Women's and Children's Hospital from January 1987 to December 2006. Methods: Data was stratified by sex, birth weight, delivery type, maternal age, gestational age, and single or multiple births. The incidence of low Apgar scores and neonatal death was calculated for each fiscal year. Main outcome measures: Trends in the fundamental status of hospital-born live births and risk factors for neonatal death. Results. 26 760 hospital live births were included. The ratio of males to females was 1.16:1. The mean gestational age decreased from 39.5 +/- 1.4 weeks to 38.4 +/- 2.5 weeks (p<0.001) and multiple births increased from 1.5 to 7.3% (p<0.001). The proportion of preterm births increased from 4.7 to 18.9% (p<0.001), maternal age increased from 25.9 +/- 3.7 years to 29.0 +/- 4.4 years (p<0.001), and cesarean deliveries increased from 23.7 to 65.5% (p<0.001). The incidence of low Apgar scores decreased from 12.9 to 1.1% (p<0.001). The incidence of neonatal death was 8.5/1 000 live births, with preterm births and low Apgar scores accounting for 72.8 and 16.2% of all neonatal deaths, respectively. Conclusion. Preterm births, multiple births, and cesarean deliveries increased dramatically. Preterm birth is the leading cause of neonatal death.
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22.
  • Huo, Kaiming, et al. (författare)
  • Lithium reduced neural progenitor apoptosis in the hippocampus and ameliorated functional deficits after irradiation to the immature mouse brain.
  • 2012
  • Ingår i: Molecular and cellular neurosciences. - : Elsevier BV. - 1095-9327 .- 1044-7431. ; 51:1-2, s. 32-42
  • Tidskriftsartikel (refereegranskat)abstract
    • Lithium was recently shown to inhibit apoptosis and promote survival of neural progenitor cells after hypoxia-ischemia in the immature rat brain. Our aim was to evaluate the effects of lithium on cell death and proliferation in the hippocampus after irradiation (IR) to the immature brain. Male mice were injected with 2 mmol/kg lithium chloride i.p. on postnatal day 9 (P9) and additional lithium injections, 1 mmol/kg, were administered at 24 h intervals for up to 7 days. BrdU was injected 4 h after lithium injections on P9 and P10. The left hemisphere received a single dose of 8 Gy (MV photons) on P11. The animals were euthanized 6 h or 7 weeks after IR. The number of BrdU-labeled cells in the subgranular zone (SGZ) of the granule cell layer (GCL) 6h after IR was 24% higher in the lithium-treated mice. The number of proliferating, phospho-histone H3-positive cells in the SGZ 7 weeks after IR was 59% higher in the lithium group, so the effect was long-lasting. The number of apoptotic cells in the SGZ 6 h after IR was lower in the lithium group, as judged by 3 different parameters, pyknosis, staining for active caspase-3 and TUNEL. Newly formed cells (BrdU-labeled 1 or 2 days before IR) showed the greatest degree of protection, as judged by 50% fewer TUNEL-positive cells, whereas non-BrdU-labeled cells showed 38% fewer TUNEL-positive cells 6 h after IR. Consequently, the growth retardation of the GCL was less pronounced in the lithium group. The number and size of microglia in the DG were also lower in the lithium group, indicating reduced inflammation. Learning was facilitated after lithium treatment, as judged by improved context-dependent fear conditioning, and improved place learning, as judged by assessment in the IntelliCage platform. In summary, lithium administration could decrease IR-induced neural progenitor cell apoptosis in the GCL of the hippocampus and ameliorate learning impairments. It remains to be shown if lithium can be used to prevent the debilitating cognitive late effects seen in children treated with cranial radiotherapy.
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23.
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24.
  • Huo, Kaiming, et al. (författare)
  • Risk factors for neurodevelopmental deficits in congenital hypothyroidism after early substitution treatment.
  • 2011
  • Ingår i: Endocrine Journal. - 1348-4540 .- 0918-8959. ; 58:5, s. 355-61
  • Tidskriftsartikel (refereegranskat)abstract
    • Neurodevelopment in children with congenital hypothyroidism who receive early treatment is generally good. However, subtle neurological deficits still exist in some patients. The aim of this investigation was to evaluate factors that may influence neurodevelopmental outcome in congenital hypothyroidism patients. The developmental quotient (DQ) of 155 children with congenital hypothyroidism was evaluated at 24 months of age, using Gesell Developmental Schedules (GDS), and compared with that of 310 healthy controls. Mean DQ scores in congenital hypothyroidism patients were 7.5 points lower for adaptive behavior than in control patients (p
  •  
25.
  • Li, B. B., et al. (författare)
  • Folic Acid and Risk of Preterm Birth: A Meta-Analysis
  • 2019
  • Ingår i: Frontiers in Neuroscience. - : Frontiers Media SA. - 1662-4548 .- 1662-453X. ; 13
  • Tidskriftsartikel (refereegranskat)abstract
    • The results from epidemiologic studies linking blood folate concentrations, folic acid supplementation, or dietary folate to the risk of preterm birth are inconsistent. In this study, we aimed to summarize the available evidence on these associations. A systematic search of the PubMed/MEDLINE, Google Scholar, Web of Science, and Cochrane Library databases up to October 20, 2018 was performed and reference lists of retrieved articles were screened. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) for the highest vs. the lowest levels of folate concentrations, folic acid supplementation, and dietary folate were calculated using random-effects models. Subgroup analyses and univariate meta-regression were performed to explore the sources of heterogeneity. Ten studies (six prospective cohort studies and four case-control studies) were included on folate concentrations, 13 cohort studies were included about folic acid supplementation, and 4 cohort studies were included regarding dietary folate intake. Higher maternal folate levels were associated with a 28% reduction in the risk of preterm birth (OR 0.72, 95% CI 0.56-0.93). Higher folic acid supplementation was associated with 10% lower risk of preterm birth (OR 0.90, 95% CI 0.85-0.95). In addition, a significant negative association was observed between dietary folate intake and the risk of preterm birth (OR 0.68, 95% CI 0.55-0.84), but no significant relation was seen between dietary folate and the risk of spontaneous preterm birth (OR 0.89, 95% CI 0.57-1.41). In the subgroup analysis, higher maternal folate levels in the third trimester were associated with a lower risk of preterm birth (OR 0.58, 95% CI 0.36-0.94). To initiate taking folic acid supplementation early before conception was adversely associated with preterm birth risk (OR 0.89, 95% CI 0.83-0.95). In conclusion, higher maternal folate levels and folic acid supplementation were significantly associated with a lower risk of preterm birth. The limited data currently available suggest that dietary folate is associated with a significantly decreased risk of preterm birth.
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26.
  • Li, Hongfu, et al. (författare)
  • Lithium-mediated long-term neuroprotection in neonatal rat hypoxia-ischemia is associated with antiinflammatory effects and enhanced proliferation and survival of neural stem/progenitor cells.
  • 2011
  • Ingår i: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 1559-7016. ; 31:10, s. 2106-2115
  • Tidskriftsartikel (refereegranskat)abstract
    • The aim of this study was to evaluate the long-term effects of lithium treatment on neonatal hypoxic-ischemic brain injury, inflammation, and neural stem/progenitor cell (NSPC) proliferation and survival. Nine-day-old male rats were subjected to unilateral hypoxia-ischemia (HI) and 2mmol/kg lithium chloride was injected intraperitoneally immediately after the insult. Additional lithium injections, 1mmol/kg, were administered at 24-hour intervals for 7 days. Animals were killed 6, 24, 72hours, or 7 weeks after HI. Lithium reduced total tissue loss by 69%, from 89.4±14.6mm(3) in controls (n=15) to 27.6±6.2mm(3) in lithium-treated animals (n=14) 7 weeks after HI (P<0.001). Microglia activation was inhibited by lithium treatment, as judged by Iba-1 and galectin-3 immunostaining, and reduced interleukin-1β and CCL2 levels. Lithium increased progenitor, rather than stem cell, proliferation in both nonischemic and ischemic brains, as judged by 5-bromo-2-deoxyuridine labeling 24 and 72hours as well as by phospho-histone H3 and brain lipid-binding protein labeling 7 weeks after HI. Lithium treatment also promoted survival of newborn NSPCs, without altering the relative levels of neuronal and astroglial differentiation. In summary, lithium conferred impressive, morphological long-term protection against neonatal HI, at least partly by inhibiting inflammation and promoting NSPC proliferation and survival.Journal of Cerebral Blood Flow & Metabolism advance online publication, 18 May 2011; doi:10.1038/jcbfm.2011.75.
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27.
  • Li, H. W., et al. (författare)
  • Novel insights into the immune cell landscape and gene signatures in autism spectrum disorder by bioinformatics and clinical analysis
  • 2023
  • Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 13
  • Tidskriftsartikel (refereegranskat)abstract
    • The pathogenesis of autism spectrum disorder (ASD) is not well understood, especially in terms of immunity and inflammation, and there are currently no early diagnostic or treatment methods. In this study, we obtained six existing Gene Expression Omnibus transcriptome datasets from the blood of ASD patients. We performed functional enrichment analysis, PPI analysis, CIBERSORT algorithm, and Spearman correlation analysis, with a focus on expression profiling in hub genes and immune cells. We validated that monocytes and nonclassical monocytes were upregulated in the ASD group using peripheral blood (30 children with ASD and 30 age and sex-matched typically developing children) using flow cytometry. The receiver operating characteristic curves (PSMC4 and ALAS2) and analysis stratified by ASD severity (LIlRB1 and CD69) showed that they had predictive value using the "training" and verification groups. Three immune cell types - monocytes, M2 macrophages, and activated dendritic cells - had different degrees of correlation with 15 identified hub genes. In addition, we analyzed the miRNA-mRNA network and agents-gene interactions using miRNA databases (starBase and miRDB) and the DSigDB database. Two miRNAs (miR-342-3p and miR-1321) and 23 agents were linked with ASD. These findings suggest that dysregulation of the immune system may contribute to ASD development, especially dysregulation of monocytes and monocyte-derived cells. ASD-related hub genes may serve as potential predictors for ASD, and the potential ASD-related miRNAs and agents identified here may open up new strategies for the prevention and treatment of ASD.
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28.
  • Li, Kenan, et al. (författare)
  • Sex differences in neonatal mouse brain injury after hypoxia-ischemia and adaptaquin treatment
  • 2019
  • Ingår i: Journal of Neurochemistry. - : Wiley. - 0022-3042 .- 1471-4159. ; 150:6, s. 759-775
  • Tidskriftsartikel (refereegranskat)abstract
    • Hypoxia-inducible factor prolyl 4-hydroxylases (HIF-PHDs) are important targets against oxidative stress. We hypothesized that inhibition HIF-PHD by adaptaquin reduces hypoxic-ischemic brain injury in a neonatal mouse model. The pups were treated intraperitoneally immediately with adaptaquin after hypoxia-ischemia (HI) and then every 24 h for 3 days. Adaptaquin treatment reduced infarction volume by an average of 26.3% at 72 h after HI compared to vehicle alone, and this reduction was more pronounced in males (34.8%) than in females (11.7%). The protection was also more pronounced in the cortex. The subcortical white matter injury as measured by tissue loss volume was reduced by 24.4% in the adaptaquin treatment group, and this reduction was also more pronounced in males (28.4%) than in females (18.9%). Cell death was decreased in the cortex as indicated by Fluoro-Jade labeling, but not in other brain regions with adaptaquin treatment. Furthermore, in the brain injury area, adaptaquin did not alter the number of cells positive for caspase-3 activation or translocation of apoptosis-inducing factor to the nuclei. Adaptaquin treatment increased glutathione peroxidase 4 mRNA expression in the cortex but had no impact on 3-nitrotyrosine, 8-hydroxy-2 deoxyguanosine, or malondialdehyde production. Hif1 alpha mRNA expression increased after HI, and adaptaquin treatment also stimulated Hif1 alpha mRNA expression, which was also more pronounced in males than in females. However, nuclear translocation of HIF1 alpha protein was decreased after HI, and adaptaquin treatment had no influence on HIF1 alpha expression in the nucleus. These findings demonstrate that adaptaquin treatment is neuroprotective, but the potential mechanisms need further investigation. Open Science Badges This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at .
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29.
  • Li, Qian, 1983, et al. (författare)
  • Lithium reduces apoptosis and autophagy after neonatal hypoxia–ischemia
  • 2010
  • Ingår i: Cell death and Disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 1:July 15
  • Tidskriftsartikel (refereegranskat)abstract
    • Lithium is used in the treatment of bipolar mood disorder. Reportedly, lithium can be neuroprotective in models of adult brain ischemia. The purpose of this study was to evaluate the effects of lithium in a model of neonatal hypoxic–ischemic brain injury. Nine-day-old male rats were subjected to unilateral hypoxia–ischemia (HI) and 2mmol/kg lithium chloride was injected i.p. immediately after the insult. Additional lithium injections, 1mmol/kg, were administered at 24-h intervals. Pups were killed 6, 24 or 72h after HI. Lithium reduced the infarct volume from 24.7±2.9 to 13.8±3.3mm3 (44.1%) and total tissue loss (degeneration + lack of growth) from 67.4±4.4 to 38.4±5.9mm3 (43.1%) compared with vehicle at 72h after HI. Injury was reduced in the cortex, hippocampus, thalamus and striatum. Lithium reduced the ischemia-induced dephosphorylation of glycogen synthase kinase-3β and extracellular signal-regulated kinase, the activation of calpain and caspase-3, the mitochondrial release of cytochrome c and apoptosis-inducing factor, as well as autophagy. We conclude that lithium could mitigate the brain injury after HI by inhibiting neuronal apoptosis. The lithium doses used were in the same range as those used in bipolar patients, suggesting that lithium might be safely used for the avoidance of neonatal brain injury.
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30.
  • Li, Tao, et al. (författare)
  • AIF Overexpression Aggravates Oxidative Stress in Neonatal Male Mice After Hypoxia-Ischemia Injury
  • 2022
  • Ingår i: Molecular Neurobiology. - : Springer Science and Business Media LLC. - 0893-7648 .- 1559-1182. ; 59:11, s. 6613-6631
  • Tidskriftsartikel (refereegranskat)abstract
    • There are sex differences in the severity, mechanisms, and outcomes of neonatal hypoxia-ischemia (HI) brain injury, and apoptosis-inducing factor (AIF) may play a critical role in this discrepancy. Based on previous findings that AIF over-expression aggravates neonatal HI brain injury, we further investigated potential sex differences in the severity and molecular mechanisms underlying the injury using mice that overexpress AIF from homozygous transgenes. We found that the male sex significantly aggravated AIF-driven brain damage, as indicated by the injury volume in the gray matter (2.25 times greater in males) and by the lost volume of subcortical white matter (1.71 greater in males) after HI. As compared to females, male mice exhibited more severe brain injury, correlating with reduced antioxidant capacities, more pronounced protein carbonylation and nitration, and increased neuronal cell death. Under physiological conditions (without HI), the doublecortin-positive area in the dentate gyrus of females was 1.15 times larger than in males, indicating that AIF upregulation effectively promoted neurogenesis in females in the long term. We also found that AIF stimulated carbohydrate metabolism in young males. Altogether, these findings corroborate earlier studies and further demonstrate that AIF is involved in oxidative stress, which contributes to the sex-specific differences observed in neonatal HI brain injury.
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31.
  • Li, Tao, et al. (författare)
  • Overexpression of apoptosis inducing factor aggravates hypoxic-ischemic brain injury in neonatal mice
  • 2020
  • Ingår i: Cell death & disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 11:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Apoptosis inducing factor (AIF) has been shown to be a major contributor to neuron loss in the immature brain after hypoxia-ischemia (HI). Indeed, mice bearing a hypomorphic mutation causing reduced AIF expression are protected against neonatal HI. To further investigate the possible molecular mechanisms of this neuroprotection, we generated an AIF knock-in mouse by introduction of a latent transgene coding for flagged AIF protein into the Rosa26 locus, followed by its conditional activation by a ubiquitously expressed Cre recombinase. Such AIF transgenic mice overexpress the pro-apoptotic splice variant of AIF (AIF1) at both the mRNA (5.9 times higher) and protein level (2.4 times higher), but not the brain-specific AIF splice-isoform (AIF2). Excessive AIF did not have any apparent effects on the phenotype or physiological functions of the mice. However, brain injury (both gray and white matter) after neonatal HI was exacerbated in mice overexpressing AIF, coupled to enhanced translocation of mitochondrial AIF to the nucleus as well as enhanced caspase-3 activation in some brain regions, as indicated by immunohistochemistry. Altogether, these findings corroborate earlier studies demonstrating that AIF plays a causal role in neonatal HI brain injury.
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32.
  • Li, W. L., et al. (författare)
  • Association between bronchopulmonary dysplasia and death or neurodevelopmental impairment at 3 years in preterm infants without severe brain injury
  • 2023
  • Ingår i: Frontiers in Neurology. - 1664-2295. ; 14
  • Tidskriftsartikel (refereegranskat)abstract
    • ObjectiveWe investigated the association between bronchopulmonary dysplasia (BPD) and 3 years death or neurodevelopmental impairment (NDI) in very preterm infants without severe brain injury.MethodOur prospective cohort study recruited preterm infants who were born prior to 32 weeks of gestational age and survived in the neonatal intensive care unit until 36 weeks of corrected age. Upon reaching 3 years of age, each infant was assessed for death or NDI such as cerebral palsy, cognitive deficit, hearing loss, and blindness. Correlations between BPD and death or NDI were determined using multiple logistic regression analyses adjusted for confounding factors.ResultA total of 1,417 infants without severe brain injury who survived until 36 weeks of corrected age were initially enrolled in the study. Over the study period, 201 infants were lost to follow-up and 5 infants were excluded. Our final dataset, therefore, included 1,211 infants, of which 17 died after 36 weeks of corrected age and 1,194 were followed up to 3 years of age. Among these infants, 337 (27.8%) developed BPD. Interestingly, by 3 years of age, BPD was demonstrated to be independently associated with death or NDI, with an adjusted odds ratio of 1.935 (95% confidence interval: 1.292-2.899, p = 0.001), in preterm infants without severe neonatal brain injury.ConclusionOur findings indicate that BPD is strongly associated with death or NDI in preterm infants without severe neonatal brain injury at 3 years of age. Further research is needed to understand the mechanisms linking the development of BPD with death or NDI and whether appropriate treatment of BPD may ameliorate or prevent the development of neurological complications.
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33.
  • Liu, Qing, et al. (författare)
  • Unraveling the unique role of brown graphitic carbon nitride in robust CO2 photoreduction
  • 2023
  • Ingår i: Applied Surface Science. - : ELSEVIER. - 0169-4332 .- 1873-5584. ; 615
  • Tidskriftsartikel (refereegranskat)abstract
    • Photocatalytic CO2 reduction is one of the important means to alleviate the energy crisis. In this work, an oxygen linked and brown graphitic carbon nitride (GACN) was successfully prepared by thermal polymerization after oil bath method. GACN introduced oxygen atoms on surface of BulkCN. Various characterizations of the material show that the prepared GACN has a different structure and higher photoelectronic activity compared to BulkCN. GACN possessed strong photocatalytic CO2 reduction capacity, and the photocatalytic activity was significantly improved compared with BulkCN. In view of density functional theory calculations, it is proved that the oxygen atoms introduced by GACN increase CO2 photoreaction reactivity, enhance electronic activity and reduce the reaction energy barrier. This work can have a positive effect on the photocatalytic application of g-C3N4 with the existence of oxygen atoms.
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34.
  • Liu, S. S., et al. (författare)
  • Early application of caffeine improves white matter development in very preterm infants
  • 2020
  • Ingår i: Respiratory Physiology & Neurobiology. - : Elsevier BV. - 1569-9048 .- 1878-1519. ; 281
  • Tidskriftsartikel (refereegranskat)abstract
    • The aim of this study was to evaluate the effect of early prophylactic caffeine treatment on white matter development in very preterm infants using cerebral magnetic resonance imaging. A total of 194 preterm infants (<= 32 weeks gestational age) were randomly assigned to the caffeine (n = 96) or placebo (n = 93) treatment group and administered with either caffeine or placebo within 72 h after birth. Cerebral magnetic resonance imaging, including diffuse tensor imaging examination, was performed at 34-36 weeks of corrected gestational age, and the fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values were measured. In total, 160 infants were included in the final analysis, including 80 cases in the placebo group and 80 cases in the caffeine group. There were fewer instances of apnea of prematurity and shorter assisted ventilation times for infants in the caffeine group compared to the placebo group (p < 0.05). Infants in the caffeine group had significantly higher FA values in white matter, including the posterior limb of the internal capsule, the corpus callosum, the frontal, occipital, and parietal white matter, the cerebellum, and the cerebral peduncle, compared to infants in the placebo group. ADC values in the above white matter areas were significantly reduced in the caffeine group. However, there were no significant differences regarding the FA and ADC in the gray matter between the two groups. These results demonstrate that early administration of caffeine improves white matter micro-structural development in preterm infants, but with no significant effect on short-term complications related to prematurity.
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35.
  • MacLennan, Alastair H, et al. (författare)
  • Genetic or Other Causation Should Not Change the Clinical Diagnosis of Cerebral Palsy.
  • 2019
  • Ingår i: Journal of child neurology. - : SAGE Publications. - 1708-8283 .- 0883-0738. ; 38:4, s. 472-6
  • Tidskriftsartikel (refereegranskat)abstract
    • High throughput sequencing is discovering many likely causative genetic variants in individuals with cerebral palsy. Some investigators have suggested that this changes the clinical diagnosis of cerebral palsy and that these individuals should be removed from this diagnostic category. Cerebral palsy is a neurodevelopmental disorder diagnosed on clinical signs, not etiology. All nonprogressive permanent disorders of movement and posture attributed to disturbances that occurred in the developing fetal and infant brain can be described as "cerebral palsy." This definition of cerebral palsy should not be changed, whatever the cause. Reasons include stability, utility and accuracy of cerebral palsy registers, direct access to services, financial and social support specifically offered to families with cerebral palsy, and community understanding of the clinical diagnosis. Other neurodevelopmental disorders, for example, epilepsy, have not changed the diagnosis when genomic causes are found. The clinical diagnosis of cerebral palsy should remain, should prompt appropriate genetic studies and can subsequently be subclassified by etiology.
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36.
  • Nazmi, Arshed, et al. (författare)
  • Lymphocytes Contribute to the Pathophysiology of Neonatal Brain Injury
  • 2018
  • Ingår i: Frontiers in Neurology. - : Frontiers Media SA. - 1664-2295. ; 9, s. 1-11
  • Tidskriftsartikel (refereegranskat)abstract
    • Periventricular leukomalacia (PVL) is the most common form of preterm brain injury affecting the cerebral white matter. This type of injury involves a multiphase process and is induced by many factors, including hypoxia-ischemia (HI) and infection. Previous studies have suggested that lymphocytes play a significant role in the pathogenesis of brain injury, and the aim of this study was to determine the contribution of lymphocyte subsets to preterm brain injury.Immunohistochemistry on brain sections from neonatal mice was performed to evaluate the extent of brain injury in wild-type and T cell and B cell-deficient neonatal mice (Rag1-/- mice) using a mouse model of HI-induced preterm brain injury. Flow cytometry was performed to determine the presence of different types of immune cells in mouse brains following HI. In addition, immunostaining for CD3 T cells and CD20 B cells was performed on postmortem preterm human infant brains with PVL.Mature lymphocyte-deficient Rag1- / - mice showed protection from white matter loss compared to wild type mice as indicated by myelin basic protein immunostaining of mouse brains. CD3+ T cells and CD20+ B cells were observed in the postmortem preterm infant brains with PVL. Flow cytometry analysis of mouse brains after HI-induced injury showed increased frequency of CD3+ T, αβT and B cells at 7days after HI in the ipsilateral (injured) hemisphere compared to the contralateral (control, uninjured) hemisphere.Lymphocytes were found in the injured brain after injury in both mice and humans, and lack of mature lymphocytes protected neonatal mice from HI-induced brain white matter injury. This finding provides insight into the pathology of perinatal brain injury and suggests new avenues for the development of therapeutic strategies.
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37.
  • Nilsson, Gisela M A, 1973, et al. (författare)
  • White matter injury but not germinal matrix hemorrhage induces elevated osteopontin expression in human preterm brains
  • 2021
  • Ingår i: Acta Neuropathologica Communications. - : Springer Science and Business Media LLC. - 2051-5960. ; 9:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Osteopontin (OPN) is a matricellular protein that mediates various physiological functions and is implicated in neuroinflammation, myelination, and perinatal brain injury. However, its expression in association with brain injury in preterm infants is unexplored. Here we examined the expression of OPN in postmortem brains of preterm infants and explored how this expression is affected in brain injury. We analyzed brain sections from cases with white matter injury (WMI) and cases with germinal matrix hemorrhage (GMH) and compared them to control cases having no brain injury. WMI cases displayed moderate to severe tissue injury in the periventricular and deep white matter that was accompanied by an increase of microglia with amoeboid morphology. Apart from visible hemorrhage in the germinal matrix, GMH cases displayed diffuse white matter injury in the periventricular and deep white matter. In non-injured preterm brains, OPN was expressed at low levels in microglia, astrocytes, and oligodendrocytes. OPN expression was significantly increased in regions with white matter injury in both WMI cases and GMH cases. The main cellular source of OPN in white matter injury areas was amoeboid microglia, although a significant increase was also observed in astrocytes in WMI cases. OPN was not expressed in the germinal matrix of any case, regardless of whether there was hemorrhage. In conclusion, preterm brain injury induces elevated OPN expression in microglia and astrocytes, and this increase is found in sites closely related to injury in the white matter regions but not with the hemorrhage site in the germinal matrix. Thus, it appears that OPN takes part in the inflammatory process in white matter injury in preterm infants, and these findings facilitate our understanding of OPN's role under both physiological and pathological conditions in the human brain that may lead to greater elucidation of disease mechanisms and potentially better treatment strategies.
  •  
38.
  • Posey, Victoria A., et al. (författare)
  • Two-dimensional heavy fermions in the van der Waals metal CeSiI
  • 2024
  • Ingår i: Nature. - : Springer Nature. - 0028-0836 .- 1476-4687. ; 625:7995, s. 483-488
  • Tidskriftsartikel (refereegranskat)abstract
    • Heavy-fermion metals are prototype systems for observing emergent quantum phases driven by electronic interactions1-6. A long-standing aspiration is the dimensional reduction of these materials to exert control over their quantum phases7-11, which remains a significant challenge because traditional intermetallic heavy-fermion compounds have three-dimensional atomic and electronic structures. Here we report comprehensive thermodynamic and spectroscopic evidence of an antiferromagnetically ordered heavy-fermion ground state in CeSiI, an intermetallic comprising two-dimensional (2D) metallic sheets held together by weak interlayer van der Waals (vdW) interactions. Owing to its vdW nature, CeSiI has a quasi-2D electronic structure, and we can control its physical dimension through exfoliation. The emergence of coherent hybridization of f and conduction electrons at low temperature is supported by the temperature evolution of angle-resolved photoemission and scanning tunnelling spectra near the Fermi level and by heat capacity measurements. Electrical transport measurements on few-layer flakes reveal heavy-fermion behaviour and magnetic order down to the ultra-thin regime. Our work establishes CeSiI and related materials as a unique platform for studying dimensionally confined heavy fermions in bulk crystals and employing 2D device fabrication techniques and vdW heterostructures12 to manipulate the interplay between Kondo screening, magnetic order and proximity effects.
  •  
39.
  • Qiu, H., et al. (författare)
  • Umbilical cord blood cells for the treatment of preterm white matter injury: Potential effects and treatment options
  • 2021
  • Ingår i: Journal of Neuroscience Research. - : Wiley. - 0360-4012 .- 1097-4547. ; 99:3, s. 778-792
  • Forskningsöversikt (refereegranskat)abstract
    • Preterm birth is a global public health problem. A large number of preterm infants survive with preterm white matter injury (PWMI), which leads to neurological deficits, and has multifaceted etiology, clinical course, monitoring, and outcomes. The principal upstream insults leading to PWMI initiation are hypoxia-ischemia and infection and/or inflammation and the key target cells are late oligodendrocyte precursor cells. Current PWMI treatments are mainly supportive, and thus have little effect in terms of protecting the immature brain or repairing injury to improve long-term outcomes. Umbilical cord blood (UCB) cells comprise abundant immunomodulatory and stem cells, which have the potential to reduce brain injury, mainly due to anti-inflammatory and immunomodulatory mechanisms, and also through their release of neurotrophic or growth factors to promote endogenous neurogenesis. In this review, we briefly summarize PWMI pathogenesis and pathophysiology, and the specific properties of different cell types in UCB. We further explore the potential mechanism by which UCB can be used to treat PWMI, and discuss the advantages of and potential issues related to UCB cell therapy. Finally, we suggest potential future studies of UCB cell therapy in preterm infants.
  •  
40.
  • Qiu, L., et al. (författare)
  • Less neurogenesis and inflammation in the immature than in the juvenile brain after cerebral hypoxia-ischemia
  • 2007
  • Ingår i: J Cereb Blood Flow Metab. - : SAGE Publications. - 0271-678X .- 1559-7016. ; 27:4, s. 785-94
  • Tidskriftsartikel (refereegranskat)abstract
    • The effects of hypoxia-ischemia (HI) on proliferation and differentiation in the immature (postnatal day 9) and juvenile (postnatal day 21) mouse hippocampus were investigated by injecting bromodeoxyuridine (50 mg/kg) daily for 7 days after the insult and evaluating the labeling 5 weeks after HI. Phenotypic differentiation was evaluated using NeuN, Iba1, APC, and S100beta as markers of neurons, microglia, oligodendrocytes, and astrocytes, respectively. The basal proliferation, in particular neurogenesis, was higher in the immature than in the juvenile hippocampus. Hypoxia-ischemia did not increase neurogenesis significantly in the immature dentate gyrus (DG), but it increased several-fold in the juvenile brain, reaching the same level as in the normal, noninjured immature brain. This suggests that the immature hippocampus is already working at the top of its proliferative capacity and that even though basal neurogenesis decreased with age, the injury-induced generation of new neurons in the juvenile hippocampus could not increase beyond the basal level of the immature brain. Generation of glial cells of all three types after HI was significantly more pronounced in the cornu ammonis of the hippocampus region of the juvenile hippocampus. In the DG, only microglia production was greater in the juvenile brain. Increased microglia proliferation correlated with increased levels of the proinflammatory cytokines MCP-1 and IL-18 3 days after HI, indicating that the inflammatory response is stronger in the juvenile hippocampus. In summary, contrary to what has been generally assumed, our results indicate that the juvenile brain has a greater capacity for neurogenesis after injury than the immature brain.
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41.
  • Rodriguez, Juan, 1983, et al. (författare)
  • Inhibiting the interaction between apoptosis-inducing factor and cyclophilin A prevents brain injury in neonatal mice after hypoxia-ischemia
  • 2020
  • Ingår i: Neuropharmacology. - : Elsevier BV. - 0028-3908 .- 1873-7064. ; 171
  • Tidskriftsartikel (refereegranskat)abstract
    • © 2020 The Authors The interaction between apoptosis-inducing factor (AIF) and cyclophilin A (CypA) has been shown to contribute to caspase-independent apoptosis. Blocking the AIF/CypA interaction protects against glutamate-induced neuronal cell death in vitro, and the purpose of this study was to determine the in vivo effect of an AIF/CypA interaction blocking peptide (AIF(370-394)-TAT) on neonatal mouse brain injury after hypoxia-ischemia (HI). The pups were treated with AIF (370-394)-TAT peptide intranasally prior to HI. Brain injury was significantly reduced at 72 h after HI in the AIF(370-394)-TAT peptide treatment group compared to vehicle-only treatment for both the gray matter and the subcortical white matter, and the neuroprotection was more pronounced in males than in females. Neuronal cell death was evaluated in males at 8 h and 24 h post-HI, and it was decreased significantly in the CA1 region of the hippocampus and the nucleus habenularis region after AIF(370-394)-TAT treatment. Caspase-independent apoptosis was decreased in the cortex, striatum, and nucleus habenularis after AIF(370-394)-TAT treatment, but no significant change was found on caspase-dependent apoptosis as indicated by the number of active caspase-3-labeled cells. Further analysis showed that both AIF and CypA nuclear accumulation were decreased after treatment with the AIF(370-394)-TAT peptide. These results suggest that AIF(370-394)-TAT inhibited AIF/CypA translocation to the nucleus and reduced HI-induced caspase-independent apoptosis and brain injury in young male mice, suggesting that blocking AIF/CypA might be a potential therapeutic target for neonatal brain injury.
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42.
  • Rodriguez, Juan, 1983, et al. (författare)
  • Lack of the brain-specific isoform of apoptosis-inducing factor aggravates cerebral damage in a model of neonatal hypoxia-ischemia.
  • 2018
  • Ingår i: Cell Death & Disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 10:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Apoptosis-inducing factor (AIF) may contribute to neuronal cell death, and its influence is particularly prominent in the immature brain after hypoxia-ischemia (HI). A brain-specific AIF splice-isoform (AIF2) has recently been discovered, but has not yet been characterized at the genetic level. The aim of this study was to determine the functional and regulatory profile of AIF2 under physiological conditions and after HI in mice. We generated AIF2 knockout (KO) mice by removing the AIF2-specific exon and found that the relative expression of Aif1 mRNA increased in Aif2 KO mice and that this increase became even more pronounced as Aif2 KO mice aged compared to their wild-type (WT) littermates. Mitochondrial morphology and function, reproductive function, and behavior showed no differences between WT and Aif2 KO mice. However, lack of AIF2 enhanced brain injury in neonatal mice after HI compared to WT controls, and this effect was linked to increased oxidative stress but not to caspase-dependent or -independent apoptosis pathways. These results indicate that AIF2 deficiency exacerbates free radical production and HI-induced neonatal brain injury.
  •  
43.
  • Song, J., et al. (författare)
  • Early amplitude-integrated electroencephalography predicts brain injury and neurological outcome in very preterm infants
  • 2015
  • Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 5
  • Tidskriftsartikel (refereegranskat)abstract
    • Early amplitude-integrated electroencephalography (aEEG) has been widely used in term infants with brain injury to predict neurodevelopmental outcomes; however, the prognostic value of early aEEG in preterm infants is unclear. We evaluated how well early aEEG could predict brain damage and long-term neurodevelopmental outcomes in very preterm infants compared with brain imaging assessments. We found that severe aEEG abnormalities (p = 0.000) and aEEG total score < 5 (p = 0.006) within 72 h after birth were positively correlated with white-matter damage, but aEEG abnormalities were not associated with intracranial hemorrhage (p = 0.186). Severe abnormalities in aEEG recordings, head ultrasound, and cranial magnetic resonance imaging (MRI) were all positively correlated with poor outcome at 18 months corrected age. The predictive power of poor outcomes of the aEEG and MRI combination was the same as the aEEG, MRI, and head ultrasound combination with a sensitivity of 52.4%, specificity of 96.2%, positive predictive value of 78.6%, and negative predictive value of 88.4%. These results indicate that severely abnormal aEEG recordings within 72 h after birth can predict white-matter damage and long-term poor outcomes in very preterm infants. Thus aEEG can be used as an early marker to monitor very preterm infants.
  •  
44.
  • Song, J., et al. (författare)
  • Erythropoietin Improves Poor Outcomes in Preterm Infants with Intraventricular Hemorrhage
  • 2021
  • Ingår i: CNS Drugs. - : Springer Science and Business Media LLC. - 1172-7047 .- 1179-1934. ; 35, s. 681-690
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Intraventricular hemorrhage (IVH) is a common complication in preterm infants that has poor outcomes, especially in severe cases, and there are currently no widely accepted effective treatments. Erythropoietin has been shown to be neuroprotective in neonatal brain injury. Objective: The objective of this study was to evaluate the protective effect of repeated low-dose recombinant human erythropoietin (rhEPO) in preterm infants with IVH. Methods: This was a single-blinded prospective randomized controlled trial. Preterm infants ≤32 weeks gestational age who were diagnosed with IVH within 72 h after birth were randomized to receive rhEPO 500 IU/kg or placebo (equivalent volume of saline) every other day for 2 weeks. The primary outcome was death or neurological disability assessed at 18 months of corrected age. Results: A total of 316 eligible infants were included in the study, with 157 in the rhEPO group and 159 in the placebo group. Although no significant differences in mortality (p=0.176) or incidence of neurological disability (p=0.055) separately at 18 months of corrected age were seen between the rhEPO and placebo groups, significantly fewer infants had poor outcomes (death and neurological disability) in the rhEPO group: 14.9 vs. 26.4%; odds ratio (OR) 0.398; 95% confidence interval (CI) 0.199–0.796; p=0.009. In addition, the incidence of Mental Development Index scores of <70 was lower in the rhEPO group than in the placebo group: 7.2 vs. 15.3%; OR 0.326; 95% CI 0.122–0.875; p=0.026. Conclusions: Treatment with repeated low-dose rhEPO improved outcomes in preterm infants with IVH. Trial Registration: The study was retrospectively registered on ClinicalTrials.gov on 16 April 2019 (NCT03914690). © 2021, The Author(s).
  •  
45.
  • Song, J., et al. (författare)
  • Recombinant Human Erythropoietin Improves Neurological Outcomes in Very Preterm Infants
  • 2016
  • Ingår i: Annals of Neurology. - : Wiley. - 0364-5134 .- 1531-8249. ; 80:1, s. 24-34
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: To evaluate the efficacy and safety of repeated low-dose human recombinant erythropoietin (rhEPO) in the improvement of neurological outcomes in very preterm infants. Methods: A total of 800 infants of <= 32-week gestational age who had been in an intensive care unit within 72 hours after birth were included in the trial between January 2009 and June 2013. Preterm infants were randomly assigned to receive rhEPO (500IU/kg; n=366) or placebo (n=377) intravenously within 72 hours after birth and then once every other day for 2 weeks. The primary outcome was death or moderate to severe neurological disability assessed at 18 months of corrected age. Results: Death and moderate/severe neurological disability occurred in 91 of 338 very preterm infants (26.9%) in the placebo group and in 43 of 330 very preterm infants (13.0%) in the rhEPO treatment group (relative risk [RR]=0.40, 95% confidence interval [CI]=0.27-0.59, p < 0.001) at 18 months of corrected age. The rate of moderate/severe neurological disability in the rhEPO group (22 of 309, 7.1%) was significantly lower compared to the placebo group (57 of 304, 18.8%; RR=0.32, 95% CI=0.19-0.55, p < 0.001), and no excess adverse events were observed. Interpretation: Repeated low-dose rhEPO treatment reduced the risk of long-term neurological disability in very preterm infants with no obvious adverse effects.
  •  
46.
  • Song, Juan, et al. (författare)
  • Temporal brain transcriptome analysis reveals key pathological events after germinal matrix hemorrhage in neonatal rats
  • 2022
  • Ingår i: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 0271-678X .- 1559-7016. ; 42:9, s. 1632-1649
  • Tidskriftsartikel (refereegranskat)abstract
    • Germinal matrix hemorrhage (GMH) is a common complication in preterm infants and is associated with high risk of adverse neurodevelopmental outcomes. We used a rat GMH model and performed RNA sequencing to investigate the signaling pathways and biological processes following hemorrhage. GMH induced brain injury characterized by early hematoma and subsequent tissue loss. At 6 hours after GMH, gene expression indicated an increase in mitochondrial activity such as ATP metabolism and oxidative phosphorylation along with upregulation of cytoprotective pathways and heme metabolism. At 24 hours after GMH, the expression pattern suggested an increase in cell cycle progression and downregulation of neurodevelopmental-related pathways. At 72 hours after GMH, there was an increase in genes related to inflammation and an upregulation of ferroptosis. Hemoglobin components and genes related to heme metabolism and ferroptosis such as Hmox1, Alox15, and Alas2 were among the most upregulated genes. We observed dysregulation of processes involved in development, mitochondrial function, cholesterol biosynthesis, and inflammation, all of which contribute to neurodevelopmental deterioration following GMH. This study is the first temporal transcriptome profile providing a comprehensive overview of the molecular mechanisms underlying brain injury following GMH, and it provides useful guidance in the search for therapeutic interventions.
  •  
47.
  • Sun, H., et al. (författare)
  • Effect of early prophylactic low-dose recombinant human erythropoietin on retinopathy of prematurity in very preterm infants
  • 2020
  • Ingår i: Journal of Translational Medicine. - : Springer Science and Business Media LLC. - 1479-5876. ; 18:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Very preterm infants are at risk of developing retinopathy of prematurity (ROP). Recombinant human erythropoietin (rhEPO) is routinely used to prevent anemia in preterm infants; however, the effect of rhEPO on ROP development is still controversial. The purpose of this study was to evaluate the effect of early prophylactic low-dose rhEPO administration on ROP development in very preterm infants. Methods: A total of 1898 preterm infants born before 32weeks of gestation were included. Preterm infants received rhEPO (n = 950; 500 U/kg, rhEPO group) or saline (n = 948, control group) intravenously within 72h of birth and then once every other day for 2weeks. Results: The total incidence of ROP was not significantly different between the two groups (10.2% vs. 13.2%, p = 0.055). Further analysis showed that rhEPO group had lower rates of type 2 ROP than the control group (2.2% vs. 4.1%, RR 0.98; 95% CI 0.96–1.00; p = 0.021). Subgroup analysis found that rhEPO treatment significantly decreased the incidence of type 2 ROP in infant boys (1.8% vs. 4.3%, p = 0.021) and in those with a gestational age of 28–296/7weeks (1.1% vs. 4.9%, p = 0.002) and birth weight of 1000–1499g (1.2% vs. 4.2%, p = 0.002). There was a small increasing tendency for the incidence of ROP in infants with a gestational age of < 28weeks after rhEPO treatment. Conclusions: Repeated low-dose rhEPO administration has no significant influence on the development of ROP; however, it may be effective for type 2 ROP in infant boys or in infants with gestational age > 28weeks and birth weight > 1500g. Trial registration The data of this study were retrieved from two clinical studies registered ClinicalTrials.gov (NCT 02036073) on January 14, 2014, https://clinicaltrials.gov/ct2/show/NCT02036073; and (NCT03919500) on April 18, 2019. https://clinicaltrials.gov/ct2/show/NCT03919500. © 2020, The Author(s).
  •  
48.
  • Sun, H., et al. (författare)
  • High-frequency oscillatory ventilation versus synchronized intermittent mandatory ventilation plus pressure support in preterm infants with severe respiratory distress syndrome
  • 2014
  • Ingår i: Respiratory care. - : Daedalus Enterprises. - 0020-1324 .- 1943-3654. ; 59:2, s. 159-169
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Mechanical ventilation and surfactants are the standard treatment of preterm respiratory distress syndrome (RDS). The effects of the primary ventilation model on bronchopulmonary dysplasia (BPD) and long-term neurodevelopment outcomes are controversial. The purpose of this study was to compare the efficacy and safety of high-frequency oscillatory ventilation (HFOV) and synchronized intermittent mandatory ventilation plus pressure support ventilation (SIMV-PSV) in preterm infants with severe RDS. METHODS: A total of 366 eligible preterm infants were randomly assigned to treatment with HFOV (n = 184) or SIMV-PSV (n = 182). Surfactant was applied if PaO2/FIO2 was < 200 mm Hg after 2 hours of ventilation. Primary outcomes were mortality or incidence of BPD. Secondary outcomes were duration of ventilation and hospitalization, surfactant requirements, pneumothorax, retinopathy of prematurity ≥ stage 2, and neurodevelopment at 18 months of corrected age. RESULTS: Survival and complete outcome data were available for 288 infants at 18 months of corrected age. The incidence of death or BPD was significantly higher in the SIMV-PSV group (P =.001). The duration of mechanical ventilation and hospitalization was shorter and the incidence of surfactant requirement and retinopathy of prematurity was lower in the HFOV group (P <.001, P =.002, P =.04, respectively). Moderate or severe neurological disability was less frequent in the HFOV group than in the SIMV-PSV group at 18 months (P =.03). The combination of HFOV and surfactant dramatically reduced negative outcomes in preterm infants with severe RDS. CONCLUSIONS: Initial ventilation with HFOV in preterm infants with severe RDS reduces the incidence of death and BPD, and improves long-term neurodevelopment outcomes. (ClinicalTrials.gov NCT01496508). © 2014 Daedalus Enterprises.
  •  
49.
  • Sun, H. Q., et al. (författare)
  • Characteristics of Respiratory Distress Syndrome in Infants of Different Gestational Ages
  • 2013
  • Ingår i: Lung. - : Springer Science and Business Media LLC. - 0341-2040 .- 1432-1750. ; 191:4, s. 425-433
  • Tidskriftsartikel (refereegranskat)abstract
    • The purpose of this study was to compare the risk factors, clinical characteristics, and complications of respiratory distress syndrome (RDS) in infants delivered very preterm, late preterm, and term in order to help optimize the management of RDS in neonates. A retrospective study was conducted on neonates admitted to the NICU between January 2006 and December 2010. The enrolled infants with RDS were categorized as very preterm (< 32(0/7) weeks gestation), moderately preterm (32(0/7)-33(6/7) weeks), late preterm (34(0/7)-36(6/7) weeks), and term (37(0/7)-42(0/7) weeks). The rates, potential risk factors, clinical characteristics, and complications of RDS of these four groups were comparatively analyzed. There was an increasing trend in incidence of RDS among the NICU admissions annually. Caesarean section without labor was significantly associated with RDS in term and late preterm infants (P < 0.001). Rates of requirements for ventilator and pulmonary surfactant were similar in very preterm and term infants but significantly lower in late preterm infants (P < 0.001). The oxygenation index value was not substantially lower in late preterm and term infants compared to very preterm infants, and the arterial oxygenation efficiency was improved slowly (P < 0.001). Incidence of pneumonia and occurrence of pneumothorax were significantly higher in term infants (P < 0.001). Term infants with RDS showed an association of RDS with caesarean section without labor and lung infection. These infants also showed slower improvement of oxygenation after surfactant administration and mechanical ventilation, and they experienced a high rate of pneumothorax complication, which was also noticed in late preterm neonates.
  •  
50.
  • Sun, Yanyan, et al. (författare)
  • Apoptosis-inducing factor downregulation increased neuronal progenitor, but not stem cell, survival in the neonatal hippocampus after cerebral hypoxiaischemia.
  • 2012
  • Ingår i: Molecular neurodegeneration. - : Springer Science and Business Media LLC. - 1750-1326. ; 7:1
  • Tidskriftsartikel (refereegranskat)abstract
    • ABSTRACT: BACKGROUND: A considerable proportion of all newly generated cells in the hippocampus will die before becoming fully differentiated, both under normal and pathological circumstances. The caspase-independent apoptosis-inducing factor (AIF) has not been investigated previously in this context. RESULTS: Postnatal day 8 (P8) harlequin (Hq) mutant mice, expressing lower levels of AIF, and wild type littermates were injected with BrdU once daily for two days to label newborn cells. On P10 mice were subjected to hypoxia-ischemia (HI) and their brains were analyzed 4 h, 24 h or 4 weeks later. Overall tissue loss was 63.5% lower in Hq mice 4 weeks after HI. Shortterm survival (4 h and 24 h) of labeled cells in the subgranular zone was neither affected by AIF downregulation, nor by HI. Long-term (4 weeks) survival of undifferentiated, BLBPpositive stem cells was reduced by half after HI, but this was not changed by AIF downregulation. Neurogenesis, however, as judged by BrdU/NeuN double labeling, was reduced by half after HI in wild type mice but preserved in Hq mice, indicating that primarily neural progenitors and neurons were protected. A wave of cell death started early after HI in the innermost layers of the granule cell layer (GCL) and moved outward, such that 24 h after HI dying cells could be detected in the entire GCL. CONCLUSIONS: These findings demonstrate that AIF downregulation provides not only long-term overall neuroprotection after HI, but also protects neural progenitor cells, thereby rescuing hippocampal neurogenesis.
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